Sharpening Host Defenses during Infection: Proteases Cut to the Chase*

The human immune system consists of an intricate network of tightly controlled pathways, where proteases are essential instigators and executioners at multiple levels. Invading microbial pathogens also encode proteases that have evolved to manipulate and dysregulate host proteins, including host proteases during the course of disease. The identification of pathogen proteases as well as their substrates and mechanisms of action have empowered significant developments in therapeutics for infectious diseases. Yet for many pathogens, there remains a great deal to be discovered. Recently, proteomic techniques have been developed that can identify proteolytically processed proteins across the proteome. These "degradomics" approaches can identify human substrates of microbial proteases during infection in vivo and expose the molecular-level changes that occur in the human proteome during infection as an operational network to develop hypotheses for further research as well as new therapeutics. This Perspective Article reviews how proteases are utilized during infection by both the human host and invading bacterial pathogens, including archetypal virulence-associated microbial proteases, such as the Clostridia spp. botulinum and tetanus neurotoxins. We highlight the potential knowledge that degradomics studies of host-pathogen interactions would uncover, as well as how degradomics has been successfully applied in similar contexts, including use with a viral protease. We review how microbial proteases have been targeted in current therapeutic approaches and how microbial proteases have shaped and even contributed to human therapeutics beyond infectious disease. Finally, we discuss how, moving forward, degradomics research can greatly contribute to our understanding of how microbial pathogens cause disease in vivo and lead to the identification of novel substrates in vivo, and the development of improved therapeutics to counter these pathogens.