Yellow fever disease severity is driven by an acute cytokine storm modulated by an interplay between the human gut microbiome and the metabolome

Infection with Yellow Fever (YF) can lead to multiple outcomes ranging from death from total organ failure to clearance of viremia and survival. The mechanisms underlying these differences in clinical outcomes have yet to be defined. We had access to a cohort of YF infected subjects that showed these range of outcomes. An unbiased integrated OMICs approach was used to identify pathways and effector molecules that drive the severe disease and death as compared to resolution of infection. We used the MELD and SIC score as objective markers of disease severity. We show that a specific signature of upregulated innate pro-inflammatory cytokines significantly demarcates subjects with severe disease leading to death from subjects who clear virus. Pathogen sequencing showed heightened levels of proteolytic bacteria at the i.e Actinobacteria and these were correlated to lower levels of tryptophan and tyrosine amino acids measured by untargeted metabolomics. These two features were significantly associated to MELD scores synonymous of milder disease. Propionate a bacterial metabolite that triggers Treg differentiation that can as well limit the hyperimmune activation associated to severe outcome was also associated to improved outcome. Our results suggest a model whereby proteolytic bacteria limit the availability of the aromatic amino acid pool available for cytokine production thereby preventing the induction of the cytokine storm that is associated to severe disease and death.