The impact of testosterone on murine models of infection and vaccination
Embargo until
2020-05-01
Date
2019-04-09
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Publisher
Johns Hopkins University
Abstract
In men, low testosterone is associated with an increased risk of all-cause and cardiovascular related mortality, and although its immunomodulatory properties have been well characterized, the impact of testosterone on both the severity of viral infection and the efficacy of vaccination remain poorly understood. The severity of influenza increases with age in men, and as circulating testosterone concentrations also decline with age in men, I hypothesized that reduced testosterone contributes to age-associated increases in influenza severity. A murine model was used, and consistent with in humans, young male mice had greater testosterone concentrations than did aged males. Following IAV infection, aged male mice experienced greater disease severity, mortality, and pulmonary inflammation than young males, while control of viral replication was delayed. Removal of testosterone in young males increased disease severity, and pulmonary inflammation independent of changes in viral replication. Because testosterone in young male mice reduced pulmonary inflammation, I further hypothesized that testosterone was altering the immune response to IAV infection. Testosterone reduced IAV severity not by changing pulmonary cytokine activity, but instead by accelerating pulmonary leukocyte contraction. To identify which immune cell types were persisting in testosterone-depleted males, we further characterized the composition of pulmonary cellular infiltrates. Testosterone depletion accelerated the contraction of IAV-specific CD8+ T cells, while inhibiting the influx of eosinophils into the lungs following clearance of virus from the lungs. The effects of testosterone on IAV-specific CD8+ T cells were mediated androgen receptor signaling and dependent on the environment in which they reside. In contrast with IAV infection where the immune suppressive effects of testosterone are protective, in the context of vaccination any reduction in immune response may be detrimental. Adult females tend to develop greater adaptive immune responses than males following vaccination in both preclinical animal studies and human clinical trials. Following vaccination with irradiated transgenic P. berghei sporozoites expressing the P. falciparum CSP protein, adult female mice mounted greater adaptive immune responses and were better protected against challenge than adult males. No sex differences in adaptive immune responses or protection were observed in mice vaccinated prior to puberty, suggesting a role for sex steroid hormones. Depletion of testosterone in males increased, whereas rescue of testosterone decreased, adaptive immune responses and protection in males following parasite challenge. Taken together, these data suggest that testosterone confers protection during IAV infection by modulating the immune response, while testosterone concentrations in males reduce adaptive immunity and contributes to reduced malaria vaccine efficacy.
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Keywords
adaptive immunity, H1N1, testosterone, vaccine, circumsporozoite protein, gender, plasmodium, androgen, elderly, pulmonary inflammation, sex steroids