Commensal bacteria inhibit viral infections via tryptophan metabolites

There is growing appreciation that commensal bacteria can impact the outcome of viral infections, though the specific bacteria and their underlying mechanisms remain poorly understood. Using HIV as a model, we bioinformatically associated the family Lachnospiraceae with reduced susceptibility to infection in cohorts of exposed nonhuman primates and humans. Moreover, we experimentally validated Lachnospiraceae isolates, including Clostridium immunis, can inhibit HIV infection in vitro. Since tryptophan metabolism is linked to HIV disease severity, we developed bacterial genetics for C. immunis and inactivated the aromatic amino acid aminotransferase (ArAT) gene, which metabolizes tryptophan into 3-indolelactic acid (3-ILA). Intriguingly, C. immunis∆ArAT no longer inhibits HIV infection, and we found that the ArAT gene from other commensal bacteria also inhibits HIV. Additionally, purified 3-ILA inhibits HIV infection by agonizing the aryl hydrocarbon receptor (AhR). Given that AhR is implicated in the control of multiple viral infections, we showed in vitro that C. immunis also inhibits CMV infection via ArAT. Importantly, metagenomic analysis of individuals at high-risk of CMV revealed the ArAT gene is less abundant in those who develop CMV disease, which confirms our findings in patients. Taken together, our results provide mechanistic insight into how the microbiome impacts viral infections, thereby adding to an emerging field of commensal bacteria–virus interactions.