Testosterone promotes Coxsackievirus B3 pathogenesis in an oral inoculation mouse model

Abstract

AbstractEnteroviruses initiate infection in the gastrointestinal tract, and sex is often a biological variable that impacts infection. The role of sex hormones on enterovirus pathogenesis, however, is unclear. Previous data indicate that sex hormones can influence intestinal replication of Coxsackievirus B3 (CVB3), an enterovirus in the Picornavirus family. To determine if testosterone promotes CVB3 infection, male mice were castrated and provided placebo or testosterone-filled capsules. We found that testosterone-treated mice shed significantly more CVB3 in the feces and succumbed to CVB3-induced disease at a higher rate than castrated mice given a placebo. Treatment of male mice with an androgen receptor antagonist, flutamide, protected male mice from CVB3-induced lethality, further confirming the role of testosterone in viral pathogenesis. We also observed higher viral loads in peripheral tissues of testosterone-treated mice and an increase in the cytokine and chemokine response. Finally, we found that testosterone treatment in female mice increased fecal CVB3 shedding but had no impact on viral lethality. Overall, these data indicate that testosterone and androgen receptor signaling can promote CVB3 replication in the intestine and enhance CVB3 lethality in a sex-dependent manner.ImportanceBiological sex plays a significant role in the outcome of various infections and diseases. The impact of sex hormones on intestinal replication and dissemination of Coxsackievirus B3 remains limited. Using an oral inoculation model, we found that testosterone enhances CVB3 shedding and lethality in male mice. Further, testosterone can promote CVB3 shedding in female mice. This work highlights the role of testosterone in intestinal replication of CVB3 and suggests that sex hormones can impact the replication of enteric viruses.