Dissecting the impact of enteric viral-bacterial co-infection on the host innate immune response and its implications for pathogenicity

Abstract Understanding how pathogens cause and maintain infection is essential to develop novel therapeutics and prevent outbreaks of emerging diseases. While the broadening of accessible methodologies has enabled mechanistic insights into single pathogen infections, the molecular mechanisms underlying co-infections remain elusive, despite their clinical frequency and relevance, generally exacerbating symptom severity and fatality. Here, we describe a first-of-its-kind, parallelized, unbiased screening of pairwise co-infections, ensuring reliability through robust quality control and validation. We subsequently decipher two distinct molecular interaction points: Firstly, mAdV3 modifies ASC-dependent inflammasome responses, altering host cell death and cytokine production, thereby impacting secondary Salmonella infection. Secondly, mAdV2 infection triggers upregulation of Mprip, a crucial mediator of phagocytosis, which in turn causes increased Yersinia uptake, specifically in virus pre-infected cells. This work encompasses both a valuable resource, which will spark further hypothesis-driven research, and molecular characterization of novel interaction points during co-infection, presenting putative targets for new therapeutic approaches.