Testosterone Promotes the Intestinal Replication and Dissemination of Coxsackievirus B3 in an Oral Inoculation Mouse Model

Dhalech, Adeeba H; Corn, Caleb; Mangale, Vrushali; Syed, Fahim; Condotta, Stephanie A.; Richer, Martin J.; Robinson, C. M.

doi:10.1128/jvi.01232-22

Cited by 7 publications

(18 citation statements)

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“…Male and female Ifnar -/- mice were orally inoculated with 5x10 7 PFUs of CVB3, and the mesenteric lymph nodes (MLNs) were harvested at 5dpi. We chose to examine immune cells at 5dpi because we have previously shown that mortality in male mice typically begins at this time point ( 26 , 27 ). Following CVB3 infection, we found that the number of CD4 + T cells showed a trending increase in the infected female mice compared to uninfected female mice ( Figures 1A , 1B ).…”

Section: Resultsmentioning

confidence: 99%

“…Research from our lab and many others have shown that sex hormones influence the pathogenesis of CVB3 in mice ( 21 , 26 – 29 ). Using an oral inoculation mouse model, our lab has demonstrated that gonadectomy impacts intestinal CVB3 replication and dissemination in male and female mice ( 26 , 27 ). Castration of male mice also completely protected males from mortality following CVB3 infection, and exogenous testosterone treatment restored lethality.…”

Section: Introductionmentioning

confidence: 99%

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A viral-specific CD4+ T cell response protects female mice from Coxsackievirus B3 infection

Pattnaik,

Dhalech,

Condotta

et al. 2024

Front. Immunol.

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BackgroundBiological 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.MethodsWe 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.ResultsWe 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.ConclusionsOverall, 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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A viral-specific CD4+ T cell response protects female mice from Coxsackievirus B3 infection

Pattnaik,

Dhalech,

Condotta

et al. 2024

Front. Immunol.

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“…Male and female Ifnar -/- mice were orally inoculated with 5x10 7 PFUs of CVB3, and the mesenteric lymph nodes (MLNs) were harvested at 5dpi. We chose to examine immune cells at 5dpi because we have previously shown that mortality in male mice typically begins at this time point (26, 27). Following CVB3 infection, we found that the number of CD4 + T cells showed a trending increase in the infected female mice compared to uninfected female mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Research from our lab and many others have shown that sex hormones influence the pathogenesis of CVB3 in mice (21,(26)(27)(28)(29). Using an oral inoculation mouse model, our lab has demonstrated that gonadectomy impacts intestinal CVB3 replication and dissemination in male and female mice (26,27). Castration of male mice also completely protected males from mortality following CVB3 infection, and exogenous testosterone treatment restored lethality.…”

Section: Introductionmentioning

confidence: 99%

A viral-specific CD4⁺T cell response protects female mice from Coxsackievirus B3 infection

Pattnaik,

Dhalech,

Condotta

et al. 2023

Preprint

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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. 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. 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 outcomes.

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“…Thus, we inoculated C57BL6/J mice with six distinct viruses -murine rotavirus strain EDIM-Cambridge (MRV, 10 4 ID50 by oral gavage), murine gamma-herpesvirus 68 (MHV68, 10 5 PFU intranasally), murine norovirus strain CR6 (MNV, 10 6 PFU orally), influenza virus strain PR8 (IAV, 300 PFU intranasally), murine astrovirus (MAstV, infectious fecal filtrate by oral gavage), and coxsackievirus B3 (CVB3, 10 8 PFU orally) -at 1-week intervals beginning when pups were 7 days old (Figure 1A). All viruses were administered at established inocula (11,(18)(19)(20)(21)…”

Section: Sequential Viral Infection Creates a Durable Pro-inflammator...mentioning

confidence: 99%

Sequential early-life viral infections modulate the microbiota and adaptive immune responses to systemic and mucosal vaccination

Li,

Molleston,

Kim

et al. 2023

Preprint

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Increasing evidence points to the microbial exposome as a critical factor in maturing and shaping the host immune system, thereby influencing responses to immune challenges such as infections or vaccines. To investigate the effect of early-life viral exposures on immune development and vaccine responses, we inoculated mice with six distinct viral pathogens in sequence beginning in the neonatal period, and then evaluated their immune signatures before and after intramuscular or intranasal vaccination against SARS-CoV-2. Sequential viral infection drove profound changes in all aspects of the immune system, including increasing circulating leukocytes, altering innate and adaptive immune cell lineages in tissues, and markedly influencing serum cytokine and total antibody levels. Beyond these immune responses changes, these exposures also modulated the composition of the endogenous intestinal microbiota. Although sequentially-infected mice exhibited increased systemic immune activation and T cell responses after intramuscular and intranasal SARS-CoV-2 immunization, we observed decreased vaccine-induced antibody responses in these animals. These results suggest that early-life viral exposures are sufficient to diminish antibody responses to vaccination in mice, and highlight their potential importance of considering prior microbial exposures when investigating vaccine responses.

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Testosterone Promotes the Intestinal Replication and Dissemination of Coxsackievirus B3 in an Oral Inoculation Mouse Model

Abstract: 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.

Cited by 7 publications

References 82 publications

A viral-specific CD4+ T cell response protects female mice from Coxsackievirus B3 infection

A viral-specific CD4+ T cell response protects female mice from Coxsackievirus B3 infection

A viral-specific CD4⁺T cell response protects female mice from Coxsackievirus B3 infection

Sequential early-life viral infections modulate the microbiota and adaptive immune responses to systemic and mucosal vaccination

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Testosterone Promotes the Intestinal Replication and Dissemination of Coxsackievirus B3 in an Oral Inoculation Mouse Model

Abstract: 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.

Cited by 7 publications

References 82 publications

A viral-specific CD4+ T cell response protects female mice from Coxsackievirus B3 infection

A viral-specific CD4+ T cell response protects female mice from Coxsackievirus B3 infection

A viral-specific CD4+T cell response protects female mice from Coxsackievirus B3 infection

Sequential early-life viral infections modulate the microbiota and adaptive immune responses to systemic and mucosal vaccination

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A viral-specific CD4⁺T cell response protects female mice from Coxsackievirus B3 infection