CNS-mediated fever after Adolescent Intermittent Ethanol

Project Summary/Abstract Alcohol use commonly starts in early adolescence with about 50–70% of 15 year-olds already reporting alcohol use (World Health Organization, 2018). Human and pre-clinical studies have shown that alcohol increases vulnerability to both bacterial and viral infections (Szabo, 2015), though adolescent sensitivity to the untoward effects of alcohol on immune function remain unclear. Importantly, neuroimmune function is severely altered by binge-like alcohol exposure in rodent models yet the role of CNS-mediated host defense processes has not been determined. The emergence of a global pandemic driven by widespread novel coronavirus SARS-CoV-2 and its associated disease state, COVID-19, has revealed unique vulnerabilities for certain demographics. Although the greatest vulnerability to adverse outcomes of COVID-19 is age, increasing data demonstrate that male patients with COVID-19 exhibit enhanced disease severity, higher complication rates, and higher mortality However, there remains great mystery regarding differences in viral infection severity, and the response to vaccine, across individuals. We propose that a history of alcohol misuse during adolescence may set the stage for adverse reactions to viral infection and vaccinations. Our prior work has shown that Adolescent Intermittent Ethanol (AIE) exposure produced long-lasting, sex-specific changes in immune function. AIE exposure substantially impaired cytokine expression in circulating lymphocytes when challenged in vivo with the bacterial antigen lipopolysaccharide (LPS), an effect that was robust in males, and completely absent in females. Similar signs of suppressed cytokine induction were subsequently observed in the hippocampus in response to mild tissue injury, with other studies reporting impaired fever responses when adolescent alcohol-exposed rats were challenged a week later with LPS, a TLR4-dependent inflammogen. Although these findings suggest that AIE may produce a global impairment in inflammatory processes, recent work from our lab suggests that the influence of alcohol may be pathogen-specific. Specifically, AIE exacerbated the febrile response to polyinosine-polycytidylic acid (Poly I:C), a synthetic double-stranded (ds)RNA that is used to model viral infections, suggesting that TLR3- dependent inflammatory processes may be pathologically sensitized by adolescent ethanol exposure. Additional data suggests that acute ethanol may interfere with the efficacy of anti-pyretic drugs, raising concerns regarding adolescent binge drinking and altered responding to pharmacotherapeutic treatments for infection later in life. Therefore, this proposal will test the hypothesis that Adolescent Intermittent Ethanol may represent a latent and previously unconsidered demographic variable that predicts sex-specific adverse COVID-19 outcomes later in life. Given the rapid evolution of SARS-CoV-2 and the development of strain variants, the more general viral model of Poly I:C affords the opportunity to establish general features of host defense that are applicable to both the current global pandemic, as well as viral outbreaks of the future.