Person: Manickam, Cordelia
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Manickam
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Cordelia
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Manickam, Cordelia
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Publication Metabolic Dysregulation in Hepacivirus Infection of Common Marmosets (Callithrix jacchus)(Public Library of Science, 2017) Manickam, Cordelia; Wachtman, Lynn; Martinot, Amanda; Giavedoni, Luis D.; Reeves, R. KeithChronic hepatitis C has been associated with metabolic syndrome that includes insulin resistance, hepatic steatosis and obesity. These metabolic aberrations are risk factors for disease severity and treatment outcome in infected patients. Experimental infection of marmosets with GBV-B serves as a tangible, small animal model for human HCV infection, and while virology and pathology are well described, a full investigation of clinical disease and the metabolic milieu is lacking. In this study six marmosets were infected intravenously with GBV-B and changes in hematologic, serum biochemical and plasma metabolic measures were investigated over the duration of infection. Infected animals exhibited signs of lymphocytopenia, but platelet and RBC counts were generally stable or even increased. Although most animals showed a transient decline in blood glucose, infection resulted in several fold increases in plasma insulin, glucagon and glucagon-like peptide 1 (GLP-1). All infected animals experienced transient weight loss within the first 28 days of infection, but also became hypertriglyceridemic and had up to 10-fold increases in adipocytokines such as resistin and plasminogen activator inhibitor 1 (PAI-1). In liver, moderate to severe cytoplasmic changes associated with steatotic changes was observed microscopically at 168 days post infection. Collectively, these results suggest that GBV-B infection is accompanied by hematologic, biochemical and metabolic abnormalities that could lead to obesity, diabetes, thrombosis and atherosclerosis, even after virus has been cleared. Our findings mirror those found in HCV patients, suggesting that metabolic syndrome could be conserved among hepaciviruses, and both mechanistic and interventional studies for treating HCV-induced metabolic complications could be evaluated in this animal model.Publication Tracking KLRC2 (NKG2C)+ memory-like NK cells in SIV+ and rhCMV+ rhesus macaques(Public Library of Science, 2018) Ram, Daniel; Manickam, Cordelia; Hueber, Brady; Itell, Hannah L.; Permar, Sallie R.; Varner, Valerie; Reeves, R. KeithNatural killer (NK) cells classically typify the nonspecific effector arm of the innate immune system, but have recently been shown to possess memory-like properties against multiple viral infections, most notably CMV. Expression of the activating receptor NKG2C is elevated on human NK cells in response to infection with CMV as well as HIV, and may delineate cells with memory and memory-like functions. A better understanding of how NKG2C+ NK cells specifically respond to these pathogens could be significantly advanced using nonhuman primate (NHP) models but, to date, it has not been possible to distinguish NKG2C from its inhibitory counterpart, NKG2A, in NHP because of unfaithful antibody cross-reactivity. Using novel RNA-based flow cytometry, we identify for the first time true memory NKG2C+ NK cells in NHP by gene expression (KLRC2), and show that these cells have elevated frequencies and diversify their functional repertoire specifically in response to rhCMV and SIV infections.Publication Innate Lymphoid Cells in HIV/SIV Infections(Frontiers Media S.A., 2017) Shah, Spandan; Manickam, Cordelia; Ram, Daniel; Reeves, R. KeithOver the past several years, new populations of innate lymphocytes have been described in mice and primates that are critical for mucosal homeostasis, microbial regulation, and immune defense. Generally conserved from mice to humans, innate lymphoid cells (ILC) have been divided primarily into three subpopulations based on phenotypic and functional repertoires: ILC1 bear similarities to natural killer cells; ILC2 have overlapping functions with TH2 cells; and ILC3 that share many functions with TH17/TH22 cells. ILC are specifically enriched at mucosal surfaces and are possibly one of the earliest responders during viral infections besides being involved in the homeostasis of gut-associated lymphoid tissue and maintenance of gut epithelial barrier integrity. Burgeoning evidence also suggests that there is an early and sustained abrogation of ILC function and numbers during HIV and pathogenic SIV infections, most notably ILC3 in the gastrointestinal tract, which leads to disruption of the mucosal barrier and dysregulation of the local immune system. A better understanding of the direct or indirect mechanisms of loss and dysfunction will be critical to immunotherapeutics aimed at restoring these cells. Herein, we review the current literature on ILC with a particular emphasis on ILC3 and their role(s) in mucosal immunology and the significance of disrupting the ILC niche during HIV and SIV infections.Publication Exosome markers associated with immune activation and oxidative stress in HIV patients on antiretroviral therapy(Nature Publishing Group UK, 2018) Chettimada, Sukrutha; Lorenz, David R.; Misra, Vikas; Dillon, Simon; Reeves, R. Keith; Manickam, Cordelia; Morgello, Susan; Kirk, Gregory D.; Mehta, Shruti H.; Gabuzda, DanaExosomes are nanovesicles released from most cell types including immune cells. Prior studies suggest exosomes play a role in HIV pathogenesis, but little is known about exosome cargo in relation to immune responses and oxidative stress. Here, we characterize plasma exosomes in HIV patients and their relationship to immunological and oxidative stress markers. Plasma exosome fractions were isolated from HIV-positive subjects on ART with suppressed viral load and HIV-negative controls. Exosomes were characterized by electron microscopy, nanoparticle tracking, immunoblotting, and LC-MS/MS proteomics. Plasma exosomes were increased in HIV-positive subjects compared to controls, and correlated with increased oxidative stress markers (cystine, oxidized cys-gly) and decreased PUFA (DHA, EPA, DPA). Untargeted proteomics detected markers of exosomes (CD9, CD63, CD81), immune activation (CD14, CRP, HLA-A, HLA-B), oxidative stress (CAT, PRDX1, PRDX2, TXN), and Notch4 in plasma exosomes. Exosomal Notch4 was increased in HIV-positive subjects versus controls and correlated with immune activation markers. Treatment of THP-1 monocytic cells with patient-derived exosomes induced expression of genes related to interferon responses and immune activation. These results suggest that exosomes in ART-treated HIV patients carry proteins related to immune activation and oxidative stress, have immunomodulatory effects on myeloid cells, and may have pro-inflammatory and redox effects during pathogenesis.Publication Modeling HCV disease in animals: virology, immunology and pathogenesis of HCV and GBV-B infections(Frontiers Media S.A., 2014) Manickam, Cordelia; Reeves, R. KeithHepatitis C virus (HCV) infection has become a global public health burden costing billions of dollars in health care annually. Even with rapidly advancing scientific technologies this disease still poses a significant threat due to a lack of vaccines and affordable treatment options. The immune correlates of protection and predisposing factors toward chronicity remain major obstacles to development of HCV vaccines and immunotherapeutics due, at least in part, to lack of a tangible infection animal model. This review discusses the currently available animal models for HCV disease with a primary focus on GB virus B (GBV-B) infection of New World primates that recapitulates the dual Hepacivirus phenotypes of acute viral clearance and chronic pathologic disease. HCV and GBV-B are also closely phylogenetically related and advances in characterization of the immune systems of New World primates have already led to the use of this model for drug testing and vaccine trials. Herein, we discuss the benefits and caveats of the GBV-B infection model and discuss potential avenues for future development of novel vaccines and immunotherapies.Publication Antigen-specific NK cell memory in rhesus macaques(2015) Reeves, R. Keith; Li, Haiying; Jost, Stephanie; Blass, Eryn; Li, Hualin; Schafer, Jamie L.; Varner, Valerie; Manickam, Cordelia; Eslamizar, Leila; Altfeld, Marcus; von Andrian-Werburg, Ulrich; Barouch, DanNatural killer (NK) cells have traditionally been considered nonspecific components of innate immunity, but recent studies have shown features of antigen-specific memory in murine NK cells. However, it has remained unclear whether this phenomenon also exists in primates. Compared to NK cells from uninfected macaques, we found splenic and hepatic NK cells from SHIV-SF162P3- and SIVmac251-infected animals specifically lysed Gag- and Env-pulsed dendritic cells (DCs) in an NKG2-dependent fashion. Moreover, splenic and hepatic NK cells from Ad26-vaccinated macaques efficiently lysed antigen-matched but not antigen-mismatched targets 5 years post-vaccination. These data demonstrate that robust, durable, antigen-specific NK cell memory can be induced in primates following both infection and vaccination, and could be important for vaccines against HIV-1 and other pathogens.