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Item A viral-specific CD4+ T cell response protects female mice from Coxsackievirus B3 infection(Frontiers Media, 2024-01-11) Pattnaik, Aryamav; Dhalech, Adeeba H.; Condotta, Stephanie A.; Corn, Caleb; Richer, Martin J.; Snell, Laura M.; Robinson, Christopher M.; Microbiology and Immunology, School of MedicineBackground: Biological sex plays an integral role in the immune response to various pathogens. The underlying basis for these sex differences is still not well defined. Here, we show that Coxsackievirus B3 (CVB3) induces a viral-specific CD4+ T cell response that can protect female mice from mortality. Methods: We inoculated C57BL/6 Ifnar-/- mice with CVB3. We investigated the T cell response in the spleen and mesenteric lymph nodes in male and female mice following infection. Results: We found that CVB3 can induce expansion of CD62Llo CD4+ T cells in the mesenteric lymph node and spleen of female but not male mice as early as 5 days post-inoculation, indicative of activation. Using a recombinant CVB3 virus expressing a model CD4+ T cell epitope, we found that this response is due to viral antigen and not bystander activation. Finally, the depletion of CD4+ T cells before infection increased mortality in female mice, indicating that CD4+ T cells play a protective role against CVB3 in our model. Conclusions: Overall, these data demonstrated that CVB3 can induce an early CD4 response in female but not male mice and further emphasize how sex differences in immune responses to pathogens affect disease.Item Genetic Determinants of Coxsackievirus B3 Pathogenesis(2020-10) Barnard, April L.; Robinson, Christopher M.; Evans-Molina, Carmella; Yu, AndyEnteric viruses are among the most common infectious human viruses worldwide, causing an estimated 10-15 million infections per year in the United States. Among enteric viruses, Coxsackievirus is commonly isolated and can lead to the development of meningitis, encephalitis, pancreatitis, and hepatitis. Furthermore, Coxsackievirus B3 is the primary cause of viral myocarditis and can lead to pleurodynia, with nearly 40,000 symptomatic cases reported in the United States each year. The enteroviral ssRNA genome contains a 5’ untranslated region (5’UTR) which consists of two structural components, the cloverleaf and the internal ribosome entry site (IRES), both shown to be integral to viral success. Additionally, the viral genome encodes four structural VP proteins as well as 11 non-structural proteins. Polymorphisms found within the CVB3 population have been linked to viral virulence. Here, we compare two CVB3 Nancy variants to elucidate the downstream effects observed in response to mutations found in the CVB3 genome. Implementing our novel oral inoculation model, we aimed to determine the impact mutations found in the 5’UTR and VP regions exert on viral pathogenesis. We also aimed to delineate the in vitro effects of the observed mutations. We investigated the role mutations found in the structural regions played in virus host cell attachment, in vitro cell viability, and replication. Our work has further confirmed the relevance and impact of mutations found in the VP region of the CVB3 genome.Item Host Factors That Influence Coxsackievirus B3 Replication and Pathogenensis(2023-04) Dhalech, Adeeba Haroon; Robinson, Christopher M.; Hurley, Thomas D.; Katzenellenbogen, Rachel A.; Richer, Martin J.; Spinola, Stanley M.Enteric viruses are infectious human pathogens that initiate infection in the gastrointestinal tract. They follow a fecal-oral route of transmission and are spread by contamination of food, water, or contact between individuals. Furthermore, enteric viruses also cause significant morbidity, mortality, and economic burdens yearly. Coxsackievirus (CV) is commonly isolated among enteric viruses and is an etiological agent of hand, foot, and mouth disease, hemorrhagic conjunctivitis, and myocarditis. The virus predominantly infects infants and young children and accounts for 11% of the fatality rate in neonates. Despite CV’s impact on human health, there are no treatments or vaccines for CV infections. Using a mouse model to study a key CV, Coxsackievirus B3 (CVB3), our laboratory has found two critical factors that impact CVB3 replication and pathogenesis. First, we have demonstrated that intestinal bacteria enhance intestinal CVB3 replication. We found that certain specific bacteria (Salmonella enterica) and its cell wall components, like lipopolysaccharides (LPS), enhanced CVB3 stability and infectivity in vitro. Additionally, we found that particular constituents of LPS are required for stability to occur. These data suggest that specific bacteria may be integral in maintaining CVB3 infectivity in the intestine. Besides virus-microbiome interaction, CVB3 is also impacted by sex hormones. Using castrated mice models, we observed a sex bias to CVB3 infection, with male mice succumbing to CVB3-induced disease at an increased rate compared to female mice. Our data suggest that testosterone, a predominant male sex hormone, enhanced CVB3 intestinal replication and viral dissemination to organs in male and female mice, but lethality only in male mice. Moreover, testosterone also affected the immune response by reducing the activation of the CD8+ T cells. CD8+ T cells are required to clear the viral infection and are integral in vaccine development. In contrast, we found an enhanced CD8+ T cell response in female mice to CVB3 infection, suggesting a sex-dependent T cell response that may underlie the sex bias in disease. Overall, these data represent an essential advancement in the CV field and will help develop future therapeutics and aid in vaccine design to limit CV infections.Item Testosterone Promotes the Intestinal Replication and Dissemination of Coxsackievirus B3 in an Oral Inoculation Mouse Model(American Society for Microbiology, 2022) Dhalech, Adeeba H.; Corn, Caleb M.; Mangale, Vrushali; Syed, Fahim; Condotta, Stephanie A.; Richer, Martin J.; Robinson, Christopher M.; Microbiology and Immunology, School of MedicineEnteroviruses initiate infection in the gastrointestinal tract, and sex is often a biological variable that impacts pathogenesis. Previous data suggest that sex hormones can influence the intestinal replication of Coxsackievirus B3 (CVB3), an enterovirus in the Picornaviridae family. However, the specific sex hormone(s) that regulates intestinal CVB3 replication is poorly understood. To determine if testosterone promotes intestinal CVB3 replication, we orally inoculated male and female Ifnar-/- mice that were treated with either placebo or testosterone-filled capsules. Following oral inoculation, we found that the testosterone-treated male and female mice shed significantly more CVB3 in their feces than did the placebo-treated mice, indicating that testosterone enhances intestinal replication. Similarly, testosterone enhanced viral dissemination in both sexes, as we observed higher viral loads in peripheral tissues following infection. Further, the testosterone-treated male mice also had a higher mortality rate than did the testosterone-depleted male mice. Finally, we observed that testosterone significantly affected the immune response to CVB3. We found that testosterone broadly increased proinflammatory cytokines and chemokines while decreasing the number of splenic B cells and dendritic cells following CVB3 infection. Moreover, while testosterone did not affect the early CD4 T cell response to CVB3, testosterone reduced the activation of CD8 T cells. These data indicate that testosterone can promote intestinal CVB3 replication and dissemination while also impacting the subsequent viral immune response. IMPORTANCE: Biological sex plays a significant role in the outcomes of various infections and diseases. The impact of sex hormones on the intestinal replication and dissemination of Coxsackievirus B3 remains poorly understood. Using an oral inoculation model, we found that testosterone enhances CVB3 shedding and dissemination in male and female mice. Further, testosterone can alter the immune response to CVB3. This work highlights the role of testosterone in CVB3 pathogenesis and suggests that sex hormones can impact the replication and dissemination of enteric viruses.