Danting Jiang, Nicole Soo, Chin Yee Tan, Sedem Dankwa, Hsuan-Yuan Wang, Barbara S. Theriot, Keyi Xue, Demitrius Hill, Amir Ardeshir, James R. Bain, Sarah M. Heston, Jillian H. Hurst, Nazema Y. Siddiqui, Koen K. A. Van Rompay, Luisa Cervantes-Barragan, Jonathan P. Smith, Rinn Song, Jatin Roper, Matthew S. Kelly, Michael G. Hudgens, Kristina De Paris, Sallie R. Permar, Ria Goswami, Neeraj K. Surana
Clinical outcomes following viral exposures exhibit substantial interindividual variability. Although developing evidence suggests commensal bacteria modulate viral infections, the specific bacteria and mechanisms remain underexplored. Here we define a pathway by which viral infections are inhibited by specific tryptophan-catabolizing bacteria. Using HIV as a model, we bioinformatically associated and experimentally validated several bacterial species that inhibited viral replication. This activity required the aromatic amino acid aminotransferase (ArAT) to metabolize tryptophan into 3-indolelactic acid, which agonizes the aryl hydrocarbon receptor (AhR). Given that AhR regulates multiple viral infections, we found that commensal bacteria also inhibit cytomegalovirus (CMV) in an ArAT-dependent manner. Finally, we confirmed that ArAT is associated with protection against disease outcomes in three distinct human cohorts at-risk for HIV, CMV, or symptomatic COVID-19. Taken together, our results provide mechanistic insight into how commensal bacteria impact viral infections, thereby adding to an emerging field focused on host-commensal-virus interactions.