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1. Elevated glycolytic metabolism of monocytes limits the generation of HIF1A-driven migratory dendritic cells in tuberculosis

Author

Mariano Maio, Joaquina Barros, Marine Joly, Zoi Vahlas, José Luis Marín Franco, Melanie Genoula, Sarah C Monard, María Belén Vecchione, Federico Fuentes, Virginia Gonzalez Polo, María Florencia Quiroga, Mónica Vermeulen, Thien-Phong Vu Manh, Rafael J Argüello, Sandra Inwentarz, Rosa Musella, Lorena Ciallella, Pablo González Montaner, Domingo Palmero, Geanncarlo Lugo Villarino, María del Carmen Sasiain, Olivier Neyrolles, Christel Vérollet, and Luciana Balboa

Subjects
immunometabolism, dendritic cells, tuberculosis, monocytes, cell migration, glycolysis, Medicine, Science, Biology (General), QH301-705.5
Abstract

During tuberculosis (TB), migration of dendritic cells (DCs) from the site of infection to the draining lymph nodes is known to be impaired, hindering the rapid development of protective T-cell-mediated immunity. However, the mechanisms involved in the delayed migration of DCs during TB are still poorly defined. Here, we found that infection of DCs with Mycobacterium tuberculosis (Mtb) triggers HIF1A-mediated aerobic glycolysis in a TLR2-dependent manner, and that this metabolic profile is essential for DC migration. In particular, the lactate dehydrogenase inhibitor oxamate and the HIF1A inhibitor PX-478 abrogated Mtb-induced DC migration in vitro to the lymphoid tissue-specific chemokine CCL21, and in vivo to lymph nodes in mice. Strikingly, we found that although monocytes from TB patients are inherently biased toward glycolysis metabolism, they differentiate into poorly glycolytic and poorly migratory DCs compared with healthy subjects. Taken together, these data suggest that because of their preexisting glycolytic state, circulating monocytes from TB patients are refractory to differentiation into migratory DCs, which may explain the delayed migration of these cells during the disease and opens avenues for host-directed therapies for TB.

Published
2024
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2. Macrophage Migration Inhibitory Factor (MIF) Promotes Increased Proportions of the Highly Permissive Th17-like Cell Profile during HIV Infection

Author

César Trifone, Lucía Baquero, Alejandro Czernikier, Paula Benencio, Lin Leng, Natalia Laufer, María Florencia Quiroga, Richard Bucala, Yanina Ghiglione, and Gabriela Turk

Subjects
HIV, MIF, MDM/CD4TL co-culture, immune pathogenesis, Microbiology, QR1-502
Abstract

In this study, we evaluate the role of the MIF/CD74 axis in the functionality of CD4+ T lymphocytes (CD4TL) during HIV infection. MDMs from healthy donors were infected with a R5-tropic or Transmitted/Founder (T/F) HIV strain. At day 11 post-MDM infection, allogeneic co-cultures with uninfected CD4TLs plus MIF stimulus were performed. Cytokine production was evaluated by ELISA. MIF plasma levels of people with HIV (PWH) were evaluated by ELISA. The phenotype and infection rate of CD4TLs from PWH were analyzed after MIF stimulus. Intracellular cytokines and transcription factors were evaluated by flow cytometry. Data were analyzed by parametric or non-parametric methods. The MIF stimulation of HIV-infected MDMs induced an increased expression of IL-6, IL-1β and IL-8. In CD4TL/MDM co-cultures, the MIF treatment increased IL-17A/RORγt-expressing CD4TLs. Higher concentrations of IL-17A in supernatants were also observed. These results were recapitulated using transmitted/founder (T/F) HIV-1 strains. The MIF treatment appeared to affect memory CD4TLs more than naïve CD4TLs. MIF blocking showed a negative impact on IL17A+CD4TL proportions. Higher MIF concentrations in PWH-derived plasma were correlated with higher IL-17A+CD4TL percentages. Finally, MIF stimulation in PWH-derived PBMCs led to an increase in Th17-like population. MIF may contribute to viral pathogenesis by generating a microenvironment enriched in activating mediators and Th17-like CD4TLs, which are known to be highly susceptible to HIV-1 infection and relevant to viral persistence. These observations establish a basis for considering MIF as a possible therapeutic target.

Published
2022
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3. Interaction Between Macrophage Migration Inhibitory Factor and CD74 in Human Immunodeficiency Virus Type I Infected Primary Monocyte-Derived Macrophages Triggers the Production of Proinflammatory Mediators and Enhances Infection of Unactivated CD4+ T Cells

Author

César Trifone, Jimena Salido, María Julia Ruiz, Lin Leng, María Florencia Quiroga, Horacio Salomón, Richard Bucala, Yanina Ghiglione, and Gabriela Turk

Subjects
human immunodeficiency virus, CD74, macrophage migration inhibitory factor, primary monocyte-derived macrophages, CD4+ T-cells, immunopathogenesis, Immunologic diseases. Allergy, RC581-607
Abstract

Understanding the mechanisms of human immunodeficiency virus type I (HIV-1) pathogenesis would facilitate the identification of new therapeutic targets to control the infection in face of current antiretroviral therapy limitations. CD74 membrane expression is upregulated in HIV-1-infected cells and the magnitude of its modulation correlates with immune hyperactivation in HIV-infected individuals. In addition, plasma level of the CD74 activating ligand macrophage migration inhibitory factor (MIF) is increased in infected subjects. However, the role played by MIF/CD74 interaction in HIV pathogenesis remains unexplored. Here, we studied the effect of MIF/CD74 interaction on primary HIV-infected monocyte-derived macrophages (MDMs) and its implications for HIV immunopathogenesis. Confocal immunofluorescence analysis of CD74 and CD44 (the MIF signal transduction co-receptor) expression indicated that both molecules colocalized at the plasma membrane specifically in wild-type HIV-infected MDMs. Treatment of infected MDMs with MIF resulted in an MIF-dependent increase in TLR4 expression. Similarly, there was a dose-dependent increase in the production of IL-6, IL-8, TNFα, IL-1β, and sICAM compared to the no-MIF condition, specifically from infected MDMs. Importantly, the effect observed on IL-6, IL-8, TNFα, and IL-1β was abrogated by impeding MIF interaction with CD74. Moreover, the use of a neutralizing αMIF antibody or an MIF antagonist reverted these effects, supporting the specificity of the results. Treatment of unactivated CD4+ T-cells with MIF-treated HIV-infected MDM-derived culture supernatants led to enhanced permissiveness to HIV-1 infection. This effect was lost when CD4+ T-cells were treated with supernatants derived from infected MDMs in which CD74/MIF interaction had been blocked. Moreover, the enhanced permissiveness of unactivated CD4+ T-cells was recapitulated by exogenous addition of IL-6, IL-8, IL-1β, and TNFα, or abrogated by neutralizing its biological activity using specific antibodies. Results obtained with BAL and NL4-3 HIV laboratory strains were reproduced using transmitted/founder primary isolates. This evidence indicated that MIF/CD74 interaction resulted in a higher production of proinflammatory cytokines from HIV-infected MDMs. This caused the generation of an inflammatory microenvironment which predisposed unactivated CD4+ T-cells to HIV-1 infection, which might contribute to viral spreading and reservoir seeding. Overall, these results support a novel role of the MIF/CD74 axis in HIV pathogenesis that deserves further investigation.

Published
2018
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4. Hepatitis C Virus (HCV) Clearance After Treatment With Direct-Acting Antivirals in Human Immunodeficiency Virus (HIV)-HCV Coinfection Modulates Systemic Immune Activation and HIV Transcription on Antiretroviral Therapy

Author

Horacio Salomón, Yanina Alexandra Ghiglione, Patricia Patterson, Alejandro Czernikier, Alicia Sisto, María Florencia Quiroga, Natalia Laufer, Gabriela Turk, Alejandra Urioste, Ajantha Rhodes, María José Rolón, María Laura Polo, Sharon R Lewin, César Ariel Trifone, and Sonia Bakkour

Subjects
0301 basic medicine, CIENCIAS MÉDICAS Y DE LA SALUD, Hepatitis C virus, Human immunodeficiency virus (HIV), Inmunología, medicine.disease_cause, HIV reservoir, immune activation, purl.org/becyt/ford/1 [https], Ciencias Biológicas, purl.org/becyt/ford/3.3 [https], 03 medical and health sciences, 0302 clinical medicine, Biología Celular, Microbiología, Transcription (biology), HIV RESERVOIR, Major Article, medicine, purl.org/becyt/ford/1.6 [https], business.industry, direct antiviral agents, Hcv clearance, virus diseases, purl.org/becyt/ford/3.1 [https], Hepatitis C, medicine.disease, Virology, IMMUNE ACTIVATION, Medicina Básica, AcademicSubjects/MED00290, 030104 developmental biology, Infectious Diseases, Oncology, Hiv hcv coinfection, Coinfection, HEPATITIS C, purl.org/becyt/ford/3 [https], 030211 gastroenterology & hepatology, hepatitis C, business, DIRECT ANTIVIRAL AGENTS, Virología, CIENCIAS NATURALES Y EXACTAS, Immune activation
Abstract

Background Hepatitis C virus (HCV) coinfection among people with human immunodeficiency virus (HIV) might perturb immune function and HIV persistence. We aimed to evaluate the impact of HCV clearance with direct-acting antivirals (DAAs) on immune activation and HIV persistence in HIV/HCV-coinfected individuals on antiretroviral therapy (ART). Methods In a prospective observational study, ART-treated participants with HIV/HCV coinfection received sofosbuvir/daclatasvir ± ribavirin (n = 19). Blood samples were collected before DAA therapy, at the end of treatment, and 12 months after DAA termination (12MPT). T- and natural killer (NK)-cell phenotype, soluble plasma factors, cell-associated (CA)-HIV deoxyribonucleic acid (DNA) forms (total, integrated, 2LTR), CA-unspliced (US) and multiple-spliced ribonucleic acid (RNA), and plasma HIV RNA were evaluated. Results Hepatitis C virus clearance was associated with (1) a downmodulation of activation and exhaustion markers in CD4+, CD8+ T, and NK cells together with (2) decreased plasma levels of Interferon gamma-induced protein 10 (IP10), interleukin-8 (IL-8), soluble (s)CD163 and soluble intercellular adhesion molecule (sICAM). Cell-associated US HIV RNA was significantly higher at 12MPT compared to baseline, with no change in HIV DNA or plasma RNA. Conclusions Elimination of HCV in HIV/HCV-coinfected individuals alters immune function and the transcriptional activity of latently infected cells. This report provides insights into the effects of HCV coinfection in HIV persistence and regards coinfected subjects as a population in which HIV remission might prove to be more challenging., This article addresses the immediate and long-term effects of direct-acting antiviral-mediated HCV clearance on the HIV reservoir dynamics and immune function, in a cohort of HIV/HCV-coinfected individuals under antiretroviral treatment.

Published
2020

5. Interaction between macrophage migration inhibitory factor and CD74 in human immunodeficiency virus type I infected primary monocyte-derived macrophages triggers the production of proinflammatory mediators and enhances infection of unactivated CD4+ T cells

Author

Jimena Salido, Yanina Alexandra Ghiglione, César Ariel Trifone, Richard Bucala, María Florencia Quiroga, Gabriela Turk, María Julia Ruiz, Lin Leng, and Horacio Salomón

Subjects
0301 basic medicine, Permissiveness, lcsh:Immunologic diseases. Allergy, CIENCIAS MÉDICAS Y DE LA SALUD, CD74, IMMUNOPATHOGENESIS, Immunology, Inmunología, primary monocyte-derived macrophages, CD4+ T-cells, Proinflammatory cytokine, 03 medical and health sciences, Immune system, Immunology and Allergy, Original Research, biology, human immunodeficiency virus, Chemistry, immunopathogenesis, purl.org/becyt/ford/3.1 [https], HUMAN IMMUNODEFICIENCY VIRUS, Medicina Básica, 030104 developmental biology, PRIMARY MONOCYTE-DERIVED MACROPHAGES, MACROPHAGE MIGRATION INHIBITORY FACTOR, TLR4, biology.protein, macrophage migration inhibitory factor, purl.org/becyt/ford/3 [https], Tumor necrosis factor alpha, Macrophage migration inhibitory factor, Antibody, lcsh:RC581-607, CD4+ T-CELLS
Abstract

Understanding the mechanisms of human immunodeficiency virus type I (HIV-1) pathogenesis would facilitate the identification of new therapeutic targets to control the infection in face of current antiretroviral therapy limitations. CD74 membrane expression is upregulated in HIV-1-infected cells and the magnitude of its modulation correlates with immune hyperactivation in HIV-infected individuals. In addition, plasma level of the CD74 activating ligand macrophage migration inhibitory factor (MIF) is increased in infected subjects. However, the role played by MIF/CD74 interaction in HIV pathogenesis remains unexplored. Here, we studied the effect of MIF/CD74 interaction on primary HIV-infected monocyte-derived macrophages (MDMs) and its implications for HIV immunopathogenesis. Confocal immunofluorescence analysis of CD74 and CD44 (the MIF signal transduction co-receptor) expression indicated that both molecules colocalized at the plasma membrane specifically in wild-type HIV-infected MDMs. Treatment of infected MDMs with MIF resulted in an MIF-dependent increase in TLR4 expression. Similarly, there was a dose-dependent increase in the production of IL-6, IL-8, TNFα, IL-1β, and sICAM compared to the no-MIF condition, specifically from infected MDMs. Importantly, the effect observed on IL-6, IL-8, TNFα, and IL-1β was abrogated by impeding MIF interaction with CD74. Moreover, the use of a neutralizing αMIF antibody or an MIF antagonist reverted these effects, supporting the specificity of the results. Treatment of unactivated CD4+ T-cells with MIF-treated HIV-infected MDM-derived culture supernatants led to enhanced permissiveness to HIV-1 infection. This effect was lost when CD4+ T-cells were treated with supernatants derived from infected MDMs in which CD74/MIF interaction had been blocked. Moreover, the enhanced permissiveness of unactivated CD4+ T-cells was recapitulated by exogenous addition of IL-6, IL-8, IL-1β, and TNFα, or abrogated by neutralizing its biological activity using specific antibodies. Results obtained with BAL and NL4-3 HIV laboratory strains were reproduced using transmitted/founder primary isolates. This evidence indicated that MIF/CD74 interaction resulted in a higher production of proinflammatory cytokines from HIV-infected MDMs. This caused the generation of an inflammatory microenvironment which predisposed unactivated CD4+ T-cells to HIV-1 infection, which might contribute to viral spreading and reservoir seeding. Overall, these results support a novel role of the MIF/CD74 axis in HIV pathogenesis that deserves further investigation. Fil: Trifone, César Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Salido, Jimena Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Ruiz, María Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Leng, Lin. University of Yale; Estados Unidos Fil: Quiroga, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Salomon, Horacio Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Bucala, Richard. University of Yale; Estados Unidos Fil: Ghiglione, Yanina Alexandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Turk, Gabriela Julia Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina

Published
2018

6. Expansion of CD25-Negative Forkhead Box P3-Positive T Cells during HIV and Mycobacterium tuberculosis Infection

Author

María Belén Vecchione, Graciela Ben, Omar Sued, Héctor Pérez, María Florencia Quiroga, Diego Ameri, Natalia Laufer, Guadalupe Verónica Suarez, Matias Tomas Angerami, and Horacio Salomón

Subjects
0301 basic medicine, lcsh:Immunologic diseases. Allergy, CIENCIAS MÉDICAS Y DE LA SALUD, medicine.medical_treatment, Population, Immunology, Inmunología, Context (language use), Biology, Flow cytometry, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Immunology and Allergy, IL-2 receptor, human, education, Original Research, education.field_of_study, medicine.diagnostic_test, INFECTIOUS IMMUNITY BACTERIA, Effector, REGULATORY MECHANISMS, CYTOKINES, FOXP3, HUMAN, EFFECTOR/MEMORY TREG POPULATIONS, purl.org/becyt/ford/3.1 [https], cytokines, regulatory mechanisms, Medicina Básica, 030104 developmental biology, Cytokine, effector/memory Treg populations, infectious immunity bacteria, purl.org/becyt/ford/3 [https], lcsh:RC581-607, 030215 immunology
Abstract

Tuberculosis (TB) and HIV alter the immune system, and coinfected (HIV-TB) individuals usually present deregulations of T-lymphocytic immune response. We previously observed an increased frequency of “unconventional” CD4+CD25−FoxP3+ Treg (uTreg) population during HIV-TB disease. Therefore, we aimed to explore the phenotype and function of uTreg and conventional CD4+CD25+FoxP3+ Treg subsets (cTreg) in this context. We evaluated the expression of CD39, programmed cell death protein 1 (PD1), glucocorticoid-induced tumor necrosis factor receptor (GITR), and the effector/memory distribution by flow cytometry in cTreg and uTreg. Also, IL-10, TGF-β, IFN-γ production, and the suppressor capacity of uTregs were analyzed in cocultures with effector lymphocytes and compared with the effect of regulatory T cells (Tregs). We found diminished expression of CD39 and higher levels of PD1 on uTreg compared to cTreg in both HIV-TB and healthy donors (HD). In addition, uTreg and cTreg showed differences in maturation status in both HIV-TB and HD groups, due to the expansion of effector memory uTregs. Interestingly, both HIV-TB and HD showed a pronounced production of IFN-γ in uTreg population, though no significant differences were observed for IL-10 and TGF-β production between uTreg and cTreg. Moreover, IFN-γ+ cells were restricted to the CD39− uTreg population. Finally, when the suppressor capacity was evaluated, both uTreg and cTreg inhibited polyclonal T cell-proliferation and IFN-γ production in a similar extent. These findings suggest that uTregs, which are expanded during HIV-TB coinfection, exert regulatory functions in a similar way to cTregs despite an altered surface expression of Treg characteristic markers and differences in cytokine production. Fil: Angerami, Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Suárez, Guadalupe Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Vecchione, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Laufer, Natalia Lorna. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Ameri, Diego. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos ; Argentina Fil: Ben, Graciela. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos ; Argentina Fil: Perez, Hector. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos ; Argentina Fil: Sued, Omar Gustavo. Fundación Huésped; Argentina Fil: Salomon, Horacio Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Quiroga, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina

Published
2017

7. Immunoendocrine Interactions during HIV-TB Coinfection: Implications for the Design of New Adjuvant Therapies

Author

Oscar Bottasso, María Florencia Quiroga, Andrea Claudia Bruttomesso, María Belén Vecchione, Guadalupe Verónica Suarez, Omar Sued, and Matias Tomas Angerami

Subjects
Tuberculosis, medicine.medical_treatment, Otras Ciencias Biológicas, Human immunodeficiency virus (HIV), lcsh:Medicine, Endocrine System, HIV Infections, Inflammation, Review Article, Biology, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, Ciencias Biológicas, purl.org/becyt/ford/1 [https], Immune system, Adjuvants, Immunologic, medicine, Humans, DHEA, purl.org/becyt/ford/1.6 [https], General Immunology and Microbiology, Coinfection, lcsh:R, IMMUNOENDOCRINE, General Medicine, medicine.disease, Virology, Hormones, HIV-TB, Cytokine, Immunology, HIV-1, Cytokines, medicine.symptom, Adjuvant, CIENCIAS NATURALES Y EXACTAS, Hormone
Abstract

Worldwide, around 14 million individuals are coinfected with both tuberculosis (TB) and human immunodeficiency virus (HIV). In coinfected individuals, both pathogens weaken immunological system synergistically through mechanisms that are not fully understood. During both HIV and TB infections, there is a chronic state of inflammation associated to dramatic changes in immune cytokine and endocrine hormone levels. Despite this, the relevance of immunoendocrine interaction on both the orchestration of an effective immune response against both pathogens and the control of the chronic inflammation induced during HIV, TB, or both infections is still controversial. The present study reviews immunoendocrine interactions occurring during HIV and TB infections. We also expose our own findings on immunoendocrine cross talk in HIV-TB coinfection. Finally, we evaluate the use of adrenal hormones and their derivatives in immune-therapy and discuss the use of some of these compounds like the adjuvant for the prevention and treatment of TB in HIV patients. Fil: Suárez, Guadalupe Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Vecchione, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina Fil: Angerami, Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Sued, Omar Gustavo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentina. Fundación Huésped; Argentina Fil: Bruttomesso, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina Fil: Bottasso, Oscar Adelmo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; Argentina Fil: Quiroga, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina

Published
2015

8. Phenotypic and functional analysis of γδ T cells in the pathogenesis of human T-cell lymphotropic virus type 1 infection

Author

Matias Ruggieri, Nicolás Ducasa, Claudia Juraske, Virginia Gonzalez Polo, Carolina Berini, Maria Florencia Quiroga, Petros Christopoulos, Susana Minguet, Mirna Biglione, and Wolfgang W. Schamel

Subjects
γδ T cells, HTLV-1, IFN-γ, mevalonate pathway, cytotoxicity, Immunologic diseases. Allergy, RC581-607
Abstract

The human T-cell leukemia virus type 1 (HTLV-1) is the cause of serious malignant and inflammatory diseases, including adult T-cell leukemia and lymphoma and tropical spastic paraparesis. The potential protective role of γδ T cells in HTLV-1 infection remains unclear. Here, demonstrate that there is a decrease in the amount of Vγ9Vδ2 T cells in patients with HTLV-1, especially in those with HTLV-1 associated pathologies. This suggests that γδ T cells could be involved in controlling the virus. Indeed, we found that Vγ9Vδ2 T cells, expanded from non-infected individuals, can kill cells expressing the viral proteins HBZ and Tax and this phenotype is reversed in the presence of mevastatin. Cytotoxicity by Vγ9Vδ2 T cells was not associated with an increase of INF-γ production. In sharp contrast, killing by NK cells was reduced by Tax expression. Thus, our study provides initial evidence for a potential protective role of Vγ9Vδ2 T cells against HTLV-1 infection. Therapeutic exploitation of these insights is feasible with current technologies of T-cell therapies and could provide novel tools to prevent and treat HTLV-1-associated malignancies and neurologic complications.

Published
2022
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9. Modulation of the phenotype and function of Mycobacterium tuberculosis-stimulated dendritic cells by adrenal steroids

Author

Guadalupe Verónica Suarez, Oscar Bottasso, Horacio Salomón, María Florencia Quiroga, Matias Tomas Angerami, and María Fernanda Pascutti

Subjects
medicine.medical_specialty, CIENCIAS MÉDICAS Y DE LA SALUD, Hydrocortisone, Adrenal Steroids, medicine.medical_treatment, Immunology, Dehydroepiandrosterone, Ciencias de la Salud, Ciencias Biológicas, purl.org/becyt/ford/1 [https], purl.org/becyt/ford/3.3 [https], Immune system, Antigen, Biología Celular, Microbiología, Internal medicine, MHC class I, medicine, Immunology and Allergy, Humans, Tuberculosis, Antigen-presenting cell, purl.org/becyt/ford/1.6 [https], Cells, Cultured, biology, Immunity to Infection, General Medicine, Mycobacterium tuberculosis, Dendritic Cells, Acquired immune system, Enfermedades Infecciosas, Cytokine, Endocrinology, Phenotype, Interleukin 12, biology.protein, Cytokines, Steroids, purl.org/becyt/ford/3 [https], hormones, hormone substitutes, and hormone antagonists, CIENCIAS NATURALES Y EXACTAS, Mycobacterium Tuberculosis
Abstract

Cell-mediated immunity, cytokines induced during the specific immune response and T-cell populations are crucial factors for containing Mycobacterium tuberculosis infection. Recent reports suggest a cross-regulation between adrenal steroids (glucocorticoids and dehydroepiandrosterone, DHEA) and the function of antigen-presenting cells (APCs). Therefore, we investigated the role of adrenal hormones on the functional capacity of M. tuberculosis-induced dendritic cells (DCs). Cortisol significantly inhibited the functions of M. tuberculosis-induced DCs. Interestingly, the presence of DHEA enhanced the M. tuberculosis-induced expression of MHC I, MHC II and CD86 and also increased ERK1/2 phosphorylation. Moreover, DHEA improved the production of IL-12 in response to M. tuberculosis stimulation, diminished IL-10 secretion and could not modify TNF-α synthesis. Importantly, we observed that DHEA enhanced the antigen-specific T-cell proliferation and IFN-γ production induced by M. tuberculosis-stimulated DC. These data show for the first time the relevance of the adrenal axis (especially of DHEA) in the modulation of DC function in the context of tuberculosis, a disease where the induction of a Th1 environment by APCs is crucial for the development of an effective immune response to the mycobacteria. Fil: Angerami, Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Suárez, Guadalupe Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Pascutti, María Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Salomon, Horacio Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Bottasso, Oscar Adelmo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; Argentina Fil: Quiroga, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina

Published
2013

10. Dynamics of adrenal steroids are related to variations in Th1 and Treg populations during Mycobacterium tuberculosis infection in HIV positive persons

Author

María Florencia Quiroga, Pedro Cahn, Natalia Santucci, José Luis Francos, Matias Tomas Angerami, Jorge Wallach, Omar Sued, Diego Ameri, Horacio Salomón, and Oscar Bottasso

Subjects
Male, Bacterial Diseases, Viral Diseases, Hydrocortisone, Lymphocyte, lcsh:Medicine, HIV Infections, Blood plasma, T-Lymphocytes, Regulatory, Biochemistry, chemistry.chemical_compound, Immune Reconstitution Inflammatory Syndrome, Adrenal Glands, polycyclic compounds, lcsh:Science, education.field_of_study, Multidisciplinary, Coinfection, virus diseases, Forkhead Transcription Factors, Regulatory T cells, Middle Aged, Infectious Diseases, medicine.anatomical_structure, Medicine, Female, Steroids, hormones, hormone substitutes, and hormone antagonists, Research Article, medicine.drug, Adult, medicine.medical_specialty, endocrine system, Tuberculosis, Immunology, Population, T cells, Dehydroepiandrosterone, Biology, Interferon-gamma, Dehydroepiandrosterone sulfate, Immune reconstitution inflammatory syndrome, Internal medicine, medicine, Humans, Immune response, education, lcsh:R, Interleukin-2 Receptor alpha Subunit, Immunity, HIV, Mycobacterium tuberculosis, Th1 Cells, Immunologic Subspecialties, medicine.disease, Endocrinology, chemistry, Immune System, lcsh:Q
Abstract

Tuberculosis (TB) remains the most frequent cause of illness and death from an infectious agent, and its interaction with HIV has devastating effects. We determined plasma levels of dehydroepiandrosterone (DHEA), its circulating form DHEA-suphate (DHEA-s) and cortisol in different stages of M. tuberculosis infection, and explored their role on the Th1 and Treg populations during different scenarios of HIV-TB coinfection, including the immune reconstitution inflammatory syndrome (IRIS), a condition related to antiretroviral treatment. DHEA levels were diminished in HIV-TB and HIV-TB IRIS patients compared to healthy donors (HD), HIV+ individuals and HIV+ individuals with latent TB (HIV-LTB), whereas dehydroepiandrosterone sulfate (DHEA-s) levels were markedly diminished in HIV-TB IRIS individuals. HIV-TB and IRIS patients presented a cortisol/DHEA ratio significantly higher than HIV+, HIV-LTB and HD individuals. A positive correlation was observed between DHEA-s and CD4 count among HIV-TB individuals. Conversely, cortisol plasma level inversely correlated with CD4 count within HIV-TB individuals. M. tuberculosis-specific Th1 lymphocyte count was increased after culturing PBMC from HIV-TB individuals in presence of DHEA. We observed an inverse correlation between DHEA-s plasma level and Treg frequency in co-infected individuals, and CD4+FoxP3+ Treg frequency was increased in HIV-TB and IRIS patients compared to other groups. Strikingly, we observed a prominent CD4+CD25-FoxP3+ population across HIV-TB and HIV-TB IRIS patients, which frequency correlated with DHEA plasma level. Finally, DHEA treatment negatively regulated FoxP3 expression without altering Treg frequency in co-infected patients. These data suggest an enhancing role for DHEA in the immune response against M. tuberculosis during HIV-TB coinfection and IRIS. Fil: Quiroga, Maria Florencia. Universidad de Buenos Aires. Facultad de Medicina. Centro Nacional de Referencia para el Sida (CNRS); Argentina. Fil: Angerami, Matias Tomas. Universidad de Buenos Aires. Facultad de Medicina. Centro Nacional de Referencia para el Sida (CNRS); Argentina. Fil: Santucci, Natalia. Universidad Nacional de Rosario, Facultad de Ciencias Médicas, Instituto de Inmunología; Argentina. Fil: Bottasso, Oscar. Universidad Nacional de Rosario, Facultad de Ciencias Médicas, Instituto de Inmunología; Argentina.

Published
2012

11. MANNOSE-CAPPED LIPOARABINOMANNAN- AND PROSTAGLANDIN E2-DEPENDENT EXPANSION OF REGULATORY T CELLS IN HUMAN Mycobacterium tuberculosis INFECTION

Author

Ankita Garg, Sugata Roy, Steven E. Weis, María Florencia Quiroga, Shiping Wu, Peter F. Barnes, Verónica E. García, Stephan R. Krutzik, and Ramakrishna Vankayalapati

Subjects
Lipopolysaccharides, Tuberculosis, Regulatory T cell, Immunology, Tuberculin, chemical and pharmacologic phenomena, Biology, Lymphocyte Activation, T-Lymphocytes, Regulatory, Article, Dinoprostone, Monocytes, Microbiology, Mycobacterium tuberculosis, medicine, Immunology and Allergy, Humans, IL-2 receptor, Cells, Cultured, Cell Proliferation, Antigens, Bacterial, Lipoarabinomannan, FOXP3, hemic and immune systems, medicine.disease, biology.organism_classification, Growth Inhibitors, medicine.anatomical_structure, Mannose, CD8
Abstract

We evaluated the role of regulatory T cells (CD4(+) CD25(+) Foxp3(+) cells, Tregs) in human Mycobacterium tuberculosis infection. Tregs were expanded in response to M. tuberculosis in healthy tuberculin reactors, but not in tuberculin-negative individuals. The M. tuberculosis mannose-capped lipoarabinomannan (ManLAM) resulted in regulatory T cell expansion, whereas the M. tuberculosis 19-kDa protein and heat shock protein 65 had no effect. Anti-IL-10 and anti-TGF-beta alone or in combination, did not reduce expansion of Tregs. In contrast, the cyclooxygenase enzyme-2 inhibitor NS398 significantly inhibited expansion of Tregs, indicating that prostaglandin E2 (PGE2) contributes to Treg expansion. Monocytes produced PGE2 upon culturing with heat-killed M. tuberculosis or ManLAM, and T cells from healthy tuberculin reactors enhanced PGE2 production by monocytes. Expanded Tregs produced significant amounts of TGF-beta and IL-10 and depletion of Tregs from PBMC of these individuals increased the frequency of M. tuberculosis-responsive CD4(+) IFN-gamma cells. Culturing M. tuberculosis-expanded Tregs with autologous CD8(+) cells decreased the frequency of IFN-gamma(+)cells. Freshly isolated PBMC from tuberculosis patients had increased percentages of Tregs, compared to healthy tuberculin reactors. These findings demonstrate that Tregs expand in response to M. tuberculosis through mechanisms that depend on ManLAM and PGE2.

Published
2008

12. 7-oxo-DHEA enhances impaired M. tuberculosis-specific T cell responses during HIV-TB coinfection

Author

María Belén Vecchione, Natalia Laufer, Omar Sued, Marcelo Corti, Horacio Salomon, and Maria Florencia Quiroga

Subjects
Human, Infectious immunity-bacteria, Hormone modulatory mechanisms, Cytokines, Effector T cells, Medicine
Abstract

Abstract Background Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), affecting approximately one third of the world’s population. Development of an adequate immune response will determine disease progression or progress to chronic infection. Risk of developing TB among human immunodeficiency virus (HIV)-coinfected patients (HIV-TB) is 20–30 times higher than those without HIV infection, and a synergistic interplay between these two pathogens accelerates the decline in immunological functions. TB treatment in HIV-TB coinfected persons is challenging and it has a prolonged duration, mainly due to the immune system failure to provide an adequate support for the therapy. Therefore, we aimed to study the role of the hormone 7-oxo-dehydroepiandrosterone (7-OD) as a modulator of anti-tuberculosis immune responses in the context of HIV-TB coinfection. Methods A cross-sectional study was conducted among HIV-TB patients and healthy donors (HD). We characterized the ex vivo phenotype of CD4 + T cells and also evaluated in vitro antigen-specific responses by Mtb stimulation of peripheral blood mononuclear cells (PBMCs) in the presence or absence of 7-OD. We assessed lymphoproliferative activity, cytokine production and master transcription factor profiles. Results Our results show that HIV-TB patients were not able to generate successful anti-tubercular responses in vitro compared to HD, as reduced IFN-γ/IL-10 and IFN-γ/IL-17A ratios were observed. Interestingly, treatment with 7-OD enhanced Th1 responses by increasing Mtb-induced proliferation and the production of IFN-γ and TNF-α over IL-10 levels. Additionally, in vitro Mtb stimulation augmented the frequency of cells with a regulatory phenotype, while 7-OD reduced the proportion of these subsets and induced an increase in CD4 + T-bet+ (Th1) subpopulation, which is associated with clinical data linked to an improved disease outcome. Conclusions We conclude that 7-OD modifies the cytokine balance and the phenotype of CD4 + T cells towards a more favorable profile for mycobacteria control. These results provide new data to delineate novel treatment approaches as co-adjuvant for the treatment of TB.

Published
2020
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13. Expression of IL-33 Receptor Is Significantly Up-Regulated in B Cells During Pregnancy and in the Acute Phase of Preterm Birth in Mice

Author

Natalin Valeff, Lorena Juriol, Florencia Quadrana, Damián Oscar Muzzio, Marek Zygmunt, Maria Florencia Quiroga, María Silvia Ventimiglia, and Federico Jensen

Subjects
B cells, pregnancy, preterm birth, IL-33, ST2, tolerance, Immunologic diseases. Allergy, RC581-607
Abstract

Interleukin-33 (IL-33) is a mucosal alarmin belonging to the IL-1 cytokine family and is now recognized to have a key role in innate and adaptive immunity, contributing to tissue homeostasis and response to environmental stresses. In addition, IL-33 has also been shown to work as a positive regulator that initiates and maintains a Th2 immune response. In the context of pregnancy, it has been recently demonstrated that upon certain stress conditions, such as an infection induced inflammation, IL-33 is released from the uterine mucosa and triggers decidual B cells to produce anti-inflammatory molecules, which in turn restore immune homeostasis and prevents the development of preterm birth. In this study we therefore performed a detailed characterization of IL-33 receptor (Il1rl1 or ST2) expression in B cells during normal pregnancy, as well as in a mouse model of preterm birth. We observed that splenic B cells significantly up-regulate the expression of Il1rl1 during pregnancy and identified the B1 B cell population as the main ST2-expressing B cell subset. A further kinetic analysis showed that percentages of ST2-expressing B1 B cells are significantly augmented on days 12 and 14 of pregnancy, both in the spleen and peritoneal cavity of pregnant mice, and then drop toward the end of pregnancy to the levels observed in non-pregnant animals. Furthermore, using a mouse model of LPS-induced preterm birth, we demonstrated that not only are the percentages of ST2-expressing B1 B cells significantly enlarged in the spleen during the acute phase of preterm birth, but decidual B cells also significantly up-regulate ST2 expression as compared to term-pregnant mice. Overall, our results suggest a functional role of ST2 expression in B cells during pregnancy and reinforce the importance of the IL-33/ST2 axis in B cells as a critical mechanism to control inflammation-induced preterm birth.

Published
2020
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