35 results on '"Wilkerson GK"'
Search Results
2. Development of an operational trap for collection, killing, and preservation of triatomines (Hemiptera: Reduviidae): the kissing bug kill trap.
- Author
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Hamer GL, Fimbres-Macias JP, Juarez JG, Downs CH, Carbajal E, Melo M, Garza DY, Killets KC, Wilkerson GK, Carrera-Treviño R, Corona-Barrera E, Tello-Campa AA, Rojas-Mesta MR, Borden JH, Banfield MG, and Hamer SA
- Abstract
Surveillance of triatomines or kissing bugs (Hemiptera: Reduviidae: Triatominae), the insect vectors of Trypanosoma cruzi, a Chagas disease agent, is hindered by the lack of an effective trap. To develop a kissing bug trap, we made iterative improvements over 3 years on a basic design resulting in 7 trap prototypes deployed across field sites in Texas, United States and Northern Mexico, yielding the capture of 325 triatomines of 4 species (Triatoma gerstaeckeri [Stål], T. sanguisuga [LeConte], T. neotomae [Neiva], and T. rubida [Uhler]). We began in 2019 with vertical transparent tarpaulin panel traps illuminated with artificial light powered by AC current, which were successful in autonomous trapping of flying triatomines, but were expensive, labor-intensive, and fragile. In 2020, we switched to white LED lights powered by a solar cell. We tested a scaled-down version of the vertical panel traps, a commercial cross-vane trap, and a multiple-funnel trap. The multiple-funnel traps captured 2.6× more kissing bugs per trap-day than cross-vane traps and approached the performance of the vertical panel traps in number of triatomines captured, number of triatomines per trap-day and triatomines per arthropod bycatch. Multiple-funnel traps required the least labor, were more durable, and had the highest triatomines per day per cost. Propylene glycol in the collection cups effectively preserved captured triatomines allowing for molecular detection of T. cruzi. The trapping experiments established dispersal patterns for the captured species. We conclude that multiple-funnel traps with solar-powered LED lights should be considered for adoption as surveillance and potentially mass-trapping management tools for triatomines., (© The Author(s) 2024. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
- Published
- 2024
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3. Mapping of susceptibility loci for Ebola virus pathogenesis in mice.
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Schäfer A, Marzi A, Furuyama W, Catanzaro NJ, Nguyen C, Haddock E, Feldmann F, Meade-White K, Thomas T, Hubbard ML, Gully KL, Leist SR, Hock P, Bell TA, De la Cruz GE, Midkiff BR, Martinez DR, Shaw GD, Miller DR, Vernon MJ, Graham RL, Cowley DO, Montgomery SA, Schughart K, de Villena FPM, Wilkerson GK, Ferris MT, Feldmann H, and Baric RS
- Subjects
- Animals, Mice, Mice, Knockout, Chromosome Mapping, Liver pathology, Liver metabolism, Humans, Mice, Inbred C57BL, Female, Male, Hemorrhagic Fever, Ebola virology, Hemorrhagic Fever, Ebola genetics, Hemorrhagic Fever, Ebola pathology, Quantitative Trait Loci genetics, Ebolavirus pathogenicity, Ebolavirus genetics, Genetic Predisposition to Disease
- Abstract
Ebola virus (EBOV), a major global health concern, causes severe, often fatal EBOV disease (EVD) in humans. Host genetic variation plays a critical role, yet the identity of host susceptibility loci in mammals remains unknown. Using genetic reference populations, we generate an F2 mapping cohort to identify host susceptibility loci that regulate EVD. While disease-resistant mice display minimal pathogenesis, susceptible mice display severe liver pathology consistent with EVD-like disease and transcriptional signatures associated with inflammatory and liver metabolic processes. A significant quantitative trait locus (QTL) for virus RNA load in blood is identified in chromosome (chr)8, and a severe clinical disease and mortality QTL is mapped to chr7, which includes the Trim5 locus. Using knockout mice, we validate the Trim5 locus as one potential driver of liver failure and mortality after infection. The identification of susceptibility loci provides insight into molecular genetic mechanisms regulating EVD progression and severity, potentially informing therapeutics and vaccination strategies., Competing Interests: Declaration of interests D.O.C. is employed by, has equity ownership in, and serves on the board of directors of TransViragen, the company that has been contracted by UNC-Chapel Hill to manage its Animal Models Core Facility. R.S.B. is a member of advisory boards for VaxArt, Takeda, and Invivyd, focused on unrelated projects., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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4. Structurally divergent and recurrently mutated regions of primate genomes.
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Mao Y, Harvey WT, Porubsky D, Munson KM, Hoekzema K, Lewis AP, Audano PA, Rozanski A, Yang X, Zhang S, Yoo D, Gordon DS, Fair T, Wei X, Logsdon GA, Haukness M, Dishuck PC, Jeong H, Del Rosario R, Bauer VL, Fattor WT, Wilkerson GK, Mao Y, Shi Y, Sun Q, Lu Q, Paten B, Bakken TE, Pollen AA, Feng G, Sawyer SL, Warren WC, Carbone L, and Eichler EE
- Subjects
- Animals, Humans, Base Sequence, Biological Evolution, Sequence Analysis, DNA, Genomic Structural Variation, Genome, Primates classification, Primates genetics
- Abstract
We sequenced and assembled using multiple long-read sequencing technologies the genomes of chimpanzee, bonobo, gorilla, orangutan, gibbon, macaque, owl monkey, and marmoset. We identified 1,338,997 lineage-specific fixed structural variants (SVs) disrupting 1,561 protein-coding genes and 136,932 regulatory elements, including the most complete set of human-specific fixed differences. We estimate that 819.47 Mbp or ∼27% of the genome has been affected by SVs across primate evolution. We identify 1,607 structurally divergent regions wherein recurrent structural variation contributes to creating SV hotspots where genes are recurrently lost (e.g., CARD, C4, and OLAH gene families) and additional lineage-specific genes are generated (e.g., CKAP2, VPS36, ACBD7, and NEK5 paralogs), becoming targets of rapid chromosomal diversification and positive selection (e.g., RGPD gene family). High-fidelity long-read sequencing has made these dynamic regions of the genome accessible for sequence-level analyses within and between primate species., Competing Interests: Declaration of interests E.E.E. is a scientific advisory board (SAB) member of Variant Bio, Inc., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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5. Gastrointestinal tract pathology of the owl monkey ( Aotus spp.).
- Author
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Hensel ME, Rodrigues-Hoffmann A, Dray BK, Wilkerson GK, Baze WB, Sulkosky S, and Hodo CL
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- Animals, Aotidae, Carcinoma, Squamous Cell veterinary, Mouth Neoplasms veterinary, Gastrointestinal Diseases veterinary
- Abstract
Owl monkeys are small nocturnal new world primates in the genus Aotus that are most used in biomedical research for malaria. Cardiomyopathy and nephropathy are well-described common diseases contributing to their morbidity and mortality; less is known about lesions affecting the gastrointestinal tract. Records from a 14-year period (2008-2022) at the Keeling Center for Comparative Medicine and Research were queried to identify instances of spontaneous gastrointestinal disease that directly contributed to the cause of death from the 235 adult owl monkeys submitted for necropsy. Of the 235, 10.6% (25/235) had gastrointestinal disease listed as a significant factor that contributed to morbidity and mortality. Diagnoses included candidiasis (3/25), gastric bloat (4/25), and intestinal incarceration and ischemia secondary (11/25), which included intussusception (4/25), mesenteric rent (3/25), strangulating lipoma (2/25), intestinal torsion (1/25), and an inguinal hernia (1/25). Intestinal adenocarcinomas affecting the jejunum (4/25) were the most common neoplasia diagnosis. Oral squamous cell carcinoma (1/25) and intestinal lymphoma (2/25) were also diagnosed. This report provides evidence of spontaneous lesions in the species that contribute to morbidity and mortality., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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- 2024
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6. Exclusion of Horizontal and Vertical Transmission as Major Sources of Trypanosoma Cruzi Infections in a Breeding Colony of Rhesus Macaques ( Macaca Mulatta ).
- Author
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Kiehl WM, Hodo CL, Hamer GL, Hamer SA, and Wilkerson GK
- Subjects
- Humans, Animals, United States, Macaca mulatta, Retrospective Studies, Chagas Disease epidemiology, Chagas Disease veterinary, Trypanosoma cruzi
- Abstract
The vector-borne protozoal parasite Trypanosoma cruzi causes Chagas disease in humans and animals. This parasite is endemic to the southern United States where outdoor-housed NHP at biomedical facilities are at risk of infection. In addi- tion to the direct morbidity caused by T. cruzi , infected animals are of limited biomedical research use because infections can produce confounding pathophysiologic changes even in animals with no clinical disease. In part due to concerns for direct T. cruzi transmission between animals, infected NHP at some institutions have been culled, removed, or otherwise isolated from uninfected animal populations. However, data that document horizontal or vertical transmission in captive NHP in the United States are not available. To evaluate the potential for inter-animal transmission and to identify environmental factors that affect the distribution of new infections in NHPs, we conducted a retrospective epidemiologic study of a rhesus macaque ( Macaca mulatta ) breeding colony in south Texas. We used archived biologic samples and husbandry records to identify the time and location of macaque seroconversion. These data were used to perform a spatial analysis of how geographic location and animal associations affected the spread of disease and to infer the importance of horizontal or vertical routes of transmission. The majority of T. cruzi infections were spatially clustered, suggesting that environmental factors promoted vector exposure in various areas of the facility. Although we cannot not rule out horizontal transmission, our data suggest that horizontal transmission was not a critical route for spread for the disease. Vertical transmission was not a contributing factor in this colony. In conclusion, our findings suggest that local triatome vectors were the major source of T. cruzi infections in captive macaques in our colony. Therefore, limiting contact with vectors, rather than segregation of infected macaques, is a key strategy for disease prevention at institutions that house macaques outdoors in the southern United States.
- Published
- 2023
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7. Frequency Variation and Dose Modification of Benznidazole Administration for the Treatment of Trypanosoma cruzi Infection in Mice, Dogs, and Nonhuman Primates.
- Author
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Bustamante JM, White BE, Wilkerson GK, Hodo CL, Auckland LD, Wang W, McCain S, Hamer SA, Saunders AB, and Tarleton RL
- Subjects
- Mice, Dogs, Humans, Animals, Clinical Protocols, Primates, Mammals, Trypanocidal Agents therapeutic use, Trypanocidal Agents pharmacology, Chagas Disease drug therapy, Chagas Disease parasitology, Trypanosoma cruzi, Nitroimidazoles therapeutic use, Nitroimidazoles pharmacology
- Abstract
Trypanosoma cruzi naturally infects a broad range of mammalian species and frequently results in the pathology that has been most extensively characterized in human Chagas disease. Currently employed treatment regimens fail to achieve parasitological cure of T. cruzi infection in the majority of cases. In this study, we have extended our previous investigations of more effective, higher dose, intermittent administration protocols using the FDA-approved drug benznidazole (BNZ), in experimentally infected mice and in naturally infected dogs and nonhuman primates (NHP). Collectively, these studies demonstrate that twice-weekly administration of BNZ for more than 4 months at doses that are ~2.5-fold that of previously used daily dosing protocols, provided the best chance to obtain parasitological cure. Dosing less frequently or for shorter time periods was less dependable in all species. Prior treatment using an ineffective dosing regimen in NHPs did not prevent the attainment of parasitological cure with an intensified BNZ dosing protocol. Furthermore, parasites isolated after a failed BNZ treatment showed nearly identical susceptibility to BNZ as those obtained prior to treatment, confirming the low risk of induction of drug resistance with BNZ and the ability to adjust the treatment protocol when an initial regimen fails. These results provide guidance for the use of BNZ as an effective treatment for T. cruzi infection and encourage its wider use, minimally in high value dogs and at-risk NHP, but also potentially in humans, until better options are available., Competing Interests: The authors declare no conflict of interest.
- Published
- 2023
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8. The role of flumazenil in generalised anxiety disorder: a pilot naturalistic open-label study with a focus on treatment resistance.
- Author
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Gallo AT, Addis S, Martyn V, Ramanathan H, Wilkerson GK, Bennett KS, Hood SD, Stampfer H, and Hulse GK
- Abstract
Background: Anxiety disorders are highly prevalent and chronic disorders with treatment resistance to current pharmacotherapies occurring in approximately one in three patients. It has been postulated that flumazenil (FMZ) is efficacious in the management of anxiety disorders via the removal of α
4 β2δ gamma-aminobutyric acid A receptors., Objective: To assess the safety and feasibility of continuous low-dose FMZ infusions for the management of generalised anxiety disorder (GAD) and collect preliminary efficacy data., Design: Uncontrolled, open-label pilot study., Method: Participants had a primary diagnosis of generalised anxiety disorder (GAD) and received two consecutive subcutaneous continuous low-dose FMZ infusions. Each infusion contained 16 mg of FMZ and was delivered over 96 ± 19.2 h. The total dose of FMZ delivered was 32 mg over approximately 8 days. Sodium valproate was given to participants at risk of seizure. The primary outcome was the change in stress and anxiety subscale scores on the Depression Anxiety Stress Scale-21 between baseline, day 8, and day 28., Results: Nine participants with a primary diagnosis of GAD were treated with subcutaneous continuous low-dose FMZ infusions; seven participants met the criteria for treatment resistance. There was a significant decrease in anxiety and stress between baseline and day 8 and baseline and day 28. There was also a significant improvement in subjective sleep quality from baseline to day 28 measured by the Jenkins Sleep Scale. No serious adverse events occurred., Conclusion: This study presents preliminary results for subcutaneous continuous low-dose FMZ's effectiveness and safety in GAD. The findings suggest that it is a safe, well-tolerated, and feasible treatment option in this group of patients. Future randomised control trials are needed in this field to determine the efficacy of this treatment., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2023.)- Published
- 2023
- Full Text
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9. Structurally divergent and recurrently mutated regions of primate genomes.
- Author
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Mao Y, Harvey WT, Porubsky D, Munson KM, Hoekzema K, Lewis AP, Audano PA, Rozanski A, Yang X, Zhang S, Gordon DS, Wei X, Logsdon GA, Haukness M, Dishuck PC, Jeong H, Del Rosario R, Bauer VL, Fattor WT, Wilkerson GK, Lu Q, Paten B, Feng G, Sawyer SL, Warren WC, Carbone L, and Eichler EE
- Abstract
To better understand the pattern of primate genome structural variation, we sequenced and assembled using multiple long-read sequencing technologies the genomes of eight nonhuman primate species, including New World monkeys (owl monkey and marmoset), Old World monkey (macaque), Asian apes (orangutan and gibbon), and African ape lineages (gorilla, bonobo, and chimpanzee). Compared to the human genome, we identified 1,338,997 lineage-specific fixed structural variants (SVs) disrupting 1,561 protein-coding genes and 136,932 regulatory elements, including the most complete set of human-specific fixed differences. Across 50 million years of primate evolution, we estimate that 819.47 Mbp or ~27% of the genome has been affected by SVs based on analysis of these primate lineages. We identify 1,607 structurally divergent regions (SDRs) wherein recurrent structural variation contributes to creating SV hotspots where genes are recurrently lost ( CARDs , ABCD7 , OLAH ) and new lineage-specific genes are generated (e.g., CKAP2 , NEK5 ) and have become targets of rapid chromosomal diversification and positive selection (e.g., RGPD s). High-fidelity long-read sequencing has made these dynamic regions of the genome accessible for sequence-level analyses within and between primate species for the first time., Competing Interests: Competing interests E.E.E. is a scientific advisory board (SAB) member of Variant Bio, Inc. The other authors declare no competing interests.
- Published
- 2023
- Full Text
- View/download PDF
10. Frequency variation and dose modification of benznidazole administration for the treatment of Trypanosoma cruzi infection in mice, dogs and non-human primates.
- Author
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Bustamante JM, White BE, Wilkerson GK, Hodo CL, Auckland LD, Wang W, McCain S, Hamer SA, Saunders AB, and Tarleton RL
- Abstract
Trypanosoma cruzi naturally infects a broad range of mammalian species and frequently results in the pathology that has been most extensively characterized in human Chagas disease. Currently employed treatment regimens fail to achieve parasitological cure of T. cruzi infection in the majority of cases. In this study, we have extended our previous investigations of more effective, higher dose, intermittent administration protocols using the FDA-approved drug benznidazole (BNZ), in experimentally infected mice and in naturally infected dogs and non-human primates (NHP). Collectively these studies demonstrate that twice-weekly administration of BNZ for more than 4 months at doses that are ∼2.5-fold that of previously used daily dosing protocols, provided the best chance to obtain parasitological cure. Dosing less frequently or for shorter time periods was less dependable in all species. Prior treatment using an ineffective dosing regimen in NHPs did not prevent the attainment of parasitological cure with an intensified BNZ dosing protocol. Furthermore, parasites isolated after a failed BNZ treatment showed nearly identical susceptibility to BNZ as those obtained prior to treatment, confirming the low risk of induction of drug resistance with BNZ and the ability to adjust the treatment protocol when an initial regimen fails. These results provide guidance for the use of BNZ as an effective treatment for T. cruzi infection and encourage its wider use, minimally in high value dogs and at-risk NHP, but also potentially in humans, until better options are available.
- Published
- 2023
- Full Text
- View/download PDF
11. Treatment Strategies and Mechanisms Associated with the Prevention of NASH-Associated HCC by a Toll-like Receptor 4 Inhibitor.
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Kwan SY, Slayden AN, Coronado AR, Marquez RC, Chen H, Wei P, Savage MI, Vornik LA, Fox JT, Sei S, Liang D, Stevenson HL, Wilkerson GK, Gagea M, Brown PH, and Beretta L
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- Animals, Mice, Endothelial Cells, Toll-Like Receptor 4, Carcinoma, Hepatocellular etiology, Carcinoma, Hepatocellular prevention & control, Liver Neoplasms etiology, Liver Neoplasms prevention & control, Non-alcoholic Fatty Liver Disease complications, Non-alcoholic Fatty Liver Disease drug therapy
- Abstract
We evaluated the cancer preventive efficacy of TAK-242, an inhibitor of Toll-like receptor 4 (TLR4), in a mouse model of hepatocellular carcinoma (HCC) occurring in the context of nonalcoholic steatohepatitis (NASH). We also assessed the cellular events associated with the preventive treatment efficacy. We tested oral administration of TAK-242, at clinically relevant but toxicity-reducing doses and scheduling, in mice with hepatocyte-specific deletion of Pten (HepPten-). The optimal dose and oral gavage formulation of TAK-242 were determined to be 30 mg/kg in 5% DMSO in 30% 2-hydroxypropyl-β-cyclodextrin. Daily oral administration of 30 mg/kg TAK-242 over 18 weeks was well tolerated and resulted in reduced development of tumors (lesions > 7.5 mm3) in HepPten- mice. This effect was accompanied by reduced macrovesicular steatosis and serum levels of alanine aminotransferase. In addition, 30 mg/kg TAK-242 daily treatment of small preexisting adenomas (lesions < 7.5 mm3) over 18 weeks, significantly reduced their progression to HCC. RNA sequencing identified 220 hepatic genes significantly altered upon TAK-242 treatment, that significantly correlated with tumor burden. Finally, cell deconvolution analysis revealed that TAK-242 treatment resulted in reduced hepatic populations of endothelial cells and myeloid-derived immune cells (Kupffer cells, Siglec-H high dendritic cells, and neutrophilic granule protein high neutrophils), while the proportion of mt-Nd4 high hepatocytes significantly increased, suggesting a decrease in hepatic inflammation and concomitant increase in mitochondrial function and oxidative phosphorylation upon TLR4 inhibition. In conclusion, this study identified treatment strategies and novel molecular and cellular mechanisms associated with the prevention of HCC in the context of NASH that merit further investigations., Prevention Relevance: Means to prevent development of HCC or progression of small adenomas to HCC in patients with NASH are urgently needed to reduce the growing mortality due to HCC. We characterized the chemopreventive effect of oral administration of the TLR4 inhibitor TAK-242 in a model of NASH-associated HCC., (©2022 American Association for Cancer Research.)
- Published
- 2023
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12. Long-Term Management of Generalised Anxiety Disorder with Low-Dose Continuous Infusions of Flumazenil: A Case Series.
- Author
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Gallo AT, Addis S, Martyn V, Ramanathan H, Wilkerson GK, Hood SD, Stampfer H, and Hulse GK
- Abstract
Background: Generalised anxiety disorder (GAD) is a common anxiety disorder associated with social and occupational impairment. Recently, a theory was postulated that dysfunctional gamma aminobutyric acid type A receptors (GABA
A ) are implicated in anxiety symptomology, which could be corrected by flumazenil, an antagonist at the benzodiazepine binding site on the GABAA receptor., Method: Participants had a primary diagnosis of GAD and were treated initially with an eight-day continuous low-dose flumazenil infusion (total 32 mg at a rate of 4 mg/24 h). Some participants were re-treated with a further four- or eight-day infusion. Treatment response was measured as a 50% reduction in anxiety or stress scores on the Depression Anxiety Stress Scale-21 (DASS-21). Remission was measured as scores ≤3 or ≤7 on the anxiety and stress subscales of the DASS-21, respectively., Results: Eight cases are reported. All cases met the criteria for treatment response on the anxiety and stress subscale of the DASS-21. Remission was achieved in seven participants on the anxiety subscale and in five on the stress subscale. No changes in hepatic, renal, or haematological function were likely attributed to flumazenil., Conclusion: Data suggest that low-dose continuous flumazenil infusion manages GAD symptoms and is safe. Although these results are promising, future randomised control trials are required to confirm these results.- Published
- 2022
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13. Primate hemorrhagic fever-causing arteriviruses are poised for spillover to humans.
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Warren CJ, Yu S, Peters DK, Barbachano-Guerrero A, Yang Q, Burris BL, Worwa G, Huang IC, Wilkerson GK, Goldberg TL, Kuhn JH, and Sawyer SL
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- Animals, Humans, Macaca, Primates, Viral Zoonoses, Virus Internalization, Virus Replication, Arterivirus physiology, Hemorrhagic Fevers, Viral veterinary, Hemorrhagic Fevers, Viral virology
- Abstract
Simian arteriviruses are endemic in some African primates and can cause fatal hemorrhagic fevers when they cross into primate hosts of new species. We find that CD163 acts as an intracellular receptor for simian hemorrhagic fever virus (SHFV; a simian arterivirus), a rare mode of virus entry that is shared with other hemorrhagic fever-causing viruses (e.g., Ebola and Lassa viruses). Further, SHFV enters and replicates in human monocytes, indicating full functionality of all of the human cellular proteins required for viral replication. Thus, simian arteriviruses in nature may not require major adaptations to the human host. Given that at least three distinct simian arteriviruses have caused fatal infections in captive macaques after host-switching, and that humans are immunologically naive to this family of viruses, development of serology tests for human surveillance should be a priority., Competing Interests: Declaration of interests S.L.S. and Q.Y. are co-founders of, equity holders of, and consultants for Darwin Biosciences. S.L.S is on the scientific advisory board for Darwin Biosciences. S.L.S. serves as a consultant for the MITRE Corporation and is a member of the Planning Committee for Countering Zoonotic Spillover of High Consequence Pathogens, sponsored by the U.S. National Academies of Sciences, Engineering, and Medicine., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2022
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14. Discovery of an orally active benzoxaborole prodrug effective in the treatment of Chagas disease in non-human primates.
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Padilla AM, Wang W, Akama T, Carter DS, Easom E, Freund Y, Halladay JS, Liu Y, Hamer SA, Hodo CL, Wilkerson GK, Orr D, White B, George A, Shen H, Jin Y, Wang MZ, Tse S, Jacobs RT, and Tarleton RL
- Subjects
- Animals, Primates, Chagas Disease drug therapy, Chagas Disease parasitology, Prodrugs pharmacology, Prodrugs therapeutic use, Trypanocidal Agents pharmacology, Trypanocidal Agents therapeutic use, Trypanosoma cruzi
- Abstract
Trypanosoma cruzi, the agent of Chagas disease, probably infects tens of millions of people, primarily in Latin America, causing morbidity and mortality. The options for treatment and prevention of Chagas disease are limited and underutilized. Here we describe the discovery of a series of benzoxaborole compounds with nanomolar activity against extra- and intracellular stages of T. cruzi. Leveraging both ongoing drug discovery efforts in related kinetoplastids, and the exceptional models for rapid drug screening and optimization in T. cruzi, we have identified the prodrug AN15368 that is activated by parasite carboxypeptidases to yield a compound that targets the messenger RNA processing pathway in T. cruzi. AN15368 was found to be active in vitro and in vivo against a range of genetically distinct T. cruzi lineages and was uniformly curative in non-human primates (NHPs) with long-term naturally acquired infections. Treatment in NHPs also revealed no detectable acute toxicity or long-term health or reproductive impact. Thus, AN15368 is an extensively validated and apparently safe, clinically ready candidate with promising potential for prevention and treatment of Chagas disease., (© 2022. The Author(s).)
- Published
- 2022
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15. Histopathological Analysis of Adrenal Glands after Simian Varicella Virus Infection.
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Niemeyer CS, Mescher T, Griggs R, Orlicky DJ, Wilkerson GK, Bubak AN, Hassell JE Jr, Feia B, Mahalingam R, Traina-Dorge V, and Nagel MA
- Subjects
- Adrenal Glands cytology, Animals, Female, Herpesviridae Infections virology, Histological Techniques, Macaca fascicularis virology, Male, Adrenal Glands pathology, Adrenal Glands virology, Herpesviridae Infections pathology, Herpesvirus 3, Human pathogenicity
- Abstract
Latent varicella zoster virus (VZV) has been detected in human adrenal glands, raising the possibility of virus-induced adrenal damage and dysfunction during primary infection or reactivation. Rare cases of bilateral adrenal hemorrhage and insufficiency associated with VZV reactivation have been reported. Since there is no animal model for VZV infection of adrenal glands, we obtained adrenal glands from two non-human primates (NHPs) that spontaneously developed varicella from primary simian varicella virus (SVV) infection, the NHP VZV homolog. Histological and immunohistochemical analysis revealed SVV antigen and DNA in the adrenal medulla and cortex of both animals. Adrenal glands were observed to have Cowdry A inclusion bodies, cellular necrosis, multiple areas of hemorrhage, and varying amounts of polymorphonuclear cells. No specific association of SVV antigen with βIII-tubulin-positive nerve fibers was found. Overall, we found that SVV can productively infect NHP adrenal glands, and is associated with inflammation, hemorrhage, and cell death. These findings suggest that further studies are warranted to examine the contribution of VZV infection to human adrenal disease. This study also suggests that VZV infection may present itself as acute adrenal dysfunction with "long-hauler" symptoms of fatigue, weakness, myalgias/arthralgias, and hypotension.
- Published
- 2021
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16. Effects of relocation on immunological and physiological measures in female squirrel monkeys (Saimiri boliviensis boliviensis).
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Nehete PN, Nehete BP, Wilkerson GK, Schapiro SJ, and Williams LE
- Subjects
- Animal Husbandry methods, Animals, Antigens, CD20, B-Lymphocytes, Cytokines blood, Female, Leukocytes, Mononuclear classification, Lymphocyte Count methods, Lymphocyte Subsets classification, Mitogens, Phenotype, Saimiri physiology, Serum chemistry, Stress, Physiological physiology, T-Lymphocytes, Transportation methods, Acclimatization immunology, Saimiri immunology, Stress, Physiological immunology
- Abstract
In the present study, we have quantified the effects of transport, relocation and acclimate/adapt to their new surroundings on female squirrel monkey. These responses are measured in blood samples obtained from squirrel monkeys, at different time points relative to their relocation from their old home to their new home. A group of squirrel monkeys we transported, by truck, for approximately 10 hours. Peripheral blood mononuclear cells (PBMCs) were assayed in order to evaluate the phenotype of lymphocyte subsets by flow, mitogen-specific immune responses of PBMCs in vitro, and levels of cytokines at various time points including immediately before transport, immediately upon arrival, and after approximately 150 days of acclimation. We observed significant changes in T cells and subsets, NK and B cells (CD4+, CD8+, CD4+/CD8+, CD16+, and CD20+). Mitogen specific (e.g. PHA, PWM and LPS) proliferation responses, IFN-γ by ELISPOT assay, and cytokines (IL-2, IL-4 and VEGF) significant changes were observed. Changes seen in the serum chemistry measurements mostly complement those seen in the hematology data. The specific goal was to empirically assess the effects of relocation stress in squirrel monkeys in terms of changes in the numbers and functions of various leukocyte subsets in the blood and the amount of time required for acclimating to their new environment. Such data will help to determine when newly arrived animals become available for use in research studies., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
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17. Reproductive Outcomes in Rhesus Macaques ( Macaca mulatta ) with Naturally-acquired Trypanosoma cruzi Infection.
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Kendricks AL, Gray SB, Wilkerson GK, Sands CM, Abee CR, Bernacky BJ, Hotez PJ, Bottazzi ME, Craig SL, and Jones KM
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- Animals, Enzyme-Linked Immunosorbent Assay veterinary, Female, Macaca mulatta, Male, Pregnancy, Retrospective Studies, Seroepidemiologic Studies, Trypanosoma cruzi isolation & purification, Chagas Disease veterinary, Monkey Diseases, Pregnancy Outcome veterinary
- Abstract
Chagas disease is a zoonotic vector-borne disease caused by infection with the protozoan parasite Trypanosoma cruzi. T. cruzi is found in Latin America and the Southern United States, where it infects many species, including humans and nonhuman primates (NHPs). NHPs are susceptible to natural infection and can develop clinical symptoms consistent with human disease, including Chagasic cardiomyopathy, gastrointestinal disease and transplacental transmission, leading to congenital infection. Due to evidence of Chagas transmission in Texas, this study hypothesized T. cruzi infection was present in a closed, outdoor-housed breeding colony of rhesus macaques ( Macaca mulatta ) located at a biomedical research facility in Central Texas. In addition, we questioned whether seropositive female rhesus macaques might experience reproductive complications consistent with maternal-fetal Chagas disease. The seroprevalence of T. cruzi infection in the colony was assessed using an Enzyme Linked Immunosorbant Assay (ELISA) to detect antibodies against Tc24 antigen as a screening assay, and a commercially available immunochromatographic test (Chagas Stat Pak) as a confirmatory assay. Retrospective serologic analysis was performed to confirm the status of all T. cruzi -infected animals between the years 2012 to 2016. The medical history of all seropositive and seronegative breeding females within the colony from 2012 to 2016 was reviewed to determine each animals' level of reproductive fitness. The percentage of T. cruzi -seropositive animals ranged from 6.7% to 9.7% in adult animals and 0% to 0.44% in juveniles or weanling animals, depending on the year. An overall 3.9% seroprevalence of T. cruzi infection was found in the total population. No significant differences in any measure of reproductive outcomes were identified between seropositive and seronegative females from 2012 to 2016. The lack of significant adverse reproductive outcomes reported here may help inform future management decisions regarding seropositive female rhesus macaques within breeding colonies.
- Published
- 2020
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18. Lymphocytes upregulate CD36 in adipose tissue and liver.
- Author
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Couturier J, Nuotio-Antar AM, Agarwal N, Wilkerson GK, Saha P, Kulkarni V, Lakhashe SK, Esquivel J, Nehete PN, Ruprecht RM, Sastry KJ, Meyer JM, Hill LR, Lake JE, Balasubramanyam A, and Lewis DE
- Subjects
- Adipose Tissue cytology, Animals, CD36 Antigens metabolism, Humans, Liver cytology, Macaca mulatta, Male, Mice, Mice, Inbred C57BL, Up-Regulation, Adipose Tissue metabolism, CD36 Antigens genetics, CD4-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes metabolism, Liver metabolism
- Abstract
CD36 is a multifunctional scavenger receptor and lipid transporter implicated in metabolic and inflammatory pathologies, as well as cancer progression. CD36 is known to be expressed by adipocytes and monocytes/macrophages, but its expression by T cells is not clearly established. We found that CD4 and CD8 T cells in adipose tissue and liver of humans, monkeys, and mice upregulated CD36 expression (ranging from ~5-40% CD36+), whereas little to no CD36 was expressed by T cells in blood, spleen, and lymph nodes. CD36 was expressed predominantly by resting CD38-, HLA.DR-, and PD-1- adipose tissue T cells in monkeys, and increased during high-fat feeding in mice. Adipose tissue and liver promote a distinct phenotype in resident T cells characterized by CD36 upregulation.
- Published
- 2019
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19. Selective use of primate CD4 receptors by HIV-1.
- Author
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Warren CJ, Meyerson NR, Dirasantha O, Feldman ER, Wilkerson GK, and Sawyer SL
- Subjects
- Animals, Aotidae, CD4 Antigens genetics, Cell Line, Disease Models, Animal, HEK293 Cells, HIV Envelope Protein gp120 genetics, HIV Infections genetics, HIV Seropositivity genetics, HIV Seropositivity immunology, HIV-1 immunology, Humans, Macaca mulatta, Primates immunology, env Gene Products, Human Immunodeficiency Virus genetics, env Gene Products, Human Immunodeficiency Virus metabolism, CD4 Antigens immunology, HIV Infections immunology, HIV-1 genetics
- Abstract
Individuals chronically infected with HIV-1 harbor complex viral populations within their bloodstreams. Recently, it has come to light that when these people infect others, the new infection is typically established by only one or a small number of virions from within this complex viral swarm. An important goal is to characterize the biological properties of HIV-1 virions that seed and exist early in new human infections because these are potentially the only viruses against which a prophylactic HIV-1 vaccine would need to elicit protection. This includes understanding how the Envelope (Env) protein of these virions interacts with the T-cell receptor CD4, which supports attachment and entry of HIV-1 into target cells. We examined early HIV-1 isolates for their ability to infect cells via the CD4 receptor of 15 different primate species. Primates were the original source of HIV-1 and now serve as valuable animal models for studying HIV-1. We find that most primary isolates of HIV-1 from the blood, including early isolates, are highly selective and enter cells through some primate CD4 receptor orthologs but not others. This phenotype is remarkably consistent, regardless of route of transmission, viral subtype, or time of isolation post infection. We show that the weak CD4 binding affinity of blood-derived HIV-1 isolates is what makes them sensitive to the small sequence differences in CD4 from one primate species to the next. To substantiate this, we engineered an early HIV-1 Env to have high, medium, or low binding affinity to CD4, and we show that it loses the ability to enter cells via the CD4 receptor of many primate species as the binding affinity gets weaker. Based on the phenotype of selective use of primate CD4, we find that weak CD4 binding appears to be a nearly universal property of HIV-1 circulating in the bloodstream. Therefore, weak binding to CD4 must be a selected and important property in the biology of HIV-1 in the body. We identify six primate species that encode CD4 receptors that fully support the entry of early HIV-1 isolates despite their low binding affinity for CD4. These findings will help inform long-standing efforts to model HIV-1 transmission and early disease in primates., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
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20. A glycan shield on chimpanzee CD4 protects against infection by primate lentiviruses (HIV/SIV).
- Author
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Warren CJ, Meyerson NR, Stabell AC, Fattor WT, Wilkerson GK, and Sawyer SL
- Subjects
- Animals, Cell Line, Glycosylation, HEK293 Cells, HIV Infections virology, Humans, Polymorphism, Single Nucleotide immunology, Simian Acquired Immunodeficiency Syndrome virology, CD4 Antigens immunology, HIV Infections immunology, HIV-1 immunology, Pan troglodytes immunology, Pan troglodytes virology, Polysaccharides immunology, Simian Acquired Immunodeficiency Syndrome immunology, Simian Immunodeficiency Virus immunology
- Abstract
Pandemic HIV-1 (group M) emerged following the cross-species transmission of a simian immunodeficiency virus from chimpanzees (SIVcpz) to humans. Primate lentiviruses (HIV/SIV) require the T cell receptor CD4 to enter into target cells. By surveying the sequence and function of CD4 in 50 chimpanzee individuals, we find that all chimpanzee CD4 alleles encode a fixed, chimpanzee-specific substitution (34T) that creates a glycosylation site on the virus binding surface of the CD4 receptor. Additionally, a single nucleotide polymorphism (SNP) has arisen in chimpanzee CD4 (68T) that creates a second glycosylation site on the same virus-binding interface. This substitution is not yet fixed, but instead alleles containing this SNP are still circulating within chimpanzee populations. Thus, all allelic versions of chimpanzee CD4 are singly glycosylated at the virus binding surface, and some allelic versions are doubly glycosylated. Doubly glycosylated forms of chimpanzee CD4 reduce HIV-1 and SIVcpz infection by as much as two orders of magnitude. Full restoration of virus infection in cells bearing chimpanzee CD4 requires reversion of both threonines at sites 34 and 68, destroying both of the glycosylation sites, suggesting that the effects of the glycans are additive. Differentially glycosylated CD4 receptors were biochemically purified and used in neutralization assays and microscale thermophoresis to show that the glycans on chimpanzee CD4 reduce binding affinity with the lentiviral surface glycoprotein, Env. These glycans create a shield that protects CD4 from being engaged by viruses, demonstrating a powerful form of host resistance against deadly primate lentiviruses., Competing Interests: The authors declare no conflict of interest.
- Published
- 2019
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21. Mammosphere Culture of Mammary Cells from Cynomolgus Macaques ( Macaca fascicularis ).
- Author
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Mariya S, Dewi FN, Suparto IH, Wilkerson GK, Cline MJ, Iskandriati D, Budiarsa NI, and Sajuthi D
- Subjects
- Animals, Breast Neoplasms pathology, Cell Differentiation, Disease Models, Animal, Female, Humans, Macaca fascicularis, Neoplastic Stem Cells pathology, Cell Proliferation physiology, Mammary Glands, Animal pathology
- Abstract
The mammary gland contains adult stem cells that are capable of self-renewal. Although these cells hold an important role in the biology and pathology of the breast, the studies of mammary stem cells are few due to the difficulty of acquiring and expanding undifferentiated adult stem cell populations. In this study, we developed mammosphere cultures from frozen mammary cells of nulliparous cynomolgus macaques ( Macaca fascicularis ) as a culture system to enrich mammary stem cells. Small samples of mammary tissues were collected by surgical biopsy; cells were cultured in epithelial cell growth medium and cryopreserved. Cryopreserved cells were cultured into mammospheres, and the expression of markers for stemness was evaluated by using quantitative PCR analysis. Cells were further differentiated by using 2D and 3D approaches to evaluate morphology and organoid budding, respectively. The study showed that mammosphere culture resulted in an increase in the expression of mammary stem cell markers with each passage. In contrast, markers for epithelial cells and pluripotency decreased across multiple passages. The 2D differentiation of the cells showed heterogeneous morphology, whereas 3D differentiation allowed for organoid formation. The results indicate that mammospheres can be successfully developed from frozen mammary cells derived from breast tissue collected from nulliparous cynomolgus macaques through surgical biopsy. Because mammosphere cultures allow for the enrichment of a mammary stem cell population, this refined method provides a model for the in vitro or ex vivo study of mammary stem cells.
- Published
- 2019
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22. Adipocytes impair efficacy of antiretroviral therapy.
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Couturier J, Winchester LC, Suliburk JW, Wilkerson GK, Podany AT, Agarwal N, Xuan Chua CY, Nehete PN, Nehete BP, Grattoni A, Sastry KJ, Fletcher CV, Lake JE, Balasubramanyam A, and Lewis DE
- Subjects
- CD4-Positive T-Lymphocytes drug effects, Cells, Cultured, Coculture Techniques, Disease Reservoirs virology, HIV Infections drug therapy, HIV-1 physiology, Humans, Prodrugs therapeutic use, Tenofovir therapeutic use, Virus Replication drug effects, Adipocytes cytology, Anti-HIV Agents therapeutic use, CD4-Positive T-Lymphocytes virology, HIV-1 drug effects, Reverse Transcriptase Inhibitors therapeutic use
- Abstract
Adequate distribution of antiretroviral drugs to infected cells in HIV patients is critical for viral suppression. In humans and primates, HIV- and SIV-infected CD4 T cells in adipose tissues have recently been identified as reservoirs for infectious virus. To better characterize adipose tissue as a pharmacological sanctuary for HIV-infected cells, in vitro experiments were conducted to assess antiretroviral drug efficacy in the presence of adipocytes, and drug penetration in adipose tissue cells (stromal-vascular-fraction cells and mature adipocytes) was examined in treated humans and monkeys. Co-culture experiments between HIV-1-infected CD4 T cells and primary human adipocytes showed that adipocytes consistently reduced the antiviral efficacy of the nucleotide reverse transcriptase inhibitor tenofovir and its prodrug forms tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). In HIV-infected persons, LC-MS/MS analysis of intracellular lysates derived from adipose tissue stromal-vascular-fraction cells or mature adipocytes suggested that integrase inhibitors penetrate adipose tissue, whereas penetration of nucleoside/nucleotide reverse transcriptase inhibitors such as TDF, emtricitabine, abacavir, and lamivudine is restricted. The limited distribution and functions of key antiretroviral drugs within fat depots may contribute to viral persistence in adipose tissue., (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Published
- 2018
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23. Trypanosoma cruzi Transmission Among Captive Nonhuman Primates, Wildlife, and Vectors.
- Author
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Hodo CL, Wilkerson GK, Birkner EC, Gray SB, and Hamer SA
- Subjects
- Animal Diseases transmission, Animals, DNA, Protozoan, Female, Male, Mephitidae parasitology, Monkey Diseases parasitology, Opossums parasitology, Polymerase Chain Reaction, Raccoons parasitology, Rodentia parasitology, Animal Diseases parasitology, Animals, Wild parasitology, Insect Vectors parasitology, Macaca mulatta parasitology, Triatominae parasitology, Trypanosoma cruzi parasitology
- Abstract
Natural infection of captive nonhuman primates (NHPs) with Trypanosoma cruzi (agent of Chagas disease) is an increasingly recognized problem in facilities across the southern USA, with negative consequences for NHP health and biomedical research. We explored a central Texas NHP facility as a nidus of transmission by characterizing parasite discrete typing units (DTU) in seropositive rhesus macaques (Macaca mulatta), identifying the wildlife reservoirs, and characterizing vector infection. In seropositive NHPs, we documented low and intermittent concentrations of circulating T. cruzi DNA, with two DTUs in equal proportions, TcI and TcIV. In contrast, consistently high concentrations of T. cruzi DNA were found in wild mesomammals at the facility, yet rodents were PCR-negative. Strong wildlife host associations were found in which raccoons (Procyon lotor) harbored TcIV and opossums (Didelphis virginiana) harbored TcI, while skunks (Mephitis mephitis) were infected with both DTUs. Active and passive vector surveillance yielded three species of triatomines from the facility and in proximity to the NHP enclosures, with 17% T. cruzi infection prevalence. Interventions to protect NHP and human health must focus on interrupting spillover from the robust sylvatic transmission in the surrounding environment.
- Published
- 2018
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24. Experimental Zika Virus Infection of Neotropical Primates.
- Author
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Vanchiere JA, Ruiz JC, Brady AG, Kuehl TJ, Williams LE, Baze WB, Wilkerson GK, Nehete PN, McClure GB, Rogers DL, Rossi SL, Azar SR, Roundy CM, Weaver SC, Vasilakis N, Simmons JH, and Abee CR
- Subjects
- Animals, Disease Susceptibility veterinary, Disease Susceptibility virology, Female, Male, Viral Load veterinary, Viremia veterinary, Viremia virology, Aotidae virology, Primate Diseases virology, Saimiri virology, Zika Virus, Zika Virus Infection veterinary
- Abstract
The establishment of a sylvatic reservoir of Zika virus (ZIKV) in the Americas is dependent on the susceptibility of primates of sufficient population density, the duration and magnitude of viremia, and their exposure to the human mosquito-borne transmission cycle. To assess the susceptibility of squirrel ( Saimiri sp.) and owl monkeys ( Aotus sp.) to infection, we inoculated four animals of each species with ZIKV from the current epidemic. Viremia in the absence of detectible disease was observed in both species and seroconversion occurred by day 28. ZIKV was detected in the spleen of three owl monkeys: one at 7 days postinoculation (dpi) and two at 14 dpi. This study confirms the susceptibility to ZIKV infection of two Neotropical primate species that live in close proximity to humans in South America, suggesting that they could support a widespread sylvatic ZIKV cycle there. Collectively, establishment of a ZIKV sylvatic transmission cycle in South America would imperil eradication efforts and could provide a mechanism for continued exposure of humans to ZIKV infection and disease.
- Published
- 2018
- Full Text
- View/download PDF
25. Owl monkey CCR5 reveals synergism between CD4 and CCR5 in HIV-1 entry.
- Author
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Nahabedian J, Sharma A, Kaczmarek ME, Wilkerson GK, Sawyer SL, and Overbaugh J
- Subjects
- Amino Acid Sequence, Animals, Aotidae, HEK293 Cells, Humans, Mutation, Receptors, CCR5 genetics, Virus Replication, CD4 Antigens physiology, HIV-1 physiology, Receptors, CCR5 metabolism, Virus Internalization
- Abstract
Studying HIV-1 replication in the presence of functionally related proteins from different species has helped define host determinants of HIV-1 infection. Humans and owl monkeys, but not macaques, encode a CD4 receptor that permits entry of transmissible HIV-1 variants due to a single residue difference. However, little is known about whether divergent CCR5 receptor proteins act as determinants of host-range. Here we show that both owl monkey (Aotus vociferans) CD4 and CCR5 receptors are functional for the entry of transmitted HIV-1 when paired with human versions of the other receptor. By contrast, the owl monkey CD4/CCR5 pair is generally a suboptimal receptor combination, although there is virus-specific variation in infection with owl monkey receptors. Introduction of the human residues 15Y and 16T within a sulfation motif into owl monkey CCR5 resulted in a gain of function. These findings suggest there is cross-talk between CD4 and CCR5 involving the sulfation motif., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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26. Use of an Implantable Loop Recorder in a Chimpanzee (Pan troglodytes) to Monitor Cardiac Arrhythmias and Assess the Effects of Acupuncture and Laser Therapy.
- Author
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Magden ER, Sleeper MM, Buchl SJ, Jones RA, Thiele EJ, and Wilkerson GK
- Subjects
- Animals, Ape Diseases physiopathology, Electrocardiography, Ambulatory instrumentation, Equipment Design, Heart Rate, Male, Predictive Value of Tests, Time Factors, Treatment Outcome, Ventricular Premature Complexes diagnosis, Ventricular Premature Complexes physiopathology, Ventricular Premature Complexes therapy, Acupuncture Therapy veterinary, Ape Diseases diagnosis, Ape Diseases therapy, Electrocardiography, Ambulatory veterinary, Laser Therapy veterinary, Pan troglodytes, Ventricular Premature Complexes veterinary
- Abstract
Cardiovascular disease is a leading cause of death in captive chimpanzees and is often associated with myocardial fibrosis, which increases the risk of cardiac arrhythmias. In this case report, we present a 36-y-old male chimpanzee (Pan troglodytes) diagnosed with frequent ventricular premature complexes (VPC). We placed a subcutaneous implantable loop recorder for continual ECG monitoring to assess his arrhythmias without the confounding effects of anesthetics. During his initial treatment with the antiarrhythmia medication amiodarone, he developed thrombocytopenia, and the drug was discontinued. After reviewing other potential therapies for the treatment of cardiac arrhythmias, we elected to try acupuncture and laser therapy in view of the positive results and the lack of adverse side effects reported in humans. We used 2 well-known cardiac acupuncture sites on the wrist, PC6 (pericardium 6) and HT7 (heart 7), and evaluated the results of the therapy by using the ECG recordings from the implantable loop recorder. Although periodic increases in the animal's excitement level introduced confounding variables that caused some variation in the data, acupuncture and laser therapy appeared to decrease the mean number of VPC/min in this chimpanzee.
- Published
- 2016
27. Mural Dissections of Brain-Supplying Arteries in a Chimpanzee (Pan troglodytes).
- Author
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Baze WB, Storts RW, Wilkerson GK, Buchl SJ, Magden ER, and Chaffee BK
- Subjects
- Animals, Female, Pan troglodytes, Arteries pathology, Brain blood supply
- Abstract
We describe the pathologic features of mural arterial dissection involving brain-supplying arteries in a 31-y-old female chimpanzee (Pan troglodytes). Several hours after examination for a possible respiratory tract infection, the chimpanzee became unresponsive, developed seizures, and died within 18 h. At necropsy, the occipital cortex of the brain had a small area of congestion, and the cerebellar cortex contained a small necrotic area. Histologic evaluation confirmed the cortical lesions and revealed an additional necrotic area in the medulla oblongata characterized by mural dissection of the brain-supplying vertebral and basilar arteries and subsequent branches. Lesions in the cortices and medulla were within areas supplied by the vertebrobasilar system. Dissection of brain-supplying arteries has been described in humans but not previously in chimpanzees (or any other NHP), suggesting that these species might be useful in understanding this condition in humans. In addition, the lesion should be added to the NHP clinician's and pathologist's differential diagnosis list for similar presentations in this species.
- Published
- 2015
28. Identification of Owl Monkey CD4 Receptors Broadly Compatible with Early-Stage HIV-1 Isolates.
- Author
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Meyerson NR, Sharma A, Wilkerson GK, Overbaugh J, and Sawyer SL
- Subjects
- Animals, Base Sequence, CD4 Antigens genetics, DNA Primers genetics, Flow Cytometry, Genotype, Molecular Sequence Data, Selection, Genetic, Sequence Analysis, DNA, Species Specificity, Aotidae genetics, CD4 Antigens metabolism, Evolution, Molecular, Genetic Variation, HIV-1 metabolism
- Abstract
Unlabelled: Most HIV-1 variants isolated from early-stage human infections do not use nonhuman primate versions of the CD4 receptor for cellular entry, or they do so poorly. We and others have previously shown that CD4 has experienced strong natural selection over the course of primate speciation, but it is unclear whether this selection has influenced the functional characteristics of CD4 as an HIV-1 receptor. Surprisingly, we find that selection on CD4 has been most intense in the New World monkeys, animals that have never been found to harbor lentiviruses related to HIV-1. Based on this, we sampled CD4 genetic diversity within populations of individuals from seven different species, including five species of New World monkeys. We found that some, but not all, CD4 alleles found in Spix's owl monkeys (Aotus vociferans) encode functional receptors for early-stage human HIV-1 isolates representing all of the major group M clades (A, B, C, and D). However, only some isolates of HIV-1 subtype C can use the CD4 receptor encoded by permissive Spix's owl monkey alleles. We characterized the prevalence of functional CD4 alleles in a colony of captive Spix's owl monkeys and found that 88% of surveyed individuals are homozygous for permissive CD4 alleles, which encode an asparagine at position 39 of the receptor. We found that the CD4 receptors encoded by two other species of owl monkeys (Aotus azarae and Aotus nancymaae) also serve as functional entry receptors for early-stage isolates of HIV-1., Importance: Nonhuman primates, particularly macaques, are used for preclinical evaluation of HIV-1 vaccine candidates. However, a significant limitation of the macaque model is the fact that most circulating HIV-1 variants cannot use the macaque CD4 receptor to enter cells and have to be adapted to these species. This is particularly true for viral variants from early stages of infection, which represent the most relevant vaccine targets. In this study, we found that some individuals from captive owl monkey populations harbor CD4 alleles that are compatible with a broad collection of HIV-1 isolates, including those isolated from early in infection in highly affected populations and representing diverse subtypes., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
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29. Rapid evolution of BRCA1 and BRCA2 in humans and other primates.
- Author
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Lou DI, McBee RM, Le UQ, Stone AC, Wilkerson GK, Demogines AM, and Sawyer SL
- Subjects
- Amino Acid Sequence, Animals, BRCA1 Protein chemistry, BRCA1 Protein metabolism, BRCA2 Protein chemistry, BRCA2 Protein metabolism, Breast Neoplasms genetics, DNA Repair, Exons, Female, Humans, Models, Molecular, Molecular Sequence Data, Mutation, Ovarian Neoplasms genetics, Polymorphism, Genetic, Primates virology, Selection, Genetic, Sequence Alignment, BRCA1 Protein genetics, BRCA2 Protein genetics, Evolution, Molecular, Genes, BRCA1, Genes, BRCA2, Primates genetics
- Abstract
Background: The maintenance of chromosomal integrity is an essential task of every living organism and cellular repair mechanisms exist to guard against insults to DNA. Given the importance of this process, it is expected that DNA repair proteins would be evolutionarily conserved, exhibiting very minimal sequence change over time. However, BRCA1, an essential gene involved in DNA repair, has been reported to be evolving rapidly despite the fact that many protein-altering mutations within this gene convey a significantly elevated risk for breast and ovarian cancers., Results: To obtain a deeper understanding of the evolutionary trajectory of BRCA1, we analyzed complete BRCA1 gene sequences from 23 primate species. We show that specific amino acid sites have experienced repeated selection for amino acid replacement over primate evolution. This selection has been focused specifically on humans and our closest living relatives, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus). After examining BRCA1 polymorphisms in 7 bonobo, 44 chimpanzee, and 44 rhesus macaque (Macaca mulatta) individuals, we find considerable variation within each of these species and evidence for recent selection in chimpanzee populations. Finally, we also sequenced and analyzed BRCA2 from 24 primate species and find that this gene has also evolved under positive selection., Conclusions: While mutations leading to truncated forms of BRCA1 are clearly linked to cancer phenotypes in humans, there is also an underlying selective pressure in favor of amino acid-altering substitutions in this gene. A hypothesis where viruses are the drivers of this natural selection is discussed.
- Published
- 2014
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30. Positive selection of primate genes that promote HIV-1 replication.
- Author
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Meyerson NR, Rowley PA, Swan CH, Le DT, Wilkerson GK, and Sawyer SL
- Subjects
- Animals, Humans, Primates, Selection, Genetic, HIV-1 physiology, Host-Pathogen Interactions, Virus Replication
- Abstract
Evolutionary analyses have revealed that most host-encoded restriction factors against HIV have experienced virus-driven selection during primate evolution. However, HIV also depends on the function of many human proteins, called host factors, for its replication. It is not clear whether virus-driven selection shapes the evolution of host factor genes to the extent that it is known to shape restriction factor genes. We show that five out of 40 HIV host factor genes (13%) analyzed do bear strong signatures of positive selection. Some of these genes (CD4, NUP153, RANBP2/NUP358) have been characterized with respect to the HIV lifecycle, while others (ANKRD30A/NY-BR-1 and MAP4) remain relatively uncharacterized. One of these, ANKRD30A, shows the most rapid evolution within this set of genes and is induced by interferon stimulation. We discuss how evolutionary analysis can aid the study of host factors for viral replication, just as it has the study of host immunity systems., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
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31. Spontaneous high-grade glial intramedullary tumor of the spine in a rhesus macaque (Macaca mulatta).
- Author
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Hanley PW, Wilkerson GK, Bernacky BJ, Barnhart KF, Baze WB, and McArthur MJ
- Subjects
- Animals, Ependymoma complications, Ependymoma diagnosis, Fatal Outcome, Female, Monkey Diseases etiology, Paresis diagnosis, Paresis etiology, Spinal Cord pathology, Spinal Cord Neoplasms complications, Spinal Cord Neoplasms diagnosis, Ependymoma veterinary, Macaca mulatta, Monkey Diseases diagnosis, Paresis veterinary, Spinal Cord Neoplasms veterinary
- Abstract
Background: A 4-year-old rhesus macaque presented with acute, progressive paresis of the extremities., Methods: A complete blood count, serum biochemical analysis, neurologic exam and necropsy were performed., Results: The clinical, histopathological, and immunohistochemical findings confirmed a high-grade intramedullary glial tumor of the spinal cord that was most consistent with an ependymoma., Conclusions: We describe a case of a naturally occurring spontaneous spinal cord neoplasia in a non-human primate., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2013
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32. Acquired amegakaryocytic thrombocytopenia purpura in a Rhesus macaque (Macaca mulatta).
- Author
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Hanley PW, Baze WB, McArthur MJ, Bernacky BJ, Wilkerson GK, and Barnhart KF
- Subjects
- Animals, Macaca mulatta, Bone Marrow Diseases diagnosis, Purpura, Thrombocytopenic diagnosis
- Abstract
A 10-y-old multiparous rhesus macaque presented for an annual routine physical examination. Clinically, the animal had pale mucous membranes, petechial and ecchymotic hemorrhages in multiple sites, and a laceration at the tail base. Severe pancytopenia was noted on hematologic evaluation. The monkey was seronegative for SIV, simian T-lymphotropic virus, simian retrovirus type D, and Macacine herpesvirus 1. Bone marrow evaluation revealed a paucity of megakaryocytic precursors in a hypercellular marrow with marked erythroid hyperplasia. In light of these findings, the diagnosis was acquired amegakaryocytic thrombocytopenia purpura. Due to the poor prognosis of the syndrome and clinical deterioration of the monkey, euthanasia was elected. A definitive cause of the thrombocytopenia was not identified; however, the syndrome may have developed secondary to a recent spontaneous abortion. To our knowledge, this case represents the first reported observation of acquired amegakaryocytic thrombocytopenia purpura in a rhesus monkey.
- Published
- 2012
33. To eat or not to eat: the effect of AICAR on food intake regulation in yellow-bellied marmots (Marmota flaviventris).
- Author
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Florant GL, Fenn AM, Healy JE, Wilkerson GK, and Handa RJ
- Subjects
- Aminoimidazole Carboxamide pharmacology, Animals, Body Temperature drug effects, Body Temperature physiology, Body Weight drug effects, Feeding Behavior drug effects, Female, Male, Sodium Chloride pharmacology, Aminoimidazole Carboxamide analogs & derivatives, Appetite Regulation drug effects, Marmota physiology, Ribonucleotides pharmacology
- Abstract
Mammals that hibernate (hibernators) exhibit a circannual rhythm of food intake and body mass. In the laboratory during the winter hibernation period, many hibernators enter a series of multi-day torpor bouts, dropping their body temperature to near ambient, and cease to feed even if food is present in their cage. The mechanism(s) that regulates food intake in hibernators is unclear. Recently, AMP-activated protein kinase (AMPK) has been shown to play a key role in the central regulation of food intake in mammals. We hypothesized that infusing an AMPK activator, 5-aminoimidazole-4-carboxamide 1 B-D-ribofuranoside (AICAR), intracerebroventricularly (ICV) into the third ventricle of the hypothalamus would stimulate yellow-bellied marmots (Marmota flaviventris) to feed during their hibernation season. Infusion of AICAR ICV into marmots at an ambient temperature of 22 degrees C caused a significant (P<0.05) increase in food intake. In addition, animals stimulated to feed did not enter torpor during the infusion period. Marmots ICV infused with saline did not increase food intake and these animals continued to undergo torpor at an ambient temperature of 22 degrees C. Our results suggest that AICAR stimulated the food intake pathway, presumably by activating AMPK. These results support the hypothesis that AMPK may be involved in regulating food intake in hibernators and that there may be common neural pathways involved in regulating feeding and eliciting torpor.
- Published
- 2010
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34. Plasma ghrelin concentrations change with physiological state in a sciurid hibernator (Spermophilus lateralis).
- Author
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Healy JE, Ostrom CE, Wilkerson GK, and Florant GL
- Subjects
- Animals, Body Temperature, Circadian Rhythm, Eating drug effects, Eating physiology, Female, Ghrelin administration & dosage, Male, Periodicity, Seasons, Ghrelin blood, Hibernation physiology, Sciuridae blood, Sciuridae physiology
- Abstract
Ghrelin is a recently discovered hormone which has profound effects on food intake and lipogenesis in mammals. In all mammals studied thus far, plasma ghrelin concentrations are increased before a meal and decrease immediately following a meal; ghrelin levels increase with fasting. The golden-mantled ground squirrel Spermophilus lateralis (also known as Callospermophilus lateralis (see Helgen et al., 2009) is a diurnal hibernator which has a robust annual cycle of body mass gain and loss that is primarily controlled by food intake. We hypothesized that in spring, summer, and autumn, the endogenous ghrelin concentrations of hibernators would be similar to those of non-hibernators, but that during the winter hibernation season, plasma ghrelin concentrations would be low or undetectable. We found that peripherally injected ghrelin significantly increased food intake in June. Plasma ghrelin concentrations were significantly increased through 5 days of fasting during a short-term fast in summer. Over a 24h period, ghrelin concentrations increased at night and decreased during the day with drops corresponding to times when squirrels were eating. In January, ghrelin concentrations are low but measurable even while animals are at low body temperature (Tb). This is the first report of ghrelin concentrations in a non-photoperiodic hibernator. We suggest that ghrelin may be important for the regulation of food intake and the body mass cycle in mammals that hibernate., ((c) 2009 Elsevier Inc. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
35. Hepatic encephalopathy in two goat kids with common paternity.
- Author
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Wilkerson GK, Bera MM, Holt TN, Callan RJ, and Pandher K
- Subjects
- Animals, Brain pathology, Female, Goat Diseases diagnosis, Goats, Male, Paternity, Pregnancy, Pregnancy Complications veterinary, Goat Diseases genetics, Hepatic Encephalopathy genetics, Hepatic Encephalopathy veterinary
- Abstract
Two juvenile, intact, female mixed-breed goats from a common sire were presented for periodic neurologic deficits, seizures, and a generalized loss of body condition that occurred over a 4-6-week period. On physical examination, both goats were thin, obtunded, blind, and ataxic. Laboratory diagnostics revealed increased serum bile acids (95 micromol/l; reference interval: 0-50 micromol/l) in one of the goats. Both goats exhibited progressive physical and mental deterioration, and were eventually euthanized. Upon necropsy, no significant macroscopic lesions were noted. Microscopic examination, however, demonstrated hepatocellular atrophy and anomalies in the hepatic microvasculature, including duplication of hepatic arteries, small-to-indistinct portal veins, and oval cell hyperplasia. In addition, spongiform change was microscopically identified throughout the parenchyma of the brain, most notably within the white matter and along the junction of gray and white matter. The diagnosis of congenital portal vein hypoperfusion (suggestive of a portosystemic shunt) with resultant hepatic encephalopathy was proposed in each case based on the characteristic microscopic lesions in conjunction with the signalment and history of the goats. The observation that the affected kids were sired by the same buck suggests a hereditary basis for the condition in these animals as well.
- Published
- 2008
- Full Text
- View/download PDF
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