92 results on '"John M. Ong’echa"'
Search Results
2. Evaluation of KIR3DL1/KIR3DS1 allelic polymorphisms in Kenyan children with endemic Burkitt lymphoma
- Author
-
Beatrice M. Muriuki, Catherine S. Forconi, Erastus K. Kirwa, Titus K. Maina, Bonface O. Ariera, Jeffrey A. Bailey, Anita Ghansah, Ann M. Moormann, and John M. Ong’echa
- Subjects
Medicine ,Science - Abstract
Endemic Burkitt lymphoma (eBL) is a fast-growing germinal center B cell lymphoma, affecting 5–10 per 100,000 children annually, in the equatorial belt of Africa. We hypothesize that co-infections with Plasmodium falciparum (Pf) malaria and Epstein-Barr virus (EBV) impair host natural killer (NK) and T cell responses to tumor cells, and thus increase the risk of eBL pathogenesis. NK cell education is partially controlled by killer immunoglobulin-like receptors and variable expression of KIR3DL1 has been associated with other malignancies. Here, we investigated whether KIR3D-mediated mechanisms contribute to eBL, by testing for an association of KIR3DL1/KIR3DS1 genotypes with the disease in 108 eBL patients and 99 healthy Kenyan children. KIR3DL1 allelic typing and EBV loads were assessed by PCR. We inferred previously observed phenotypes from the genotypes. The frequencies of KIR3DL1/KIR3DL1 and KIR3DL1/KIR3DS1 did not differ significantly between cases and controls. Additionally, none of the study participants was homozygous for KIR3DS1 alleles. EBV loads did not differ by the KIR3DL1 genotypes nor were they different between eBL survivors and non-survivors. Our results suggest that eBL pathogenesis may not simply involve variations in KIR3DL1 and KIR3DS1 genotypes. However, considering the complexity of the KIR3DL1 locus, this study could not exclude a role for copy number variation in eBL pathogenesis.
- Published
- 2023
3. Distinctive Kaposi Sarcoma-Associated Herpesvirus Serological Profile during Acute Plasmodium falciparum Malaria Episodes
- Author
-
Peter O. Oluoch, Catherine S. Forconi, Cliff I. Oduor, Dominic A. Ritacco, Hoseah M. Akala, Jeffrey A. Bailey, Jonathan J. Juliano, John M. Ong’echa, Christian Münz, and Ann M. Moormann
- Subjects
Kaposi sarcoma-associated herpesvirus ,Epstein–Barr virus ,acute malaria infection ,endemic Kaposi sarcoma ,sub-Saharan Africa ,lytic replication ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The seroprevalence of Kaposi sarcoma-associated herpesvirus (KSHV) and the incidence of endemic Kaposi sarcoma (KS) overlap with regions of malaria endemicity in sub-Saharan Africa. Multiple studies have shown an increased risk of KSHV seroconversion in children from high malaria compared to low malaria regions; however, the impact of acute episodes of Plasmodium falciparum (P. falciparum) malaria on KSHV’s biphasic life cycle and lytic reactivation has not been determined. Here, we examined KSHV serological profiles and viral loads in 134 children with acute malaria and 221 healthy children from high malaria regions in Kisumu, as well as 77 healthy children from low malaria regions in Nandi. We assayed KSHV, Epstein–Barr virus (EBV), and P. falciparum malaria antibody responses in these three by multiplexed Luminex assay. We confirmed that KSHV seroprevalence was significantly associated with malaria endemicity (OR = 1.95, 1.18–3.24 95% CI, p = 0.01) with 71–77% seropositivity in high-malaria (Kisumu) compared to 28% in low-malaria (Nandi) regions. Furthermore, KSHV serological profiles during acute malaria episodes were distinct from age-matched non-malaria-infected children from the same region. Paired IgG levels also varied after malaria treatment, with significantly higher anti-ORF59 at day 0 but elevated ORF38, ORF73, and K8.1 at day 3. Acute malaria episodes is characterized by perturbation of KSHV latency in seropositive children, providing further evidence that malaria endemicity contributes to the observed increase in endemic KS incidence in sub-Saharan Africa.
- Published
- 2023
- Full Text
- View/download PDF
4. Association of killer cell immunoglobulin-like receptors with endemic Burkitt lymphoma in Kenyan children
- Author
-
Beatrice M. Muriuki, Catherine S. Forconi, Peter O. Oluoch, Jeffrey A. Bailey, Anita Ghansah, Ann M. Moormann, and John M. Ong’echa
- Subjects
Medicine ,Science - Abstract
Abstract Endemic Burkitt lymphoma (eBL) is an aggressive pediatric B cell lymphoma, common in Equatorial Africa. Co-infections with Epstein-Barr virus (EBV) and Plasmodium falciparum, coupled with c-myc translocation are involved in eBL etiology. Infection-induced immune evasion mechanisms to avoid T cell cytotoxicity may increase the role of Natural killer (NK) cells in anti-tumor immunosurveillance. Killer immunoglobulin-like receptor (KIR) genes on NK cells exhibit genotypic and allelic variations and are associated with susceptibility to diseases and malignancies. However, their role in eBL pathogenesis remains undefined. This retrospective study genotyped sixteen KIR genes and compared their frequencies in eBL patients (n = 104) and healthy geographically-matched children (n = 104) using sequence-specific primers polymerase chain reaction (SSP-PCR) technique. The relationship between KIR polymorphisms with EBV loads and eBL pathogenesis was investigated. Possession of ≥ 4 activating KIRs predisposed individuals to eBL (OR = 3.340; 95% CI 1.530–7.825; p = 0.004). High EBV levels were observed in Bx haplogroup (p = 0.016) and AB genotypes (p = 0.042) relative to AA haplogroup and AA genotype respectively, in eBL patients but not in healthy controls. Our results suggest that KIR-mediated NK cell stimulation could mute EBV control, contributing to eBL pathogenesis.
- Published
- 2021
- Full Text
- View/download PDF
5. KSHV infection drives poorly cytotoxic CD56-negative natural killer cell differentiation in vivo upon KSHV/EBV dual infection
- Author
-
Nicole Caduff, Donal McHugh, Lisa Rieble, Catherine S. Forconi, John M. Ong’echa, Peter O. Oluoch, Ana Raykova, Anita Murer, Michelle Böni, Lara Zuppiger, Thomas F. Schulz, David J. Blackbourn, Obinna Chijioke, Ann M. Moormann, and Christian Münz
- Subjects
Kaposi sarcoma-associated herpesvirus ,KSHV ,Epstein-Barr virus ,EBV ,humanized mouse model ,natural killer cells ,Biology (General) ,QH301-705.5 - Abstract
Summary: Herpesvirus infections shape the human natural killer (NK) cell compartment. While Epstein-Barr virus (EBV) expands immature NKG2A+ NK cells, human cytomegalovirus (CMV) drives accumulation of adaptive NKG2C+ NK cells. Kaposi sarcoma-associated herpesvirus (KSHV) is a close relative of EBV, and both are associated with lymphomas, including primary effusion lymphoma (PEL), which nearly always harbors both viruses. In this study, KSHV dual infection of mice with reconstituted human immune system components leads to the accumulation of CD56–CD16+CD38+CXCR6+ NK cells. CD56–CD16+ NK cells were also more frequently found in KSHV-seropositive Kenyan children. This NK cell subset is poorly cytotoxic against otherwise-NK-cell-susceptible and antibody-opsonized targets. Accordingly, NK cell depletion does not significantly alter KSHV infection in humanized mice. These data suggest that KSHV might escape NK-cell-mediated immune control by driving CD56–CD16+ NK cell differentiation.
- Published
- 2021
- Full Text
- View/download PDF
6. Genetic variation in interleukin-7 is associated with a reduced erythropoietic response in Kenyan children infected with Plasmodium falciparum
- Author
-
Lily E. Kisia, Prakasha Kempaiah, Samuel B. Anyona, Elly O. Munde, Angela O. Achieng, John M. Ong’echa, Christophe G. Lambert, Kiprotich Chelimo, Collins Ouma, Douglas J. Perkins, and Evans Raballah
- Subjects
IL7 variation ,Plasmodium falciparum ,Severe malarial anemia ,Inefficient erythropoiesis ,Internal medicine ,RC31-1245 ,Genetics ,QH426-470 - Abstract
Abstract Background Severe malarial anemia (SMA) is a leading cause of malaria-related morbidity and mortality in children. The genetic factors that influence development of SMA and inefficient erythropoiesis, a central pathogenic feature of SMA, are only partially understood. Methods We performed a pilot Genome-wide Association Study (GWAS) on children with Plasmodium falciparum. The GWAS was performed using the Illumina® Infinium® HD Super Assay in conjunction with Illumina’s® Human Omni2.5-8v1 BeadChip (with > 2.45 M markers). Data were analyzed using single SNP logistic regression analysis with an additive model of inheritance controlling for covariates. Results from our pilot global genomics study identified that variation in interleukin (IL)-7 was associated with enhanced risk of SMA. To validate this finding, we investigated the relationship between genotypes and/or haplotypes of two single nucleotide polymorphisms (SNPs) in IL7 [72194 T/C and − 2440 A/G] and susceptibility to both SMA and inefficient erythropoiesis [i.e., reticulocyte production index (RPI) TA > CG; P
- Published
- 2019
- Full Text
- View/download PDF
7. Integrated OMICS platforms identify LAIR1 genetic variants as novel predictors of cross-sectional and longitudinal susceptibility to severe malaria and all-cause mortality in Kenyan childrenResearch in context
- Author
-
Angela O. Achieng, Nicolas W. Hengartner, Evans Raballah, Qiuying Cheng, Samuel B. Anyona, Nick Lauve, Bernard Guyah, Ivy Foo-Hurwitz, John M. Ong'echa, Benjamin H. McMahon, Collins Ouma, Christophe G. Lambert, and Douglas J. Perkins
- Subjects
Medicine ,Medicine (General) ,R5-920 - Abstract
Background: Severe malarial anaemia (SMA) is a leading cause of childhood mortality in holoendemic Plasmodium falciparum regions. Methods: To gain an improved understanding of SMA pathogenesis, whole genome and transcriptome profiling was performed in Kenyan children (n = 144, 3–36 months) with discrete non-SMA and SMA phenotypes. Leukocyte associated immunoglobulin like receptor 1 (LAIR1) emerged as a predictor of susceptibility to SMA (P A); rs2287827 (18835G>A)] and clinical outcomes were investigated in individuals (n = 1512,
- Published
- 2019
- Full Text
- View/download PDF
8. Molecular basis of reduced LAIR1 expression in childhood severe malarial anaemia: Implications for leukocyte inhibitory signallingResearch in context
- Author
-
Angela O. Achieng, Bernard Guyah, Qiuying Cheng, John M. Ong'echa, Collins Ouma, Christophe G. Lambert, and Douglas J. Perkins
- Subjects
Medicine ,Medicine (General) ,R5-920 - Abstract
Background: Leukocyte-associated immunoglobulin like receptor-1 (LAIR1) is a transmembrane inhibitory receptor that influences susceptibility to a myriad of inflammatory diseases. Our recent investigations of severe malarial anaemia (SMA) pathogenesis in Kenyan children discovered that novel LAIR1 genetic variants which were associated with decreased LAIR1 transcripts enhanced the longitudinal risk of SMA and all-cause mortality. Methods: To characterize the molecular mechanism(s) responsible for altered LAIR1 signalling in severe malaria, we determined LAIR1 transcripts and protein, sLAIR1, sLAIR2, and complement component 1q (C1q) in children with malarial anaemia, followed by a series of in vitro experiments investigating the LAIR1 signalling cascade. Findings: Kenyan children with SMA had elevated circulating levels of soluble LAIR1 (sLAIR1) relative to non-SMA (1.69-fold P
- Published
- 2019
- Full Text
- View/download PDF
9. A New Hope for CD56negCD16pos NK Cells as Unconventional Cytotoxic Mediators: An Adaptation to Chronic Diseases
- Author
-
Catherine S. Forconi, Cliff I. Oduor, Peter O. Oluoch, John M. Ong'echa, Christian Münz, Jeffrey A. Bailey, and Ann M. Moormann
- Subjects
natural killer cells ,CD56negCD16pos subset ,endemic Burkitt lymphoma ,malaria ,epstein-barr virus ,transcription profile ,Microbiology ,QR1-502 - Abstract
Natural Killer (NK) cells play an essential role in antiviral and anti-tumoral immune responses. In peripheral blood, NK cells are commonly classified into two major subsets: CD56brightCD16neg and CD56dimCD16pos despite the characterization of a CD56negCD16pos subset 25 years ago. Since then, several studies have described the prevalence of an CD56negCD16pos NK cell subset in viral non-controllers as the basis for their NK cell dysfunction. However, the mechanistic basis for their cytotoxic impairment is unclear. Recently, using a strict flow cytometry gating strategy to exclude monocytes, we reported an accumulation of CD56negCD16pos NK cells in Plasmodium falciparum malaria-exposed children and pediatric cancer patients diagnosed with endemic Burkitt lymphoma (eBL). Here, we use live-sorted cells, histological staining, bulk RNA-sequencing and flow cytometry to confirm that this CD56negCD16pos NK cell subset has the same morphological features as the other NK cell subsets and a similar transcriptional profile compared to CD56dimCD16pos NK cells with only 120 genes differentially expressed (fold change of 1.5, p < 0.01 and FDR
- Published
- 2020
- Full Text
- View/download PDF
10. Interplay between IL-10, IFN-γ, IL-17A and PD-1 Expressing EBNA1-Specific CD4+ and CD8+ T Cell Responses in the Etiologic Pathway to Endemic Burkitt Lymphoma
- Author
-
Catherine S. Forconi, David H. Mulama, Priya Saikumar Lakshmi, Joslyn Foley, Juliana A. Otieno, Jonathan D. Kurtis, Leslie J. Berg, John M. Ong’echa, Christian Münz, and Ann M. Moormann
- Subjects
endemic Burkitt lymphoma ,EBV ,T-cells ,EBNA1 ,cytokines ,PD-1 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Children diagnosed with endemic Burkitt lymphoma (eBL) are deficient in interferon-γ (IFN-γ) responses to Epstein–Barr Nuclear Antigen1 (EBNA1), the viral protein that defines the latency I pattern in this B cell tumor. However, the contributions of immune-regulatory cytokines and phenotypes of the EBNA1-specific T cells have not been characterized for eBL. Using a bespoke flow cytometry assay we measured intracellular IFN-γ, IL-10, IL-17A expression and phenotyped CD4+ and CD8+ T cell effector memory subsets specific to EBNA1 for eBL patients compared to two groups of healthy children with divergent malaria exposures. In response to EBNA1 and a malaria antigen (PfSEA-1A), the three study groups exhibited strikingly different cytokine expression and T cell memory profiles. EBNA1-specific IFN-γ-producing CD4+ T cell response rates were lowest in eBL (40%) compared to children with high malaria (84%) and low malaria (66%) exposures (p < 0.0001 and p = 0.0004, respectively). However, eBL patients did not differ in CD8+ T cell response rates or the magnitude of IFN-γ expression. In contrast, eBL children were more likely to have EBNA1-specific CD4+ T cells expressing IL-10, and less likely to have polyfunctional IFN-γ+IL-10+ CD4+ T cells (p = 0.02). They were also more likely to have IFN-γ+IL-17A+, IFN-γ+ and IL-17A+ CD8+ T cell subsets compared to healthy children. Cytokine-producing T cell subsets were predominantly CD45RA+CCR7+ TNAIVE-LIKE cells, yet PD-1, a marker of persistent activation/exhaustion, was more highly expressed by the central memory (TCM) and effector memory (TEM) T cell subsets. In summary, our study suggests that IL-10 mediated immune regulation and depletion of IFN-γ+ EBNA1-specific CD4+ T cells are complementary mechanisms that contribute to impaired T cell cytotoxicity in eBL pathogenesis.
- Published
- 2021
- Full Text
- View/download PDF
11. Haplotype of non-synonymous mutations within IL-23R is associated with susceptibility to severe malaria anemia in a P. falciparum holoendemic transmission area of Kenya
- Author
-
Elly O. Munde, Evans Raballah, Winnie A. Okeyo, John M. Ong’echa, Douglas J. Perkins, and Collins Ouma
- Subjects
Il-23R ,Exon ,Genotypes ,Haplotypes ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background Improved understanding of the molecular mechanisms involved in pediatric severe malarial anemia (SMA) pathogenesis is a crucial step in the design of novel therapeutics. Identification of host genetic susceptibility factors in immune regulatory genes offers an important tool for deciphering malaria pathogenesis. The IL-23/IL-17 immune pathway is important for both immunity and erythropoiesis via its effects through IL-23 receptors (IL-23R). However, the impact of IL-23R variants on SMA has not been fully elucidated. Methods Since variation within the coding region of IL-23R may influence the pathogenesis of SMA, the association between IL-23R rs1884444 (G/T), rs7530511 (C/T), and SMA (Hb
- Published
- 2017
- Full Text
- View/download PDF
12. Association between Fcγ receptor IIA, IIIA and IIIB genetic polymorphisms and susceptibility to severe malaria anemia in children in western Kenya
- Author
-
Elly O. Munde, Winnie A. Okeyo, Evans Raballah, Samuel B. Anyona, Tom Were, John M. Ong’echa, Douglas J. Perkins, and Collins Ouma
- Subjects
FcγRs ,Susceptibility ,Polymorphisms ,Malaria anemia ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background Naturally-acquired immunity to Plasmodium falciparum malaria develops after several episodes of infection. Fc gamma receptors (FcγRs) bind to immunoglobulin G (IgG) antibodies and mediate phagocytosis of opsonized microbes, thereby, linking humoral and cellular immunity. FcγR polymorphisms influence binding affinity to IgGs and consequently, can influence clinical malaria outcomes. Specifically, variations in FcγRIIA -131Arg/His, FcγRIIIA-176F/V and FcγRIIIB-NA1/NA2 modulate immune responses through altered binding preferences to IgGs and immune complexes. Differential binding, in turn, changes ability of immune cells to respond to infection through production of inflammatory mediators during P. falciparum infection. Methods We determined the association between haplotypes of FcγRIIA-131Arg/His, FcγRIIIA-176F/V and FcγRIIIB-NA1/NA2 variants and severe malarial anemia (SMA; hemoglobin
- Published
- 2017
- Full Text
- View/download PDF
13. Reduced Parasite Burden in Children with Falciparum Malaria and Bacteremia Coinfections: Role of Mediators of Inflammation
- Author
-
Gregory C. Davenport, James B. Hittner, Vincent Otieno, Zachary Karim, Harshini Mukundan, Paul W. Fenimore, Nicolas W. Hengartner, Benjamin H. McMahon, Prakasha Kempaiah, John M. Ong’echa, and Douglas J. Perkins
- Subjects
Pathology ,RB1-214 - Abstract
Bacteremia and malaria coinfection is a common and life-threatening condition in children residing in sub-Saharan Africa. We previously showed that coinfection with Gram negative (G[−]) enteric Bacilli and Plasmodium falciparum (Pf[+]) was associated with reduced high-density parasitemia (HDP, >10,000 parasites/μL), enhanced respiratory distress, and severe anemia. Since inflammatory mediators are largely unexplored in such coinfections, circulating cytokines were determined in four groups of children (n=206, aged
- Published
- 2016
- Full Text
- View/download PDF
14. Association of killer cell immunoglobulin-like receptors with endemic Burkitt lymphoma in Kenyan children
- Author
-
Catherine Forconi, Anita Ghansah, Jeffrey A. Bailey, John M. Ong’echa, Peter O Oluoch, Beatrice M. Muriuki, and Ann M. Moormann
- Subjects
0301 basic medicine ,Herpesvirus 4, Human ,Adolescent ,Endemic Diseases ,Genotype ,Molecular biology ,Science ,Immunology ,Virus ,Article ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Receptors, KIR ,medicine ,Humans ,B-cell lymphoma ,Child ,Cancer ,Retrospective Studies ,Multidisciplinary ,biology ,Infant ,Viral Load ,medicine.disease ,Burkitt Lymphoma ,Kenya ,Lymphoma ,Immunosurveillance ,030104 developmental biology ,030220 oncology & carcinogenesis ,Child, Preschool ,biology.protein ,Medicine ,Antibody - Abstract
Endemic Burkitt lymphoma (eBL) is an aggressive pediatric B cell lymphoma, common in Equatorial Africa. Co-infections with Epstein-Barr virus (EBV) and Plasmodium falciparum, coupled with c-myc translocation are involved in eBL etiology. Infection-induced immune evasion mechanisms to avoid T cell cytotoxicity may increase the role of Natural killer (NK) cells in anti-tumor immunosurveillance. Killer immunoglobulin-like receptor (KIR) genes on NK cells exhibit genotypic and allelic variations and are associated with susceptibility to diseases and malignancies. However, their role in eBL pathogenesis remains undefined. This retrospective study genotyped sixteen KIR genes and compared their frequencies in eBL patients (n = 104) and healthy geographically-matched children (n = 104) using sequence-specific primers polymerase chain reaction (SSP-PCR) technique. The relationship between KIR polymorphisms with EBV loads and eBL pathogenesis was investigated. Possession of ≥ 4 activating KIRs predisposed individuals to eBL (OR = 3.340; 95% CI 1.530–7.825; p = 0.004). High EBV levels were observed in Bx haplogroup (p = 0.016) and AB genotypes (p = 0.042) relative to AA haplogroup and AA genotype respectively, in eBL patients but not in healthy controls. Our results suggest that KIR-mediated NK cell stimulation could mute EBV control, contributing to eBL pathogenesis.
- Published
- 2021
15. Endemic Burkitt lymphoma avatar mouse models for exploring inter-patient tumor variation and testing targeted therapies
- Author
-
Priya Saikumar Lakshmi, Cliff I Oduor, Catherine S Forconi, Viriato M’Bana, Courtney Bly, Rachel M Gerstein, Juliana A Otieno, John M Ong’echa, Christian Münz, Micah A Luftig, Michael A Brehm, Jeffrey A Bailey, and Ann M Moormann
- Subjects
Ecology ,Health, Toxicology and Mutagenesis ,Plant Science ,Biochemistry, Genetics and Molecular Biology (miscellaneous) - Abstract
Endemic Burkitt lymphoma (BL) is a childhood cancer in sub-Saharan Africa characterized by Epstein–Barr virus and malaria-associated aberrant B-cell activation andMYCchromosomal translocation. Survival rates hover at 50% after conventional chemotherapies; therefore, clinically relevant models are necessary to test additional therapies. Hence, we established five patient-derived BL tumor cell lines and corresponding NSG-BL avatar mouse models. Transcriptomics confirmed that our BL lines maintained fidelity from patient tumors to NSG-BL tumors. However, we found significant variation in tumor growth and survival among NSG-BL avatars and in Epstein–Barr virus protein expression patterns. We tested rituximab responsiveness and found one NSG-BL model exhibiting direct sensitivity, characterized by apoptotic gene expression counterbalanced by unfolded protein response and mTOR pro-survival pathways. In rituximab-unresponsive tumors, we observed an IFN-α signature confirmed by the expression of IRF7 and ISG15. Our results demonstrate significant inter-patient tumor variation and heterogeneity, and that contemporary patient-derived BL cell lines and NSG-BL avatars are feasible tools to guide new therapeutic strategies and improve outcomes for these children.
- Published
- 2023
16. Low sensitivity of the careHPV™ Assay for detection of Oncogenic Human Papillomavirus in cervical samples from HIV-infected and HIV-uninfected Kenyan women
- Author
-
John M. Ong’echa, Patrick J. Loehrer, Chelimo K, Barry Rosen, P. Tonui, Aaron C. Ermel, M. Titus, Kapten Muthoka, Omenge Orang’o, Darron R. Brown, Susan Cu-Uvin, Ann Moormann, and Peter Itsura
- Subjects
business.industry ,Hiv infected ,Human immunodeficiency virus (HIV) ,medicine ,Human papillomavirus ,medicine.disease_cause ,business ,Virology - Published
- 2020
17. Interplay between IL-10, IFN-γ, IL-17A and PD-1 Expressing EBNA1-Specific CD4+ and CD8+ T Cell Responses in the Etiologic Pathway to Endemic Burkitt Lymphoma
- Author
-
Juliana A. Otieno, Priya Saikumar Lakshmi, John M. Ong’echa, Christian Münz, David H. Mulama, Leslie J. Berg, Ann Moormann, Jonathan D. Kurtis, Catherine S. Forconi, Joslyn Foley, University of Zurich, and Moormann, Ann M
- Subjects
Cancer Research ,T cell ,malaria ,610 Medicine & health ,Biology ,10263 Institute of Experimental Immunology ,Article ,Flow cytometry ,Interferon ,EBV ,hemic and lymphatic diseases ,PD-1 ,medicine ,Cytotoxic T cell ,1306 Cancer Research ,endemic Burkitt lymphoma ,RC254-282 ,B cell ,EBNA1 ,medicine.diagnostic_test ,T-cells ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Kenya ,cytokines ,Interleukin 10 ,medicine.anatomical_structure ,Oncology ,Immunology ,570 Life sciences ,biology ,2730 Oncology ,Intracellular ,CD8 ,medicine.drug - Abstract
Children diagnosed with endemic Burkitt lymphoma (eBL) are deficient in interferon-γ (IFN-γ) responses to Epstein–Barr Nuclear Antigen1 (EBNA1), the viral protein that defines the latency I pattern in this B cell tumor. However, the contributions of immune-regulatory cytokines and phenotypes of the EBNA1-specific T cells have not been characterized for eBL. Using a bespoke flow cytometry assay we measured intracellular IFN-γ, IL-10, IL-17A expression and phenotyped CD4+ and CD8+ T cell effector memory subsets specific to EBNA1 for eBL patients compared to two groups of healthy children with divergent malaria exposures. In response to EBNA1 and a malaria antigen (PfSEA-1A), the three study groups exhibited strikingly different cytokine expression and T cell memory profiles. EBNA1-specific IFN-γ-producing CD4+ T cell response rates were lowest in eBL (40%) compared to children with high malaria (84%) and low malaria (66%) exposures (p <, 0.0001 and p = 0.0004, respectively). However, eBL patients did not differ in CD8+ T cell response rates or the magnitude of IFN-γ expression. In contrast, eBL children were more likely to have EBNA1-specific CD4+ T cells expressing IL-10, and less likely to have polyfunctional IFN-γ+IL-10+ CD4+ T cells (p = 0.02). They were also more likely to have IFN-γ+IL-17A+, IFN-γ+ and IL-17A+ CD8+ T cell subsets compared to healthy children. Cytokine-producing T cell subsets were predominantly CD45RA+CCR7+ TNAIVE-LIKE cells, yet PD-1, a marker of persistent activation/exhaustion, was more highly expressed by the central memory (TCM) and effector memory (TEM) T cell subsets. In summary, our study suggests that IL-10 mediated immune regulation and depletion of IFN-γ+ EBNA1-specific CD4+ T cells are complementary mechanisms that contribute to impaired T cell cytotoxicity in eBL pathogenesis.
- Published
- 2021
- Full Text
- View/download PDF
18. KSHV infection drives poorly cytotoxic CD56-negative natural killer cell differentiation in vivo upon KSHV/EBV dual infection
- Author
-
Peter O Oluoch, Ann M. Moormann, Lara Zuppiger, Nicole Caduff, Thomas F. Schulz, David J. Blackbourn, Lisa Rieble, Christian Münz, Anita Murer, Ana Raykova, Obinna Chijioke, Donal McHugh, John M. Ong’echa, Catherine Forconi, and Michelle Böni
- Subjects
0301 basic medicine ,Human cytomegalovirus ,Epstein-Barr Virus Infections ,humanized mouse model ,QH301-705.5 ,viruses ,Cell ,chemical and pharmacologic phenomena ,KSHV ,Biology ,CD38 ,medicine.disease_cause ,Kaposi sarcoma-associated herpesvirus ,General Biochemistry, Genetics and Molecular Biology ,Virus ,Natural killer cell differentiation ,Mice ,03 medical and health sciences ,0302 clinical medicine ,EBV ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Cytotoxic T cell ,Epstein-Barr virus ,Biology (General) ,natural killer cells ,virus diseases ,Cell Differentiation ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,Virology ,Epstein–Barr virus ,Killer Cells, Natural ,030104 developmental biology ,medicine.anatomical_structure ,Herpesvirus 8, Human ,Primary effusion lymphoma ,030217 neurology & neurosurgery - Abstract
Summary Herpesvirus infections shape the human natural killer (NK) cell compartment. While Epstein-Barr virus (EBV) expands immature NKG2A+ NK cells, human cytomegalovirus (CMV) drives accumulation of adaptive NKG2C+ NK cells. Kaposi sarcoma-associated herpesvirus (KSHV) is a close relative of EBV, and both are associated with lymphomas, including primary effusion lymphoma (PEL), which nearly always harbors both viruses. In this study, KSHV dual infection of mice with reconstituted human immune system components leads to the accumulation of CD56–CD16+CD38+CXCR6+ NK cells. CD56–CD16+ NK cells were also more frequently found in KSHV-seropositive Kenyan children. This NK cell subset is poorly cytotoxic against otherwise-NK-cell-susceptible and antibody-opsonized targets. Accordingly, NK cell depletion does not significantly alter KSHV infection in humanized mice. These data suggest that KSHV might escape NK-cell-mediated immune control by driving CD56–CD16+ NK cell differentiation.
- Published
- 2021
19. The whole-genome landscape of Burkitt lymphoma subtypes
- Author
-
Yuan Zhuang, David B. Dunson, Nestory Masalu, Sarah L. Ondrejka, Anupama Reddy, Tushar Dave, Randy D. Gascoyne, Cassandra Love, Eric D. Hsi, Yen-Yu Lin, Howard J. Meyerson, Rex Au-Yeung, Micah A. Luftig, Govind Bhagat, William W.L. Choi, Brooke C. Palus, Sandeep S. Dave, John M. Ong’echa, Georg Lenz, Juliana A. Otieno, So Young Kim, Vidya Seshadri, Guojie Li, Razvan Panea, Cliff I. Oduor, Megan Agajanian, Devang Thakkar, Harshit Sahay, Yuri Fedoriw, Jeffrey A. Bailey, Bachir Alobeid, Rodney R. Miles, Kristy L. Richards, Nelson J. Chao, Jennifer R. Shingleton, Christopher R. Flowers, Ann M. Moormann, Minerva Mukhopadyay, Grzegorz Rymkiewicz, Michael B. Major, Alexander Waldrop, Wolfgang Hartmann, Shawn Levy, and Kristin Schroeder
- Subjects
0301 basic medicine ,Genetics ,Mutation ,Immunology ,Bare lymphocyte syndrome ,Cell Biology ,Hematology ,Biology ,medicine.disease ,medicine.disease_cause ,BCL6 ,Biochemistry ,Phenotype ,Lymphoma ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,medicine ,Carcinogenesis ,Gene ,Burkitt's lymphoma - Abstract
Burkitt lymphoma (BL) is an aggressive, MYC-driven lymphoma comprising 3 distinct clinical subtypes: sporadic BLs that occur worldwide, endemic BLs that occur predominantly in sub-Saharan Africa, and immunodeficiency-associated BLs that occur primarily in the setting of HIV. In this study, we comprehensively delineated the genomic basis of BL through whole-genome sequencing (WGS) of 101 tumors representing all 3 subtypes of BL to identify 72 driver genes. These data were additionally informed by CRISPR screens in BL cell lines to functionally annotate the role of oncogenic drivers. Nearly every driver gene was found to have both coding and non-coding mutations, highlighting the importance of WGS for identifying driver events. Our data implicate coding and non-coding mutations in IGLL5, BACH2, SIN3A, and DNMT1. Epstein-Barr virus (EBV) infection was associated with higher mutation load, with type 1 EBV showing a higher mutational burden than type 2 EBV. Although sporadic and immunodeficiency-associated BLs had similar genetic profiles, endemic BLs manifested more frequent mutations in BCL7A and BCL6 and fewer genetic alterations in DNMT1, SNTB2, and CTCF. Silencing mutations in ID3 were a common feature of all 3 subtypes of BL. In vitro, mass spectrometry–based proteomics demonstrated that the ID3 protein binds primarily to TCF3 and TCF4. In vivo knockout of ID3 potentiated the effects of MYC, leading to rapid tumorigenesis and tumor phenotypes consistent with those observed in the human disease.
- Published
- 2019
20. Molecular basis of reduced LAIR1 expression in childhood severe malarial anaemia: Implications for leukocyte inhibitory signalling
- Author
-
Qiuying Cheng, John M. Ong'echa, Angela O. Achieng, Bernard Guyah, Collins Ouma, Christophe G. Lambert, and Douglas J Perkins
- Subjects
Male ,0301 basic medicine ,Research paper ,medicine.medical_treatment ,Interleukin-1beta ,PBMCs, Peripheral blood mononuclear cells ,LAIR2, Leukocyte-associated immunoglobulin like receptor-2 ,PfHz, Plasmodium falciparum haemozoin ,LAIR1, Leukocyte-associated immunoglobulin like receptor-1 ,SHP-1, SH2 domain-containing tyrosine phosphatase-1 ,Pathogenesis ,chemistry.chemical_compound ,0302 clinical medicine ,PCN, Pigment containing neutrophils ,TNF-α, Tumor necrosis factor alpha ,Malaria, Falciparum ,Receptors, Immunologic ,050207 economics ,Receptor ,Leukocyte-associated immunoglobulin like receptor-1 ,Leukocyte-associated immunoglobulin like receptor-2 ,P. falciparum, Plasmodium falciparum ,050208 finance ,CLL, Chronic lymphocytic leukaemia ,ITIM, immuno-tyrosine inhibition motifs ,biology ,Protein Tyrosine Phosphatase, Non-Receptor Type 6 ,05 social sciences ,Anemia ,General Medicine ,SMA ,Severe malarial anaemia ,3. Good health ,HFRS, haemorrhagic fever with renal syndrome ,Child, Preschool ,HIV-1, Human immunodeficiency virus 1 ,030220 oncology & carcinogenesis ,IL-6, Interleukin 6 ,Female ,Tumor necrosis factor alpha ,Antibody ,Signal Transduction ,C1q, Complement component 1q ,Hemeproteins ,SHP-2, SH2 domain-containing tyrosine phosphatase-2 ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Immune system ,Phagocytosis ,SLE, Systemic lupus erythematosus ,Complement component 1q ,In vivo ,0502 economics and business ,medicine ,Humans ,SMA, severe malarial anaemia ,Interleukin 6 ,Plasmodium falciparum malaria ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,business.industry ,Complement C1q ,LAIR1 ,Plasmodium falciparum haemozoin ,Antagonist ,Infant ,PCM, Pigment containing monocytes ,NF-κB ,Immunotherapy ,AML, Acute myeloid leukaemia ,030104 developmental biology ,chemistry ,NF-κB, Nuclear factor-kappa beta ,Immunology ,Leukocytes, Mononuclear ,IL-1β, Interleukin 1 beta ,biology.protein ,PCR, Polymerase chain reaction ,business ,Biomedical sciences - Abstract
Background: Leukocyte-associated immunoglobulin like receptor-1 (LAIR1) is a transmembrane inhibitory receptor that influences susceptibility to a myriad of inflammatory diseases. Our recent investigations of severe malarial anemia (SMA) pathogenesis in Kenyan children discovered that novel LAIR1 genetic variants associated with decreased LAIR1 enhanced the longitudinal risk of SMA and all-cause mortality. Methods: To further characterize LAIR1 expression and identify novel molecular mechanisms, at least in part, responsible for reduced LAIR1 in severe malaria, we conducted a series of experiments in samples from children with malaria, followed by in vitro investigations driven by the in vivo findings. Findings: Kenyan children with SMA had elevated circulating levels of soluble LAIR1 (sLAIR1) relative to non-SMA (1.69-fold P
- Published
- 2019
21. Integrated OMICS platforms identify LAIR1 genetic variants as novel predictors of cross-sectional and longitudinal susceptibility to severe malaria and all-cause mortality in Kenyan childrenResearch in context
- Author
-
Qiuying Cheng, Benjamin H. McMahon, Bernard Guyah, Nicolas W. Hengartner, Douglas J. Perkins, Christophe G. Lambert, Angela O. Achieng, John M. Ong’echa, Collins Ouma, Samuel B. Anyona, Evans Raballah, Nick Lauve, and Ivy Foo-Hurwitz
- Subjects
0301 basic medicine ,Male ,Research paper ,Genotype ,Holoendemic ,lcsh:Medicine ,General Biochemistry, Genetics and Molecular Biology ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Phagocytosis ,Medicine ,Humans ,Malaria, Falciparum ,Receptors, Immunologic ,lcsh:R5-920 ,Plasmodium falciparum malaria ,biology ,business.industry ,Haplotype ,lcsh:R ,Infant ,Plasmodium falciparum ,Anemia ,General Medicine ,biology.organism_classification ,SMA ,Omics ,All-cause mortality ,Kenya ,Severe malarial anaemia ,3. Good health ,030104 developmental biology ,Carriage ,Gene Expression Regulation ,Haplotypes ,030220 oncology & carcinogenesis ,Child, Preschool ,Immunology ,Leukocytes, Mononuclear ,Female ,business ,lcsh:Medicine (General) ,Leukocyte associated immunoglobulin like receptor 1 ,Signal Transduction - Abstract
Background: Severe malarial anaemia (SMA) is a leading cause of childhood mortality in holoendemic Plasmodium falciparum regions. Methods: To gain an improved understanding of SMA pathogenesis, whole genome and transcriptome profiling was performed in Kenyan children (n = 144, 3–36 months) with discrete non-SMA and SMA phenotypes. Leukocyte associated immunoglobulin like receptor 1 (LAIR1) emerged as a predictor of susceptibility to SMA (P A); rs2287827 (18835G>A)] and clinical outcomes were investigated in individuals (n = 1512
- Published
- 2019
22. A cross-sectional analysis of factors associated with detection of oncogenic human papillomavirus in human immunodeficiency virus-infected and uninfected Kenyan women
- Author
-
Ann Mwangi, Yan Tong, Patrick J. Loehrer, Aaron Ermel, M. Titus, Kapten Muthoka, Susan Cu-Uvin, Nelson Wong, Omenge Orang’o, Darron R. Brown, Joseph W. Hogan, Ann M. Moormann, Stephen Kiptoo, P. Tonui, and John M. Ong’echa
- Subjects
0301 basic medicine ,Oncology ,Adult ,medicine.medical_specialty ,Longitudinal study ,Kenyan women ,Genotype ,Cross-sectional study ,030106 microbiology ,Prevalence ,HIV Infections ,lcsh:Infectious and parasitic diseases ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Medical microbiology ,5. Gender equality ,Risk Factors ,Internal medicine ,medicine ,Odds Ratio ,Humans ,lcsh:RC109-216 ,030212 general & internal medicine ,Longitudinal Studies ,Cervix ,Cervical cancer ,Human papillomavirus 16 ,business.industry ,Incidence (epidemiology) ,Papillomavirus Infections ,Age Factors ,virus diseases ,Middle Aged ,medicine.disease ,Oncogenic HPV ,HIV infection ,Kenya ,3. Good health ,Vaccination ,Infectious Diseases ,medicine.anatomical_structure ,Cross-Sectional Studies ,Logistic Models ,Sexual Partners ,Vagina ,Female ,business ,Research Article - Abstract
Background Cervical cancer is caused by oncogenic human papillomaviruses (HPV) and is one of the most common malignancies in women living in sub-Saharan Africa. Women infected with the human immunodeficiency virus (HIV) have a higher incidence of cervical cancer, but the full impact on HPV detection is not well understood, and associations of biological and behavioral factors with oncogenic HPV detection have not been fully examined. Therefore, a study was initiated to investigate factors that are associated with oncogenic HPV detection in Kenyan women. Methods Women without cervical dysplasia were enrolled in a longitudinal study. Data from enrollment are presented as a cross-sectional analysis. Demographic and behavioral data was collected, and HPV typing was performed on cervical swabs. HIV-uninfected women (n = 105) and HIV-infected women (n = 115) were compared for demographic and behavioral characteristics using t-tests, Chi-square tests, Wilcoxon sum rank tests or Fisher’s exact tests, and for HPV detection using logistic regression or negative binomial models adjusted for demographic and behavioral characteristics using SAS 9.4 software. Results Compared to HIV-uninfected women, HIV-infected women were older, had more lifetime sexual partners, were less likely to be married, were more likely to regularly use condoms, and were more likely to have detection of HPV 16, other oncogenic HPV types, and multiple oncogenic types. In addition to HIV, more lifetime sexual partners was associated with a higher number of oncogenic HPV types (aIRR 1.007, 95% CI 1.007–1.012). Greater travel distance to the clinic was associated with increased HPV detection (aOR for detection of ≥ 2 HPV types: 3.212, 95% CI 1.206–8.552). Older age (aOR for HPV 16 detection: 0.871, 95% CI 0.764–0.993) and more lifetime pregnancies (aOR for detection of oncogenic HPV types: 0.706, 95% CI, 0.565–0.883) were associated with reduced detection. Conclusion HIV infection, more lifetime sexual partners, and greater distance to health-care were associated with a higher risk of oncogenic HPV detection, in spite of ART use in those who were HIV-infected. Counseling of women about sexual practices, improved access to health-care facilities, and vaccination against HPV are all potentially important in reducing oncogenic HPV infections.
- Published
- 2019
23. Antimalarials: Review of Plasmepsins as Drug Targets and HIV Protease Inhibitors Interactions
- Author
-
Angela O. Achieng, Ravi Durvasula, Joshua Teye, Brijesh Rathi, Whelton A. Miller, Prakasha Kempaiah, Reagan M. Mogire, Hoseah M. Akala, Samuel K. Kwofie, and John M. Ong’echa
- Subjects
Proteases ,Plasmodium vivax ,Plasmepsin ,01 natural sciences ,Plasmodium ,Antimalarials ,Drug Delivery Systems ,parasitic diseases ,Drug Discovery ,medicine ,Aspartic Acid Endopeptidases ,Humans ,HIV Protease Inhibitor ,Artemisinin ,biology ,Plasmodium falciparum ,HIV Protease Inhibitors ,General Medicine ,biology.organism_classification ,medicine.disease ,Virology ,Malaria ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,medicine.drug - Abstract
Malaria is a major global health concern with the majority of cases reported in regions of South-East Asia, Eastern Mediterranean, Western Pacific, the Americas, and Sub-Saharan Africa. The World Health Organization (WHO) estimated 216 million worldwide reported cases of malaria in 2016. It is an infection of the red blood cells by parasites of the genus Plasmodium with most severe and common forms caused by Plasmodium falciparum (P. falciparum or Pf) and Plasmodium vivax (P. vivax or Pv). Emerging parasite resistance to available antimalarial drugs poses great challenges to treatment. Currently, the first line of defense includes artemisinin combination therapies (ACTs), increasingly becoming less effective and challenging to combat new occurrences of drug-resistant parasites. This necessitates the urgent need for novel antimalarials that target new molecular pathways with a different mechanism of action from the traditional antimalarials. Several new inhibitors and potential drug targets of the parasites have been reported over the years. This review focuses on the malarial aspartic proteases known as plasmepsins (Plms) as novel drug targets and antimalarials targeting Plms. It further discusses inhibitors of hemoglobin-degrading plasmepsins Plm I, Plm II, Plm IV and Histo-aspartic proteases (HAP), as well as HIV protease inhibitors of plasmepsins.
- Published
- 2019
24. Comparative genomic and phenotypic characterization of invasive non-typhoidal Salmonella isolates from Siaya, Kenya
- Author
-
Jessica Z. Kubicek-Sutherland, Samuel B. Anyona, Priya Dighe, Qiuying Cheng, Norman A. Doggett, Lindsey Jacobs, Harshini Mukundan, Vincent Otieno, Loreen R. Stromberg, Karen W. Davenport, John M. Ong’echa, Evans Raballah, Prakasha Kempaiah, Migun Shakya, Gary Xie, Hajnalka E. Daligault, Zachary R. Stromberg, Patrick S. G. Chain, Collins Ouma, Benjamin H. McMahon, and Douglas J Perkins
- Subjects
0301 basic medicine ,Male ,Salmonella typhimurium ,Bacterial Diseases ,Salmonella ,Physiology ,RC955-962 ,Drug resistance ,medicine.disease_cause ,Pathology and Laboratory Medicine ,Geographical Locations ,Plasmid ,Medical Conditions ,Arctic medicine. Tropical medicine ,Drug Resistance, Multiple, Bacterial ,Genotype ,Medicine and Health Sciences ,Genomics ,Antimicrobial ,Anti-Bacterial Agents ,Bacterial Pathogens ,Electrophysiology ,Phenotype ,Infectious Diseases ,Medical Microbiology ,Child, Preschool ,Salmonella Infections ,Female ,Public aspects of medicine ,RA1-1270 ,Pathogens ,Research Article ,030106 microbiology ,Biology ,Microbiology ,Membrane Potential ,03 medical and health sciences ,Antibiotic resistance ,Enterobacteriaceae ,Microbial Control ,medicine ,Genetics ,Parasitic Diseases ,Humans ,Microbial Pathogens ,Pharmacology ,Bacteria ,Public Health, Environmental and Occupational Health ,Infant, Newborn ,Organisms ,Infant ,Biology and Life Sciences ,medicine.disease ,Tropical Diseases ,Kenya ,Malaria ,030104 developmental biology ,nervous system ,Salmonella enteritidis ,Antibiotic Resistance ,People and Places ,Africa ,Antimicrobial Resistance - Abstract
Non-typhoidal Salmonella (NTS) is a major global health concern that often causes bloodstream infections in areas of the world affected by malnutrition and comorbidities such as HIV and malaria. Developing a strategy to control the emergence and spread of highly invasive and antimicrobial resistant NTS isolates requires a comprehensive analysis of epidemiological factors and molecular pathogenesis. Here, we characterize 11 NTS isolates that caused bloodstream infections in pediatric patients in Siaya, Kenya from 2003–2010. Nine isolates were identified as S. Typhimurium sequence type 313 while the other two were S. Enteritidis. Comprehensive genotypic and phenotypic analyses were performed to compare these isolates to those previously identified in sub-Saharan Africa. We identified a S. Typhimurium isolate referred to as UGA14 that displayed novel plasmid, pseudogene and resistance features as compared to other isolates reported from Africa. Notably, UGA14 is able to ferment both lactose and sucrose due to the acquisition of insertion elements on the pKST313 plasmid. These findings show for the first time the co-evolution of plasmid-mediated lactose and sucrose metabolism along with cephalosporin resistance in NTS further elucidating the evolutionary mechanisms of invasive NTS phenotypes. These results further support the use of combined genomic and phenotypic approaches to detect and characterize atypical NTS isolates in order to advance biosurveillance efforts that inform countermeasures aimed at controlling invasive and antimicrobial resistant NTS., Author summary Non-typhoidal Salmonella (NTS) has been associated with life-threatening bacteremia in sub-Saharan Africa where co-morbidities such as HIV and malaria are highly prevalent. Children under the age of 5 are especially vulnerable to invasive NTS infections. The emergence and spread of multi-drug resistant invasive NTS isolates have limited the availability of effective treatment options. Understanding the molecular mechanisms that drive the evolution of invasive and antimicrobial resistant NTS strains is key to mitigating their impact on human health. In this study, we obtained 11 NTS isolates from the bloodstreams of children in Siaya, Kenya and performed both genotypic and phenotypic characterization compared to antimicrobial sensitive NTS strains. One strain, named UGA14, displayed a unique plasmid makeup compared to the other 10 isolates, which encoded for cephalosporin resistance as well as novel metabolic features allowing it to metabolize both lactose and sucrose. Not only was UGA14 multi-drug resistant but its unique metabolic profile made it indistinguishable from Escherichia coli on brilliant green agar indicating the failure of traditional culture-based techniques to inform diagnosis and treatment decisions. These findings highlight the importance of comparative genotypic and phenotypic analyses to understand the driving mechanisms of invasive and drug-resistant pathogens and support the development of effective countermeasures.
- Published
- 2020
25. Detection of types of HPV among HIV-infected and HIV-uninfected Kenyan women undergoing cryotherapy or loop electrosurgical excision procedure
- Author
-
Darron R. Brown, Elkanah Omenge Orang'o, Yan Tong, Victor Omodi, Jordan P. Emont, Patrick J. Loehrer, Tao Liu, Susan Cu-Uvin, Ann M. Moormann, Stephen Kiptoo, John M. Ong’echa, Philip Tonui, Joseph W. Hogan, Aaron Ermel, Kapten Muthoka, Peter Itsura, and Titus Maina
- Subjects
Adult ,medicine.medical_specialty ,Kenya ,Electrosurgery ,medicine.medical_treatment ,Human immunodeficiency virus (HIV) ,Uterine Cervical Neoplasms ,Cryotherapy ,HIV Infections ,Cervical intraepithelial neoplasia ,medicine.disease_cause ,Article ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,030219 obstetrics & reproductive medicine ,business.industry ,Papillomavirus Infections ,HPV infection ,Obstetrics and Gynecology ,virus diseases ,General Medicine ,Odds ratio ,Middle Aged ,medicine.disease ,Uterine Cervical Dysplasia ,Loop electrosurgical excision procedure ,HIV-1 ,Female ,business - Abstract
Objective To assess the baseline types of HPV infection among HIV-positive and HIV-negative women in western Kenya undergoing cryotherapy or loop electrosurgical excision procedure (LEEP) for cervical intraepithelial neoplasia. Methods A prospective observational study was conducted of baseline HPV characteristics of women undergoing visual inspection with acetic acid (VIA) and cryotherapy or LEEP. After a positive VIA in HIV-positive and HIV-negative women, data on demographics, CD4 count, and use of antiretroviral therapy and a cervical swab were collected. HPV typing was performed using the Roche Linear Array. Results Of 175 participants, 86 (49.1%) were HIV-positive and had a higher prevalence of low-risk HPV types (odds ratio [OR] 5.28, P=0.005) compared with HIV-negative women. The most common high-risk (HR)-HPV types in HIV-positive women were HPV 16 (13.9%) and HPV 18 (11.1%). HIV-positive women requiring LEEP were more likely to have HR-HPV types (OR 6.67, P=0.012) and to be infected with multiple HR-HPV types (OR 7.79, P=0.024) compared to those undergoing cryotherapy. Conclusion HIV-positive women requiring LEEP versus cryotherapy had a higher prevalence of any HR-HPV type and multiple HR-HPV types. There were no such differences in HPV types identified among HIV-negative women.
- Published
- 2020
26. A New Hope for CD56
- Author
-
Catherine S, Forconi, Cliff I, Oduor, Peter O, Oluoch, John M, Ong'echa, Christian, Münz, Jeffrey A, Bailey, and Ann M, Moormann
- Subjects
CD56negCD16pos subset ,natural killer cells ,epstein-barr virus ,Receptors, IgG ,malaria ,Flow Cytometry ,CD56 Antigen ,transcription profile ,Killer Cells, Natural ,Cellular and Infection Microbiology ,Signaling Lymphocytic Activation Molecule Family ,Chronic Disease ,Humans ,Immunotherapy ,endemic Burkitt lymphoma ,Child ,Original Research - Abstract
Natural Killer (NK) cells play an essential role in antiviral and anti-tumoral immune responses. In peripheral blood, NK cells are commonly classified into two major subsets: CD56brightCD16neg and CD56dimCD16pos despite the characterization of a CD56negCD16pos subset 25 years ago. Since then, several studies have described the prevalence of an CD56negCD16pos NK cell subset in viral non-controllers as the basis for their NK cell dysfunction. However, the mechanistic basis for their cytotoxic impairment is unclear. Recently, using a strict flow cytometry gating strategy to exclude monocytes, we reported an accumulation of CD56negCD16pos NK cells in Plasmodium falciparum malaria-exposed children and pediatric cancer patients diagnosed with endemic Burkitt lymphoma (eBL). Here, we use live-sorted cells, histological staining, bulk RNA-sequencing and flow cytometry to confirm that this CD56negCD16pos NK cell subset has the same morphological features as the other NK cell subsets and a similar transcriptional profile compared to CD56dimCD16pos NK cells with only 120 genes differentially expressed (fold change of 1.5, p < 0.01 and FDR
- Published
- 2019
27. Epstein-Barr Virus Genomes Reveal Population Structure and Type 1 Association with Endemic Burkitt Lymphoma
- Author
-
Juliana A. Otieno, Micah A. Luftig, John M. Ong’echa, Ozkan Aydemir, Cliff I. Oduor, Ann M. Moormann, Jeffrey A. Bailey, and Yasin Kaymaz
- Subjects
Nonsynonymous substitution ,Male ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,Adolescent ,Immunology ,Receptor, Macrophage Colony-Stimulating Factor ,Genome, Viral ,Biology ,medicine.disease_cause ,Microbiology ,Virus ,03 medical and health sciences ,Viral Proteins ,0302 clinical medicine ,Virology ,hemic and lymphatic diseases ,Genetic variation ,medicine ,Odds Ratio ,Humans ,Child ,Gene ,030304 developmental biology ,Genetic association ,0303 health sciences ,Genetic Variation ,Infant ,Sequence Analysis, DNA ,Epstein–Barr virus ,Pediatric cancer ,Burkitt Lymphoma ,Kenya ,Lytic cycle ,Epstein-Barr Virus Nuclear Antigens ,Genetic Diversity and Evolution ,030220 oncology & carcinogenesis ,Insect Science ,Child, Preschool ,DNA, Viral ,Female ,Genome-Wide Association Study - Abstract
Endemic Burkitt lymphoma (eBL), the most prevalent pediatric cancer in sub-Saharan Africa, is distinguished by its inclusion of Epstein-Barr virus (EBV). In order to better understand the impact of EBV variation in eBL tumorigenesis, we improved viral DNA enrichment methods and generated a total of 98 new EBV genomes from both eBL cases (n = 58) and healthy controls (n = 40) residing in the same geographic region in Kenya. Using our unbiased methods, we found that EBV type 1 was significantly more prevalent in eBL patients (74.5%) than in healthy children (47.5%) (odds ratio = 3.24, 95% confidence interval = 1.36 to 7.71, P = 0.007), as opposed to similar proportions in both groups. Controlling for EBV type, we also performed a genome-wide association study identifying six nonsynonymous variants in the genes EBNA1, EBNA2, BcLF1, and BARF1 that were enriched in eBL patients. In addition, viruses isolated from plasma of eBL patients were identical to their tumor counterparts consistent with circulating viral DNA originating from the tumor. We also detected three intertypic recombinants carrying type 1 EBNA2 and type 2 EBNA3 regions, as well as one novel genome with a 20-kb deletion, resulting in the loss of multiple lytic and virion genes. Comparing EBV types, viral genes displayed differential variation rates as type 1 appeared to be more divergent, while type 2 demonstrated novel substructures. Overall, our findings highlight the complexities of the EBV population structure and provide new insight into viral variation, potentially deepening our understanding of eBL oncogenesis. IMPORTANCE Improved viral enrichment methods conclusively demonstrate EBV type 1 to be more prevalent in eBL patients than in geographically matched healthy controls, which previously underrepresented the prevalence of EBV type 2. Genome-wide association analysis between cases and controls identifies six eBL-associated nonsynonymous variants in EBNA1, EBNA2, BcLF1, and BARF1 genes. Analysis of population structure reveals that EBV type 2 exists as two genomic subgroups and was more commonly found in female than in male eBL patients.
- Published
- 2019
28. Kaposi Sarcoma-Associated Herpesvirus Infection and Endemic Burkitt Lymphoma
- Author
-
Peter O Oluoch, Ann M. Moormann, Christian Münz, John M. Ong’echa, Dirk P. Dittmer, Cliff I. Oduor, Jeffrey A. Bailey, and Catherine Forconi
- Subjects
0301 basic medicine ,Male ,Adolescent ,viruses ,medicine.disease_cause ,Virus ,03 medical and health sciences ,Major Articles and Brief Reports ,0302 clinical medicine ,Antigen ,Seroepidemiologic Studies ,hemic and lymphatic diseases ,parasitic diseases ,medicine ,Immunology and Allergy ,Seroprevalence ,Humans ,Child ,Sarcoma, Kaposi ,Herpesviridae ,biology ,business.industry ,Coinfection ,Age Factors ,virus diseases ,Infant ,Plasmodium falciparum ,Herpesviridae Infections ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,biology.organism_classification ,Epstein–Barr virus ,Virology ,Burkitt Lymphoma ,Kenya ,Lymphoma ,030104 developmental biology ,Infectious Diseases ,030220 oncology & carcinogenesis ,Child, Preschool ,Female ,business ,Burkitt's lymphoma ,Malaria - Abstract
Background Endemic Burkitt lymphoma (eBL) is associated with Epstein-Barr virus (EBV) and Plasmodium falciparum malaria coinfections. However, the role of Kaposi sarcoma-associated herpesvirus (KSHV), also endemic in Africa, has not been evaluated as a cofactor in eBL pathogenesis. Methods Multiplexed seroprofiles for EBV, malaria, and KSHV were generated for 266 eBL patients, 78 non-eBL cancers, and 202 healthy children. KSHV and EBV loads were quantified by PCR. Results KSHV seroprevalence did not differ by study group but was associated with age. Seropositivity, defined by K8.1/LANA or in combination with 5 other KSHV antigens (ORF59, ORF65, ORF61, ORF38, and K5) was associated with antimalarial antibody levels to AMA1 (odds ratio [OR], 2.41, P Conclusions Although KSHV-EBV dual infection does not increase eBL risk, EBV appears to suppress reactivation of KSHV while malaria exposure is associated with KSHV infection and/or reactivation. Both EBV and malaria should, therefore, be considered as potential effect modifiers for KSHV-associated cancers in sub-Saharan Africa.
- Published
- 2019
29. Integrative microRNA and mRNA deep-sequencing expression profiling in endemic Burkitt lymphoma
- Author
-
Yasin Kaymaz, Juliana A. Otieno, Kiprotich Chelimo, John M. Ong’echa, Ann M. Moormann, Jeffrey A. Bailey, and Cliff I. Oduor
- Subjects
0301 basic medicine ,Male ,Cancer Research ,mRNA ,Biology ,medicine.disease_cause ,Models, Biological ,lcsh:RC254-282 ,Deep sequencing ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,microRNA ,Genetics ,medicine ,Humans ,Epigenetics ,RNA, Messenger ,Child ,miRNA ,Oncogene ,Gene Expression Profiling ,Germinal center ,Computational Biology ,High-Throughput Nucleotide Sequencing ,RNA sequencing ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Molecular biology ,Burkitt Lymphoma ,Lymphomagenesis ,Gene expression profiling ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030104 developmental biology ,Cell Transformation, Neoplastic ,Oncology ,030220 oncology & carcinogenesis ,Child, Preschool ,Endemic Burkitt lymphoma ,Cancer research ,Female ,RNA Interference ,Carcinogenesis ,Research Article ,Signal Transduction - Abstract
Background Burkitt lymphoma (BL) is characterized by overexpression of the c-myc oncogene, which in the vast majority of cases is a consequence of an IGH/MYC translocation. While myc is the seminal event, BL is a complex amalgam of genetic and epigenetic changes causing dysregulation of both coding and non-coding transcripts. Emerging evidence suggest that abnormal modulation of mRNA transcription via miRNAs might be a significant factor in lymphomagenesis. However, the alterations in these miRNAs and their correlations to their putative mRNA targets have not been extensively studied relative to normal germinal center (GC) B cells. Methods Using more sensitive and specific transcriptome deep sequencing, we compared previously published small miRNA and long mRNA of a set of GC B cells and eBL tumors. MiRWalk2.0 was used to identify the validated target genes for the deregulated miRNAs, which would be important for understanding the regulatory networks associated with eBL development. Results We found 211 differentially expressed (DE) genes (79 upregulated and 132 downregulated) and 49 DE miRNAs (22 up-regulated and 27 down-regulated). Gene Set enrichment analysis identified the enrichment of a set of MYC regulated genes. Network propagation-based method and correlated miRNA-mRNA expression analysis identified dysregulated miRNAs, including miR-17~95 cluster members and their target genes, which have diverse oncogenic properties to be critical to eBL lymphomagenesis. Central to all these findings, we observed the downregulation of ATM and NLK genes, which represent important regulators in response to DNA damage in eBL tumor cells. These tumor suppressors were targeted by multiple upregulated miRNAs (miR-19b-3p, miR-26a-5p, miR-30b-5p, miR-92a-5p and miR-27b-3p) which could account for their aberrant expression in eBL. Conclusion Combined loss of p53 induction and function due to miRNA-mediated regulation of ATM and NLK, together with the upregulation of TFAP4, may be a central role for human miRNAs in eBL oncogenesis. This facilitates survival of eBL tumor cells with the IGH/MYC chromosomal translocation and promotes MYC-induced cell cycle progression, initiating eBL lymphomagenesis. This characterization of miRNA-mRNA interactions in eBL relative to GC B cells provides new insights on miRNA-mediated transcript regulation in eBL, which are potentially useful for new improved therapeutic strategies. Electronic supplementary material The online version of this article (10.1186/s12885-017-3711-9) contains supplementary material, which is available to authorized users.
- Published
- 2017
30. Comprehensive Transcriptome and Mutational Profiling of Endemic Burkitt Lymphoma Reveals EBV Type–Specific Differences
- Author
-
Juliana A. Otieno, Jeffrey A. Bailey, Hongbo Yu, Yasin Kaymaz, Ann M. Moormann, Cliff I. Oduor, and John M. Ong’echa
- Subjects
Male ,0301 basic medicine ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,Cancer Research ,Adolescent ,Endemic Diseases ,Genome, Viral ,Biology ,medicine.disease_cause ,Article ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Mutation Rate ,hemic and lymphatic diseases ,medicine ,Humans ,PTEN ,Gene Regulatory Networks ,Child ,Molecular Biology ,Epstein–Barr virus infection ,Gene ,Sequence Analysis, RNA ,Gene Expression Profiling ,medicine.disease ,Burkitt Lymphoma ,Kenya ,Pediatric cancer ,Lymphoma ,Gene expression profiling ,030104 developmental biology ,Oncology ,Child, Preschool ,030220 oncology & carcinogenesis ,Mutation ,Immunology ,Cancer research ,biology.protein ,Female ,Carcinogenesis - Abstract
Endemic Burkitt lymphoma (eBL) is the most common pediatric cancer in malaria-endemic equatorial Africa and nearly always contains Epstein–Barr virus (EBV), unlike sporadic Burkitt lymphoma (sBL) that occurs with a lower incidence in developed countries. Given these differences and the variable clinical presentation and outcomes, we sought to further understand pathogenesis by investigating transcriptomes using RNA sequencing (RNAseq) from multiple primary eBL tumors compared with sBL tumors. Within eBL tumors, minimal expression differences were found based on: anatomical presentation site, in-hospital survival rates, and EBV genome type, suggesting that eBL tumors are homogeneous without marked subtypes. The outstanding difference detected using surrogate variable analysis was the significantly decreased expression of key genes in the immunoproteasome complex (PSMB9/β1i, PSMB10/β2i, PSMB8/β5i, and PSME2/PA28β) in eBL tumors carrying type 2 EBV compared with type 1 EBV. Second, in comparison with previously published pediatric sBL specimens, the majority of the expression and pathway differences was related to the PTEN/PI3K/mTOR signaling pathway and was correlated most strongly with EBV status rather than geographic designation. Third, common mutations were observed significantly less frequently in eBL tumors harboring EBV type 1, with mutation frequencies similar between tumors with EBV type 2 and without EBV. In addition to the previously reported genes, a set of new genes mutated in BL, including TFAP4, MSH6, PRRC2C, BCL7A, FOXO1, PLCG2, PRKDC, RAD50, and RPRD2, were identified. Overall, these data establish that EBV, particularly EBV type 1, supports BL oncogenesis, alleviating the need for certain driver mutations in the human genome. Implications: Genomic and mutational analyses of Burkitt lymphoma tumors identify key differences based on viral content and clinical outcomes suggesting new avenues for the development of prognostic molecular biomarkers and therapeutic interventions. Mol Cancer Res; 15(5); 563–76. ©2017 AACR.
- Published
- 2017
31. Association between Fcγ receptor IIA, IIIA and IIIB genetic polymorphisms and susceptibility to severe malaria anemia in children in western Kenya
- Author
-
Samuel B. Anyona, Douglas J Perkins, Collins Ouma, Winnie A. Okeyo, Elly O. Munde, Tom Were, John M. Ong’echa, and Evans Raballah
- Subjects
0301 basic medicine ,Male ,Cellular immunity ,Genotype ,Holoendemic ,Parasitemia ,Biology ,GPI-Linked Proteins ,Immunoglobulin G ,Parasite Load ,lcsh:Infectious and parasitic diseases ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,parasitic diseases ,medicine ,Humans ,Genetic Predisposition to Disease ,lcsh:RC109-216 ,Malaria, Falciparum ,Malaria anemia ,Polymorphism, Genetic ,Haplotype ,Receptors, IgG ,Infant ,Plasmodium falciparum ,Anemia ,medicine.disease ,biology.organism_classification ,Virology ,Kenya ,FcγRs ,3. Good health ,Malaria ,030104 developmental biology ,Infectious Diseases ,Cross-Sectional Studies ,Haplotypes ,Susceptibility ,Child, Preschool ,Immunology ,biology.protein ,Female ,Antibody ,Polymorphisms ,Polymorphism, Restriction Fragment Length ,030215 immunology ,Research Article - Abstract
Background Naturally-acquired immunity to Plasmodium falciparum malaria develops after several episodes of infection. Fc gamma receptors (FcγRs) bind to immunoglobulin G (IgG) antibodies and mediate phagocytosis of opsonized microbes, thereby, linking humoral and cellular immunity. FcγR polymorphisms influence binding affinity to IgGs and consequently, can influence clinical malaria outcomes. Specifically, variations in FcγRIIA -131Arg/His, FcγRIIIA-176F/V and FcγRIIIB-NA1/NA2 modulate immune responses through altered binding preferences to IgGs and immune complexes. Differential binding, in turn, changes ability of immune cells to respond to infection through production of inflammatory mediators during P. falciparum infection. Methods We determined the association between haplotypes of FcγRIIA-131Arg/His, FcγRIIIA-176F/V and FcγRIIIB-NA1/NA2 variants and severe malarial anemia (SMA; hemoglobin
- Published
- 2017
32. Genetic variation in interleukin-7 is associated with a reduced erythropoietic response in Kenyan children infected with Plasmodium falciparum
- Author
-
Samuel B. Anyona, Evans Raballah, Prakasha Kempaiah, Elly O. Munde, Kiprotich Chelimo, Angela O. Achieng, John M. Ong’echa, Douglas J. Perkins, Lily E. Kisia, Collins Ouma, and Christophe G. Lambert
- Subjects
Male ,0301 basic medicine ,lcsh:Internal medicine ,Genotype ,lcsh:QH426-470 ,Plasmodium falciparum ,Pilot Projects ,Genome-wide association study ,Single-nucleotide polymorphism ,030105 genetics & heredity ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Genetic variation ,Genetics ,Humans ,Erythropoiesis ,Genetic Predisposition to Disease ,Malaria, Falciparum ,lcsh:RC31-1245 ,Genetics (clinical) ,biology ,Interleukin-7 ,Haplotype ,Genetic Variation ,Infant ,Anemia ,SMA ,biology.organism_classification ,Kenya ,3. Good health ,lcsh:Genetics ,Severe malarial anemia ,030104 developmental biology ,Haplotypes ,Case-Control Studies ,Immunology ,IL7 variation ,Inefficient erythropoiesis ,Female ,Research Article ,Genome-Wide Association Study - Abstract
Background Severe malarial anemia (SMA) is a leading cause of malaria-related morbidity and mortality in children. The genetic factors that influence development of SMA and inefficient erythropoiesis, a central pathogenic feature of SMA, are only partially understood. Methods We performed a pilot Genome-wide Association Study (GWAS) on children with Plasmodium falciparum. The GWAS was performed using the Illumina® Infinium® HD Super Assay in conjunction with Illumina’s® Human Omni2.5-8v1 BeadChip (with > 2.45 M markers). Data were analyzed using single SNP logistic regression analysis with an additive model of inheritance controlling for covariates. Results from our pilot global genomics study identified that variation in interleukin (IL)-7 was associated with enhanced risk of SMA. To validate this finding, we investigated the relationship between genotypes and/or haplotypes of two single nucleotide polymorphisms (SNPs) in IL7 [72194 T/C and − 2440 A/G] and susceptibility to both SMA and inefficient erythropoiesis [i.e., reticulocyte production index (RPI) TA > CG; P
- Published
- 2019
33. Cyclooxygenase-2 haplotypes influence the longitudinal risk of malaria and severe malarial anemia in Kenyan children from a holoendemic transmission region
- Author
-
Benjamin H. McMahon, Paul W. Fenimore, Evans Raballah, Nicolas W. Hengartner, Collins Ouma, Samuel B. Anyona, Christophe G. Lambert, John M. Ong’echa, Douglas J. Perkins, Nick Lauve, and Qiuying Cheng
- Subjects
0301 basic medicine ,Male ,Risk ,medicine.medical_specialty ,Genotype ,Holoendemic ,030105 genetics & heredity ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,Polymorphism (computer science) ,Internal medicine ,parasitic diseases ,Genetics ,medicine ,SNP ,Humans ,Genetic Predisposition to Disease ,Longitudinal Studies ,Malaria, Falciparum ,Child ,Promoter Regions, Genetic ,Genetics (clinical) ,biology ,business.industry ,Haplotype ,Infant ,Plasmodium falciparum ,Anemia ,biology.organism_classification ,medicine.disease ,SMA ,Kenya ,Malaria ,030104 developmental biology ,Haplotypes ,Cyclooxygenase 2 ,Child, Preschool ,Female ,business - Abstract
Cyclooxygenase-2 [(COX-2) or prostaglandin endoperoxide H2 synthase-2 (PTGS-2)] induces the production of prostaglandins as part of the host-immune response to infections. Although a number of studies have demonstrated the effects of COX-2 promoter variants on autoimmune and inflammatory diseases, their role in malaria remains undefined. As such, we investigated the relationship between four COX-2 promoter variants (COX-2 −512 C > T, −608 T > C, −765 G > C, and −1195 A > G) and susceptibility to malaria and severe malarial anemia (SMA) upon enrollment and longitudinally over a 36-month follow-up period. All-cause mortality was also explored. The investigation was carried out in children (n = 1081, age; 2–70 months) residing in a holoendemic Plasmodium falciparum transmission region of western Kenya. At enrollment, genotypes/haplotypes (controlling for anemia-promoting covariates) did not reveal any strong effects on susceptibility to either malaria or SMA. Longitudinal analyses showed decreased malaria episodes in children who inherited the −608 CC mutant allele (RR = 0.746, P = 1.811 × 10(−4)) and −512C/−608T/−765G/−1195G (CTGG) haplotype (RR = 0.856, P = 0.011), and increased risk in TTCA haplotype carriers (RR = 1.115, P = 0.026). Over the follow-up period, inheritance of the rare TTCG haplotype was associated with enhanced susceptibility to both malaria (RR = 1.608, P = 0.016) and SMA (RR = 5.714, P = 0.004), while carriage of the rare TTGG haplotype increased the risk of malaria (RR = 1.755, P = 0.007), SMA (RR = 8.706, P = 3.97 × 10(−4)), and all-cause mortality (HR = 110.000, P = 0.001). Collectively, these results show that SNP variations in the COX-2 promoter, and their inherited combinations, are associated with the longitudinal risk of malaria, SMA, and all-cause mortality among children living in a high transmission area for P. falciparum.
- Published
- 2019
34. Factors influencing survival among Kenyan children diagnosed with endemic Burkitt lymphoma between 2003 and 2011: A historical cohort study
- Author
-
Juliana A. Otieno, Jeffrey A. Bailey, John M. Ong’echa, Terry A. Vik, Andrew Schroeder, Joslyn Foley, Jodi L. Skiles, Jennifer Lemberger, Alan G. Rosmarin, Ann M. Moormann, Geoffrey Buckle, Scot C. Remick, Mara M. Epstein, John M. Vulule, and Louise Maranda
- Subjects
0301 basic medicine ,Cancer Research ,Chemotherapy ,medicine.medical_specialty ,Cyclophosphamide ,business.industry ,Anemia ,medicine.medical_treatment ,Hazard ratio ,medicine.disease ,Pediatric cancer ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Internal medicine ,Immunology ,Medicine ,business ,Prospective cohort study ,Survival rate ,medicine.drug ,Cohort study - Abstract
Discovering how to improve survival and establishing clinical reference points for children diagnosed with endemic Burkitt lymphoma (eBL) in resource-constrained settings has recaptured international attention. Using multivariate analyses, we evaluated 428 children with eBL in Kenya for age, gender, tumor stage, nutritional status, hemoglobin, lactate dehydrogenase (LDH), Epstein-Barr virus (EBV) and Plasmodium falciparum prior to induction of chemotherapy (cyclophosphamide, vincristine, methotrexate and doxorubicin) to identify predictive and prognostic biomarkers of survival. During this 10 year prospective study period, 22% died in-hospital and 78% completed six-courses of chemotherapy. Of those, 16% relapsed or died later; 31% achieved event-free-survival; and 31% were lost to follow-up; the overall one-year survival was 45%. After adjusting for covariates, low hemoglobin ( 400 mU/ml) were associated with increased risk of death (adjusted Hazard Ratio (aHR) = 1.57 [0.97-2.41]) and aHR = 1.84, [0.91-3.69], respectively). Anemic children with malaria were 3.55 times more likely to die [1.10-11.44] compared to patients without anemia or malarial infection. EBV load did not differ by tumor stage nor was it associated with survival. System-level factors can also contribute to poor outcomes. Children were more likely to die when inadvertently overdosed by more than 115% of the correct dose of cyclophosphamide (a HR = 1.43 [0.84-2.43]) or doxorubicin (a HR = 1.25, [0.66-2.35]), compared with those receiving accurate doses of the respective agent in this setting. This study codifies risk factors associated with poor outcomes for eBL patients in Africa and provides a benchmark by which to assess improvements in survival for new chemotherapeutic approaches.
- Published
- 2016
35. Reduced Hsp70 and Glutamine in Pediatric Severe Malaria Anemia: Role of hemozoin in Suppressing Hsp70 and NF-κB Activation
- Author
-
Evans Raballah, Prakasha Kempaiah, Zachary Karim, Pope L. Moseley, Douglas J. Perkins, Karol Dokladny, and John M. Ong’echa
- Subjects
0301 basic medicine ,biology ,Hemozoin ,lcsh:RM1-950 ,Plasmodium falciparum ,SMA ,biology.organism_classification ,Molecular medicine ,3. Good health ,HSPA1A ,Proinflammatory cytokine ,lcsh:Biochemistry ,Glutamine ,Pathogenesis ,03 medical and health sciences ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,Immunology ,Genetics ,Molecular Medicine ,lcsh:QD415-436 ,Molecular Biology ,Genetics (clinical) ,Research Article - Abstract
Severe malarial anemia (SMA; hemoglobin [Hb]
- Published
- 2016
36. Abstract A18: Characterization of checkpoint inhibitors in the tumor microenvironment (TME) and peripheral blood in endemic Burkitt Lymphoma
- Author
-
Patrick W Marsh, Priya Saikumar-Lakshmi, Catherine Forconi, John M. Ong’echa, Jeffrey A. Bailey, Cliff I. Oduor, and Ann M. Moormann
- Subjects
Cancer Research ,Tumor microenvironment ,LAG3 ,business.industry ,medicine.medical_treatment ,Immunotherapy ,medicine.disease ,Pediatric cancer ,Lymphoma ,Oncology ,TIGIT ,Cancer research ,Medicine ,Cytotoxic T cell ,business ,CD8 - Abstract
Introduction: The tumor microenvironment and the interaction between immune checkpoint inhibitors (ICIs) and tumor cells are essential to understand for designing future immunotherapy strategies. In this study, we aim to characterize the tumor microenvironment (TME) in children diagnosed with endemic Burkitt lymphoma (eBL), the most common pediatric cancer in Africa. A history of chronic malaria (Plasmodium falciparum) and Epstein-Barr virus (EBV) coinfections are both risk factors in the etiology of eBL. Methods: Using multicolor flow cytometry and single-cell RNA sequencing, we analyzed the expression of immune checkpoint inhibitors in T cells from the tumor microenvironment and from peripheral blood mononuclear cells (PBMC) of eBL patients, along with age-matched controls with different malaria exposure. Additionally, CD8 T-cell infiltration was confirmed by immunohistochemistry. Results: PD-1+ CD4 T cells from eBL PBMCs were increased in number compared to healthy controls from the malaria-endemic area (p=0.03). Both CD4 and CD8 T cells from eBL PBMCs reveal higher frequency of TIGIT expressers compared to healthy controls (non-malaria endemic) (p=0.002, p=0.007 respectively). PD1+ TIGIT+ IFNG- memory CD4 T cells phenotype from eBL PBMCs was increased upon short stimulation with PMA/ionomycin, as well as “naive-like” CD95+ PD1high TIGIT+ CTLA4+ IFNG+ CD8T cells. Tumor samples from 4 eBL patient were used on single-cell analysis; we observed activated T-cells profile that highly upregulated TIGIT within the tumor microenvironment. We also noticed relatively low expression of other ICIs such as PD1, TIM3, LAG3, and CTLA4. Base on all these data, we calculated an exhaustion score that was higher than the cytotoxicity score in our eBL-derived tumor-infiltrating lymphocytes (TILs). In addition, we use immunohistochemistry staining to confirm CD8 T-cell infiltration and ICI expression in eBL tumor fine needle aspirates. Our future directions will employ TIGIT blockade inhibitor studies of CD8 T cells, in order to increase expansion and function of CD8 TILs. Our results will help support future development of ICI therapies in endemic Burkitt lymphoma. Citation Format: Priya Saikumar-Lakshmi, Cliff Oduor, Catherine Forconi, Patrick Marsh, John Michael Ong’echa, Jeffrey Bailey, Ann Moormann. Characterization of checkpoint inhibitors in the tumor microenvironment (TME) and peripheral blood in endemic Burkitt Lymphoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A18.
- Published
- 2020
37. Abstract A60: Transcriptional profile of CD56negCD16pos Natural Killer cells within endemic Burkitt lymphoma
- Author
-
Cliff I. Oduor, Catherine Forconi, John M. Ong’echa, Jeffrey A. Bailey, and Ann M. Moormann
- Subjects
Cancer Research ,medicine.diagnostic_test ,Cancer ,Biology ,medicine.disease ,Pediatric cancer ,Virus ,Lymphoma ,Flow cytometry ,Oncology ,Perforin ,Immunology ,medicine ,biology.protein ,Interleukin 18 ,KIR3DL1 - Abstract
Endemic Burkitt lymphoma (eBL), the most common pediatric cancer in equatorial Africa, has long been associated with two etiologic agents: Epstein-Barr virus (EBV) and Plasmodium falciparum malaria. On the other hand, Natural Killer (NK) cells are essential in the clearance of infected cells as well as play a critical role in tumor immunosurveillance. Despite chronic viral infections as HIV, HCV, which have been found to promote the expansion of a CD56 (negative) NK cell subset with impaired effector function, previous cancer studies have been limited to investigations of CD56dimCD16pos NK cells. We previously published that eBL children had significantly more CD56negCD16pos NK cells compared to age-matched healthy children from a low and high malaria transmission area. Here, we characterized this CD56negCD16pos NK subset using histology staining, multicolor flow cytometry, and RNA-sequencing. We found CD56negCD16pos NK cells to be morphologically similar to CD56dimCD16pos NK cells but had higher expression of FCGR3B (CD16b) (p=0.000008) and MPEG1 (Perforin 2) (p=0.0000007), and lower expression of KLRF1 (NKp80), IL18RAP and IL18R1 (IL18 receptor) (p=0.000003, p=0.000003 and p=0.00005, respectively). Phenotypically, CD56negCD16pos NK cells share characteristics of adaptive NK cells; however, they differ from “memory-like” NK cells, with consistent expression of NKG2C/CD57, lower expression of NKp46 and CD160, and higher expression of KIR3DL1 compared to CD56dimCD16pos NK cells. Finally, higher plasma levels of IL-12p70 and IL-2 (known to help NK cell activation and proliferation) and IL-6 and MIP1a were found in healthy compared to eBL children. Together, these findings suggest that the expansion of CD56negCD16pos NK cells could help explain diminished tumor immunosurveillance and might be a mechanism by which EBV-infected cells evades NK-cell mediated immunity. Citation Format: Catherine S. Forconi, Cliff Oduor, John M. Ong’echa, Jeff Bailey, Ann M. Moormann. Transcriptional profile of CD56negCD16pos Natural Killer cells within endemic Burkitt lymphoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A60.
- Published
- 2020
38. Poorly cytotoxic terminally differentiated CD56negCD16pos NK cells accumulate in Kenyan children with Burkitt lymphomas
- Author
-
Ann M. Moormann, Juliana A. Otieno, Pryia Saikumar-Lakshmi, Catherine Forconi, Galit Alter, Joslyn Foley, Christina E. Nixon, Christian Münz, John M. Ong’echa, and Cormac Cosgrove
- Subjects
0301 basic medicine ,Cellular differentiation ,CD16 ,Virus ,03 medical and health sciences ,parasitic diseases ,medicine ,Cytotoxic T cell ,Humans ,Child ,biology ,business.industry ,Plasmodium falciparum ,Cell Differentiation ,Hematology ,medicine.disease ,biology.organism_classification ,Burkitt Lymphoma ,Kenya ,CD56 Antigen ,Lymphoma ,Immunosurveillance ,Killer Cells, Natural ,030104 developmental biology ,Child, Preschool ,Immunology ,Global Advances ,business ,Burkitt's lymphoma - Abstract
Natural killer (NK) cells are critical for restricting viral infections and mediating tumor immunosurveillance. Epstein-Barr virus (EBV) and Plasmodium falciparum malaria are known risk factors for endemic Burkitt lymphoma (eBL), the most common childhood cancer in equatorial Africa. To date, the composition and function of NK cells have not been evaluated in eBL etiology or pathogenesis. Therefore, using multiparameter flow cytometry and in vitro killing assays, we compared NK cells from healthy children and children diagnosed with eBL in Kenya. We defined 5 subsets based on CD56 and CD16 expression, including CD56negCD16pos We found that licensed and terminally differentiated perforin-expressing CD56negCD16pos NK cells accumulated in eBL children, particularly in those with high EBV loads (45.2%) compared with healthy children without (6.07%) or with (13.5%) malaria exposure (P = .0007 and .002, respectively). This progressive shift in NK cell proportions was concomitant with fewer CD56dimCD16pos cells. Despite high MIP-1β expression, CD56negCD16pos NK cells had diminished cytotoxicity, with lower expression of activation markers NKp46, NKp30, and CD160 and the absence of TNF-α. Of note, the accumulation of poorly cytotoxic CD56negCD16pos NK cells resolved in long-term eBL survivors. Our study demonstrates impaired NK cell-mediated immunosurveillance in eBL patients but with the potential to restore a protective NK cell repertoire after cancer treatment. Characterizing NK cell dysfunction during coinfections with malaria and EBV has important implications for designing immunotherapies to improve outcomes for children diagnosed with eBL.
- Published
- 2018
39. High pathogen burden in childhood promotes the development of unconventional innate-like CD8+ T cells
- Author
-
Jeffrey A. Bailey, Yasin Kaymaz, Yves T. Falanga, Leslie J. Berg, Ann M. Moormann, Michela Frascoli, Catherine Forconi, and John M. Ong’echa
- Subjects
0301 basic medicine ,medicine.medical_treatment ,T cell ,Innate lymphoid cell ,General Medicine ,Biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,Cytokine ,medicine.anatomical_structure ,Granzyme ,Immunology ,biology.protein ,medicine ,Cytotoxic T cell ,Tumor necrosis factor alpha ,CD8 ,Research Article ,030215 immunology - Abstract
Cellular and humoral constituents of the immune system differ significantly between children and adults, yet very little is known about the impact of early-life pathogen exposure on this immunologic transition. We examined CD4+ and CD8+ T cell subsets defined by CCR7 and CD45RA expression in two longitudinal pediatric cohorts experiencing divergent levels of pathogen burden. Using multiparameter flow cytometry, along with serological, cytokine, and transcriptomic data, we show that cumulative pathogen burden promotes the development of atypical CD8dim T cells with an innate-like profile (Granzyme Bhi, IFNγlow, TNFαlow, PLFZhi, ID2hi, IKZF2hi) in contrast to age-matched children residing in a low pathogen–exposure area who display a more conventional CD8bright profile (IFNγ+, TNFα+, CCL4+). Furthermore, these unconventional T cells had stunted proliferation, distinct transcriptional programs, and impaired T cell receptor signaling and were enriched in hallmark TNFα, NF-κB, and IL-6 gene signaling pathways, reminiscent of NK cells and type-1 innate lymphoid cells. Our findings suggest that these unconventional CD8dim T cells arise in a very particular immunological context and may provide a deeper understanding of the heterogeneity in human immune responses.
- Published
- 2017
40. Antimalarials: Molecular Drug Targets and Mechanism of Action
- Author
-
Angela O. Achieng, Manmeet Rawat, Bernhards Ogutu, John M. Ong’echa, Bernard Guyah, Douglas J. Perkins, and Prakasha Kempaiah
- Subjects
0301 basic medicine ,Drug ,Plasmodium ,media_common.quotation_subject ,Drug Resistance ,General Medicine ,Drug resistance ,Disease ,Pharmacology ,Biology ,medicine.disease ,Bioinformatics ,Antimalarials ,03 medical and health sciences ,030104 developmental biology ,Mechanism of action ,parasitic diseases ,Drug Discovery ,medicine ,Animals ,Humans ,medicine.symptom ,Malaria control ,Malaria ,media_common - Abstract
Background: Despite a reduction in the global burden of malaria, the disease remains responsible for 214 million cases and 438,000 deaths annually with 88% of the mortality occurring in sub-Saharan Africa. Malaria control largely depends on effective chemotherapy. However, the historic and current emergence and spread of multi-drug resistant parasite strains provides significant challenges to malaria control and consequently, reduction of malaria-associated morbidity and mortality. Combating parasite drug resistance requires pharmacological compounds that target both known and novel metabolic pathways that are crucial for parasite survival. In addition, the identification of novel therapeutic agents that target distinct molecular pathways, apart from those of the conventional antimalarials, offers an approach for minimizing drug resistance. Conclusion: This review summarizes current anti-malarial approaches and strategies, therapeutic efficacy for conventional and non-conventional antimalarials, parasitic targets, and the mechanisms responsible for the development of drug resistance.
- Published
- 2017
41. Haplotype of non-synonymous mutations within IL-23R is associated with susceptibility to severe malaria anemia in a P. falciparum holoendemic transmission area of Kenya
- Author
-
Evans Raballah, Winnie A. Okeyo, John M. Ong’echa, Douglas J Perkins, Elly O. Munde, and Collins Ouma
- Subjects
Male ,Il-23R ,0301 basic medicine ,Genotype ,Anemia ,Holoendemic ,Genotypes ,030231 tropical medicine ,Exon ,Biology ,Polymorphism, Single Nucleotide ,lcsh:Infectious and parasitic diseases ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Genetic predisposition ,Humans ,Genetic Predisposition to Disease ,lcsh:RC109-216 ,Malaria, Falciparum ,Haplotype ,Infant ,Receptors, Interleukin ,medicine.disease ,SMA ,Kenya ,3. Good health ,030104 developmental biology ,Infectious Diseases ,Haplotypes ,Child, Preschool ,Mutation ,Immunology ,Female ,Malaria ,Research Article - Abstract
Background Improved understanding of the molecular mechanisms involved in pediatric severe malarial anemia (SMA) pathogenesis is a crucial step in the design of novel therapeutics. Identification of host genetic susceptibility factors in immune regulatory genes offers an important tool for deciphering malaria pathogenesis. The IL-23/IL-17 immune pathway is important for both immunity and erythropoiesis via its effects through IL-23 receptors (IL-23R). However, the impact of IL-23R variants on SMA has not been fully elucidated. Methods Since variation within the coding region of IL-23R may influence the pathogenesis of SMA, the association between IL-23R rs1884444 (G/T), rs7530511 (C/T), and SMA (Hb
- Published
- 2017
42. Human and Epstein-Barr Virus miRNA Profiling as Predictive Biomarkers for Endemic Burkitt Lymphoma
- Author
-
Juliana A. Otieno, Cliff I. Oduor, Yasin Kaymaz, John M. Ong’echa, Jeffrey A. Bailey, Mercedeh Movassagh, Kiprotich Chelimo, and Ann M. Moormann
- Subjects
0301 basic medicine ,Microbiology (medical) ,microRNA expression ,Biology ,medicine.disease_cause ,Microbiology ,Deep sequencing ,03 medical and health sciences ,0302 clinical medicine ,EBV ,microRNA ,medicine ,endemic Burkitt lymphoma ,B-cell lymphoma ,Gene ,Original Research ,RNAseq ,medicine.disease ,Epstein–Barr virus ,3. Good health ,Lymphoma ,Biomarker (cell) ,030104 developmental biology ,030220 oncology & carcinogenesis ,Immunology ,Carcinogenesis ,miR-10a-5p - Abstract
Endemic Burkitt lymphoma (eBL) is an aggressive B cell lymphoma and is associated with Epstein-Barr virus (EBV) and Plasmodium falciparum malaria co-infections. Central to BL oncogenesis is the over-expression of the MYC proto-oncogene which is caused by a translocation of an Ig enhancer in approximation to the myc gene. While whole genome/transcriptome sequencing methods have been used to define driver mutations and transcriptional dysregulation, microRNA (miRNA) dysregulation and differential expression has yet to be fully characterized. We hypothesized that both human and EBV miRNAs contribute to eBL clinical presentation, disease progression, and poor outcomes. Using sensitive and precise deep sequencing, we identified miRNAs from 17 Kenyan eBL patient tumor samples and delineated the complement of both host and EBV miRNAs. One human miRNA, hsa-miR-10a-5p was found to be differentially expressed (DE), being down-regulated in jaw tumors relative to abdominal and in non-survivors compared to survivors. We also examined EBV miRNAs, which made up 2.7% of the miRNA composition in the eBL samples. However, we did not find any significant associations regarding initial patient outcome or anatomical presentation. Gene ontology analysis and pathway enrichment of previously validated targets of miR-10a-5p suggest that it can promote tumor cell survival as well as aid in evasion of apoptosis. To examine miR-10a-5p regulatory effect on gene expression in eBL, we performed a pairwise correlation coefficient analysis on the expression levels of all its validated targets. We found a significant enrichment of correlated target genes consistent with miR-10a-5p impacting expression. The functions of genes and their correlation fit with multiple target genes impacting tumor resilience. The observed downregulation of miR-10a and associated genes suggests a role for miRNA in eBL patient outcomes and has potential as a predictive biomarker that warrants further investigation.
- Published
- 2017
43. Detection of lipopolysaccharides in serum using a waveguide-based optical biosensor
- Author
-
Norman A. Doggett, John M. Ong’echa, Loreen R. Stromberg, Prakasha Kempaiah, Zachary Karim, Harshini Mukundan, Aaron S. Anderson, Douglas J Perkins, Benjamin H. McMahon, Priya Dighe, and Aneesa Noormohamed
- Subjects
0301 basic medicine ,Medical diagnostic ,Membrane insertion ,business.industry ,Nanotechnology ,02 engineering and technology ,Optical biosensor ,021001 nanoscience & nanotechnology ,03 medical and health sciences ,030104 developmental biology ,Immunology ,Medicine ,0210 nano-technology ,business ,Pathogen ,Point of care - Abstract
Direct ultra-sensitive detection of pathogen biomarkers in blood could provide a universal strategy for diagnosis of bacterial infections, which remain a leading cause of morbidity and mortality in many areas of the world. Many factors complicate diagnosis, including the presence of multiple co-infections in a given patient, and lack of infrastructure in rural settings. In some pediatric patients, such as those in areas with poor resources, an additional challenge exists with low sample volumes due to age and other health factors such as anemia and dehydration. Our team is working on developing novel diagnostic assays, with a waveguide-based biosensor platform, to rapidly and specifically identify pathogen biomarkers from small samples of serum or plasma, allowing for the timely and sensitive diagnosis of infection at the point of care. In addition to the platform, we have developed novel membrane insertion and lipoprotein capture assay methods, to capture lipidated pathogen biomarkers in aqueous blood, by virtue of their interactions with host lipoprotein carriers. Herein, we demonstrate our efforts to adapt the lipoprotein capture assay for the detection of small concentrations of pathogen-secreted lipopolysaccharides in aqueous blood, with the ultimate aim of diagnosing Gram-negative infections effectively.
- Published
- 2017
44. CD4 T-cell expression of IFN-γ and IL-17 in pediatric malarial anemia
- Author
-
Michael F. Otieno, Evans Raballah, George O. Orinda, Prakasha Kempaiah, Zachary Karim, John M. Ong’echa, and Douglas J Perkins
- Subjects
CD4-Positive T-Lymphocytes ,Male ,0301 basic medicine ,Physiology ,Quantitative Parasitology ,medicine.medical_treatment ,lcsh:Medicine ,Pathogenesis ,Parasitemia ,Pathology and Laboratory Medicine ,Hemoglobins ,White Blood Cells ,0302 clinical medicine ,Animal Cells ,Immune Physiology ,Medicine and Health Sciences ,Lymphocytes ,Malaria, Falciparum ,lcsh:Science ,Protozoans ,Innate Immune System ,Multidisciplinary ,biology ,T Cells ,Chemistry ,Interleukin-17 ,Malarial Parasites ,Anemia ,Hematology ,SMA ,3. Good health ,Cytokine ,Child, Preschool ,Cytokines ,Female ,Interleukin 17 ,Inflammation Mediators ,Cellular Types ,Antibody ,Research Article ,medicine.medical_specialty ,Immune Cells ,Holoendemic ,Immunology ,030231 tropical medicine ,Interferon-gamma ,03 medical and health sciences ,Internal medicine ,Parasitic Diseases ,medicine ,Humans ,Blood Cells ,lcsh:R ,Organisms ,Infant ,Biology and Life Sciences ,Plasmodium falciparum ,Cell Biology ,Molecular Development ,Tropical Diseases ,medicine.disease ,biology.organism_classification ,Parasitic Protozoans ,Malaria ,030104 developmental biology ,Endocrinology ,Immune System ,biology.protein ,Parasitology ,lcsh:Q ,Developmental Biology - Abstract
In Plasmodium falciparum holoendemic transmission regions of western Kenya, life-threatening pediatric malaria manifests primarily as severe malarial anemia (SMA, Hb≤6.0 g/dL with any density parasitemia). To determine the role that CD4+ T-cell-driven inflammatory responses have in the pathogenesis of SMA, peripheral CD4+ T-cell populations and their intracellular production of pro-inflammatory cytokines (IFN-γ and IL-17) were characterized in children aged 12–36 months of age stratified into two groups: non-severe malarial anemia (non-SMA, Hb≥6.0 g/dL, n = 50) and SMA (n = 39). In addition, circulating IFN-γ and IL-17 were measured as part of a Cytokine 25-plex Antibody Bead Kit, Human (BioSource™ International). Children with SMA had higher overall proportions of circulating lymphocytes (P = 0.003) and elevated proportions of lymphocytes expressing IFN-γ (P = 0.014) and comparable IL-17 (P = 0.101). In addition, SMA was characterized by decreased memory-like T-cells (CD4+CD45RA-) expressing IL-17 (P = 0.009) and lower mean fluorescence intensity in memory-like CD4+ T-cells for both IFN-γ (P = 0.063) and IL-17 (P = 0.006). Circulating concentrations of IFN-γ were higher in children with SMA (P = 0.009), while IL-17 levels were comparable between the groups (P = 0.164). Furthermore, circulating levels of IFN-γ were negatively correlated with IL-17 levels in both groups of children (SMA: r = -0.610, P = 0.007; and non-SMA: r = -0.516, P = 0.001), while production of both cytokines by lymphocytes were positively correlated (SMA: r = 0.349, P = 0.037; and non-SMA: r = 0.475, P = 0.001). In addition, this correlation was only maintained by the memory-like CD4+ T cells (r = 0.365, P = 0.002) but not the naïve-like CD4+ T cells. However, circulating levels of IFN-γ were only associated with naïve-like CD4+ T cells producing IFN-γ (r = 0.547, P = 0.028), while circulating levels of IL-17 were not associated with any of the cell populations. Taken together, these results suggest that enhanced severity of malarial anemia is associated with higher overall levels of circulating lymphocytes, enhanced intracellular production of IFN-γ by peripheral lymphocytes and high circulating IFN-γ levels. In addition, the observed inverse relationship between the circulating levels of IFN-γ and IL-17 together with the reduction in the levels of memory-like CD4+ T cells expressing IL-17 in children with SMA may suggest possible relocation of these cells in the deeper tissues for their pathological effect.
- Published
- 2017
45. Regulatory T Cells in Endemic Burkitt Lymphoma Patients Are Associated with Poor Outcomes: A Prospective, Longitudinal Study
- Author
-
Juliana A. Otieno, John M. Vulule, Ann M. Moormann, John M. Ong’echa, Christian Münz, V. Ann Stewart, Christina E. Nixon, Emily Parsons, and University of Zurich
- Subjects
0301 basic medicine ,Herpesvirus 4, Human ,Physiology ,Programmed Cell Death 1 Receptor ,Protozoan Proteins ,lcsh:Medicine ,CD8-Positive T-Lymphocytes ,10263 Institute of Experimental Immunology ,Parasitemia ,T-Lymphocytes, Regulatory ,0302 clinical medicine ,Spectrum Analysis Techniques ,Cellular types ,Medicine ,IL-2 receptor ,Longitudinal Studies ,Prospective Studies ,Malaria, Falciparum ,Prospective cohort study ,lcsh:Science ,Child ,Immunologic Surveillance ,Pathology and laboratory medicine ,Cells, Cultured ,Multidisciplinary ,Immune cells ,FOXP3 ,Regulatory T cells ,Hematology ,Medical microbiology ,Viral Load ,Flow Cytometry ,Burkitt Lymphoma ,3. Good health ,Body Fluids ,Interleukin-10 ,medicine.anatomical_structure ,Infectious Diseases ,Blood ,Spectrophotometry ,030220 oncology & carcinogenesis ,Child, Preschool ,Viruses ,White blood cells ,Cytophotometry ,Pathogens ,Anatomy ,Research Article ,Cell biology ,Blood cells ,Herpesviruses ,Infectious Disease Control ,Adolescent ,T cell ,Immunology ,T cells ,610 Medicine & health ,Cytotoxic T cells ,Antigens, Protozoan ,1100 General Agricultural and Biological Sciences ,Research and Analysis Methods ,Microbiology ,03 medical and health sciences ,Antigen ,1300 General Biochemistry, Genetics and Molecular Biology ,Parasitic Diseases ,Epstein-Barr virus ,Humans ,Medicine and health sciences ,1000 Multidisciplinary ,Biology and life sciences ,business.industry ,lcsh:R ,Organisms ,Viral pathogens ,medicine.disease ,Tropical Diseases ,Pediatric cancer ,Kenya ,Lymphoma ,Malaria ,Microbial pathogens ,CD4 Lymphocyte Count ,030104 developmental biology ,Animal cells ,Epstein-Barr Virus Nuclear Antigens ,570 Life sciences ,biology ,lcsh:Q ,business ,DNA viruses ,CD8 ,Biomarkers - Abstract
Deficiencies in Epstein-Barr virus (EBV)-specific T cell immunosurveillance appear to precede the development of endemic Burkitt lymphoma (eBL), a malaria-associated pediatric cancer common in sub-Saharan Africa. However, T cell contributions to eBL disease progression and survival have not been characterized. Our objective was to investigate regulatory and inflammatory T cell responses in eBL patients associated with clinical outcomes. By multi-parameter flow cytometry, we examined peripheral blood mononuclear cells from 38 eBL patients enrolled in a prospective cohort study in Kisumu, Kenya from 2008-2010, and 14 healthy age-matched Kenyan controls. Children diagnosed with eBL were prospectively followed and outcomes categorized as 2-year event-free survivors, cases of relapses, or those who died. At the time of diagnosis, eBL children with higher CD25+Foxp3+ regulatory T (Treg) cell frequencies were less likely to survive than patients with lower Treg frequencies (p = 0·0194). Non-survivors also had higher absolute counts of CD45RA+Foxp3lo naive and CD45RA-Foxp3hi effector Treg subsets compared to survivors and healthy controls. Once patients went into clinical remission, Treg frequencies remained low in event-free survivors. Patients who relapsed, however, showed elevated Treg frequencies months prior to their adverse event. Neither concurrent peripheral blood EBV load nor malaria infection could explain higher Treg cell frequencies. CD8+ T cell PD-1 expression was elevated in all eBL patients at time of diagnosis, but relapse patients tended to have persistently high PD-1 expression compared to long-term survivors. Non-survivors produced more CD4+ T-cell IL-10 in response to both Epstein-Barr Nuclear Antigen-1 (EBNA-1) (p = 0·026) and the malaria antigen Plasmodium falciparum Schizont Egress Antigen-1 (p = 0·0158) compared to survivors, and were concurrently deficient in (EBNA-1)-specific CD8+ T-cell derived IFN-γ production (p = 0·002). In addition, we identified the presence of Foxp3-IL10+ regulatory Type 1 cells responding to EBNA-1 in contrast to the malaria antigen tested. These novel findings suggest that poor outcomes in eBL patients are associated with a predominantly immuno-regulatory environment. Therefore, Treg frequencies could be a predictive biomarker of disease progression and manipulation of Treg activity has potential as a therapeutic target to improve eBL survival.
- Published
- 2016
46. Comparison of HPV detection in HIV-infected and HIV-uninfected Kenyan women with or without cervical dysplasia
- Author
-
Patrick J. Loehrer, Tao Liu, Darron R. Brown, Stephen Kiptoo, Titus Maina, Philip Tonui, Aaron Ermel, YeungChing Wong, Yan Tong, Kapten Muthoka, Joseph W. Hogan, Elkanah Omenge, John M. Ong’echa, Peter Itsura, Susan Cu-Uvin, and Ann Moormann
- Subjects
Cervical cancer ,Cancer Research ,Kenya ,business.industry ,Human immunodeficiency virus (HIV) ,virus diseases ,Hpv detection ,Malignancy ,medicine.disease ,medicine.disease_cause ,Virology ,Oncology ,Dysplasia ,Hiv infected ,medicine ,Human papillomavirus ,business - Abstract
e17015 Background: Cervical cancer, a malignancy caused by human papillomavirus (HPV) infection, is the most common malignancy in women living in sub-Saharan African countries including Kenya. HIV co-infection accelerates the natural course of cervical cancer. To determine the specific HPV type distribution in HIV-infected women compared to HIV-uninfected women, with and without evidence of cervical dysplasia. Methods: Demographic information, behavioral data, and a cervical swab were collected from women 18 and 45 years of age, HIV-infected or HIV-uninfected, who presented for cervical cancer screening at Moi Referral and Teaching Hospital in Eldoret, Kenya. Women were triaged based on the presence or absence of cervical dysplasia. HPV testing was performed using the Roche Linear Array Assay. Results were compared between women with or without HIV co-infection and between those with or without cervical dysplasia, using Chi-square tests or Fisher’s exact tests. Results: 223 women had normal VIAs. All had HPV testing, 221 had valid results: 115 HIV-infected women (mean age 37 years) and 106 HIV-uninfected (mean age 33 years). 175 women had abnormal VIAs. 143 women had HPV testing performed, 140 had valid results: 70 HIV-infected women (mean age 38.5 years) and 70 HIV-uninfected (mean age 31.3 years). Greater than 90% of all HIV-infected women in both projects were receiving anti-retroviral therapy at enrollment. HPV of any type was detected in 48% of all women with normal VIA vs. 61% of women with abnormal VIA (P = 0.018). High risk (HR)-HPV was detected in 38% of all women with normal VIA vs. 51% of all women with abnormal VIA (P = 0.012). HIV-uninfected women with normal VIA had significantly lower detection of all HPV (P = 0.026), high risk-HPV (P = 0.018), IARC high risk-HPV (P = 0.047), A9 types (P = 0.050), and individual types HPV 16 (P = 0.0274), HPV 18 (P = 0.007), and HPV 51 (P = 0.009) than HIV-uninfected women with abnormal VIA. Among HIV-infected women, there was no difference in detection of any group of HPV types or individual types with respect to VIA results. Conclusions: HIV-uninfected women without cervical dysplasia had lower detection of oncogenic HPV than HIV-uninfected women with dysplasia. In contrast, HPV detection did not differ among HIV-infected women between those with or without cervical dysplasia. In addition, VIA appears to lack specificity for HPV-associated cervical dysplasia, as 39% of women with abnormal VIA examinations did not have any HPV detected, and 49% of women with abnormal VIA examinations did not have any HR-HPV detected.
- Published
- 2019
47. Suppressed circulating bicyclo-PGE2 levels and leukocyte COX-2 transcripts in children co-infected with P. falciparum malaria and HIV-1 or bacteremia
- Author
-
John M. Vulule, Samuel B. Anyona, James B. Hittner, Prakasha Kempaiah, Douglas J. Perkins, John M. Ong’echa, and Gregory C. Davenport
- Subjects
Male ,Anemia ,Holoendemic ,Plasmodium falciparum ,Biophysics ,Bacteremia ,HIV Infections ,Biochemistry ,Dinoprostone ,Article ,Bridged Bicyclo Compounds ,parasitic diseases ,Leukocytes ,medicine ,Animals ,Humans ,RNA, Messenger ,Malaria, Falciparum ,Molecular Biology ,Pregnancy ,biology ,business.industry ,Transmission (medicine) ,Infant ,Cell Biology ,medicine.disease ,biology.organism_classification ,Cyclooxygenase 2 ,Cerebral Malaria ,Immunology ,HIV-1 ,Female ,business ,Malaria - Abstract
In holoendemic Plasmodium falciparum transmission regions, malarial anemia is a leading cause of childhood morbidity and mortality. Identifying biomarkers of malaria disease severity is important for identifying at-risk groups and for improved understanding of the molecular pathways that influence clinical outcomes. We have previously shown that decreased cyclooxygenase (COX)-2-derived prostaglandin E2 (PGE2) levels are associated with enhanced clinical severity in cerebral malaria, malarial anemia, and malaria during pregnancy. Since children with malaria often have increased incidence of additional infections, such as bacteremia and HIV-1, we extend our previous findings by investigating COX-2 and PGE2 in children with falciparum malaria and co-infection with either bacteremia or HIV-1. Plasma bicyclo-PGE2/creatinine levels and peripheral blood COX-2 transcripts were significantly reduced in co-infected children relative to those with malaria mono-infection. Furthermore, suppression of circulating bicyclo-PGE2 was significantly associated with reduced hemoglobin levels in both mono- and co-infected children with malaria, suggesting that bicyclo-PGE2 may represent both a marker and mediator of malaria pathogenesis.
- Published
- 2013
48. Reduced Parasite Burden in Children with Falciparum Malaria and Bacteremia Coinfections: Role of Mediators of Inflammation
- Author
-
Benjamin H. McMahon, Douglas J Perkins, Zachary Karim, Vincent Otieno, Nicolas W. Hengartner, Paul W. Fenimore, Gregory C. Davenport, James B. Hittner, Harshini Mukundan, Prakasha Kempaiah, and John M. Ong’echa
- Subjects
0301 basic medicine ,Male ,Staphylococcus aureus ,Article Subject ,Immunology ,Alpha interferon ,Bacteremia ,Parasitemia ,03 medical and health sciences ,Interferon-gamma ,Immune system ,Salmonella ,parasitic diseases ,lcsh:Pathology ,medicine ,Humans ,Malaria, Falciparum ,Inflammation ,Interleukin-15 ,biology ,business.industry ,Coinfection ,Tumor Necrosis Factor-alpha ,Interleukin-7 ,Interleukin-17 ,Infant, Newborn ,Infant ,Interferon-alpha ,Plasmodium falciparum ,Cell Biology ,medicine.disease ,biology.organism_classification ,Virology ,Interleukin-12 ,3. Good health ,Interleukin-10 ,Interleukin 10 ,030104 developmental biology ,Child, Preschool ,Female ,Interleukin-4 ,Interleukin-5 ,business ,Malaria ,lcsh:RB1-214 ,Research Article - Abstract
Bacteremia and malaria coinfection is a common and life-threatening condition in children residing in sub-Saharan Africa. We previously showed that coinfection with Gram negative (G[−]) enteric Bacilli andPlasmodium falciparum(Pf[+]) was associated with reduced high-density parasitemia (HDP, >10,000 parasites/μL), enhanced respiratory distress, and severe anemia. Since inflammatory mediators are largely unexplored in such coinfections, circulating cytokines were determined in four groups of children (n=206, aged Pf[+] alone; G[−] coinfected; and G[+] coinfected.Staphylococcus aureusand non-TyphiSalmonellawere the most frequently isolated G[+] and G[−] organisms, respectively. Coinfected children, particularly those with G[−] pathogens, had lower parasite burden (peripheral and geometric mean parasitemia and HDP). In addition, both coinfected groups had increased IL-4, IL-5, IL-7, IL-12, IL-15, IL-17, IFN-γ, and IFN-αand decreased TNF-αrelative to malaria alone. Children with G[−] coinfection had higher IL-1βand IL-1Ra and lower IL-10 than thePf[+] group and higher IFN-γthan the G[+] group. To determine how the immune response to malaria regulates parasitemia, cytokine production was investigated with a multiple mediation model. Cytokines with the greatest mediational impact on parasitemia were IL-4, IL-10, IL-12, and IFN-γ. Results here suggest that enhanced immune activation, especially in G[−] coinfected children, acts to reduce malaria parasite burden.
- Published
- 2016
49. Reduced systemic bicyclo-prostaglandin-E2 and cyclooxygenase-2 gene expression are associated with inefficient erythropoiesis and enhanced uptake of monocytic hemozoin in children with severe malarial anemia
- Author
-
James B. Hittner, Stephen N. Konah, Evans Raballah, John M. Ong’echa, Tom Were, Samuel B. Anyona, John M. Vulule, Gregory C. Davenport, Douglas J. Perkins, Prakasha Kempaiah, and C. W. Gichuki
- Subjects
Hemeproteins ,Male ,medicine.medical_specialty ,Anemia ,Holoendemic ,Reticulocyte production index ,Biology ,Parasitemia ,Severity of Illness Index ,Article ,Dinoprostone ,Gene Expression Regulation, Enzymologic ,Monocytes ,chemistry.chemical_compound ,Phagocytosis ,Internal medicine ,medicine ,Humans ,Erythropoiesis ,Malaria, Falciparum ,Creatinine ,Hemozoin ,Infant ,Plasmodium falciparum ,Hematology ,medicine.disease ,biology.organism_classification ,Endocrinology ,chemistry ,Cyclooxygenase 2 ,Child, Preschool ,Immunology ,Female ,Hemoglobin - Abstract
In holoendemic Plasmodium falciparum transmission areas, severe malaria primarily occurs in children aged
- Published
- 2012
50. Reduced interferon (IFN)-α conditioned by IFNA2 (−173) and IFNA8 (−884) haplotypes is associated with enhanced susceptibility to severe malarial anemia and longitudinal all-cause mortality
- Author
-
James B. Hittner, Tom Were, Evans Raballah, Samuel B. Anyona, John M. Ong’echa, Prakasha Kempaiah, Douaglas J. Perkins, and Gregory C. Davenport
- Subjects
Male ,Holoendemic ,medicine.medical_treatment ,Biology ,Polymerase Chain Reaction ,Article ,Cell Line ,Loss of heterozygosity ,Cause of Death ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Longitudinal Studies ,Genetics (clinical) ,DNA Primers ,Base Sequence ,Haplotype ,Wild type ,Infant ,Interferon-alpha ,Anemia ,Plasmodium falciparum ,SMA ,biology.organism_classification ,Molecular medicine ,Malaria ,Cytokine ,Haplotypes ,Immunology ,Female - Abstract
Severe malarial anemia (SMA) is a leading cause of pediatric morbidity and mortality in holoendemic Plasmodium falciparum transmission areas. Although dysregulation in cytokine production is an important etiology of SMA, the role of IFN-α in SMA has not been reported. As such, we investigated the relationship between IFN-α promoter polymorphisms [i.e., IFNA2 (A-173T) and IFNA8 (T-884A)], SMA, and functional changes in IFN-α production in children (n = 663
- Published
- 2012
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.