Bacterial Proteases as Potentially Exploitable Modulators of SARS-CoV-2 Infection: Logic from the Literature, Informatics, and Inspiration from the Dog

(1) Background: The COVID-19 pandemic left many intriguing mysteries. Retrospective vulnerability trends tie as strongly to odd demographics as to exposure profiles, genetics, health, or prior medical history. This article documents the importance of nasal microbiome profiles in distinguishing infection rate trends among differentially affected subgroups. (2) Hypothesis: From a detailed literature survey, microbiome profiling experiments, bioinformatics, and molecular simulations, we propose that specific commensal bacterial species in the Pseudomonadales genus confer protection against SARS-CoV-2 infections by expressing proteases that may interfere with the proteolytic priming of the Spike protein. (3) Evidence: Various reports have found elevated Moraxella fractions in the nasal microbiomes of subpopulations with higher resistance to COVID-19 (e.g., adolescents, COVID-19-resistant children, people with strong dietary diversity, and omnivorous canines) and less abundant ones in vulnerable subsets (the elderly, people with narrower diets, carnivorous cats and foxes), along with bioinformatic evidence that Moraxella bacteria express proteases with notable homology to human TMPRSS2. Simulations suggest that these proteases may proteolyze the SARS-CoV-2 spike protein in a manner that interferes with TMPRSS2 priming.