Sharpening Host Defenses during Infection: Proteases Cut to the Chase

Abstract

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.

Overview of Brain-to-Gut Axis Exposed to Chronic CNS Bacterial Infection(s) and a Predictive Urinary Metabolic Profile of a Brain Infected by Mycobacterium tuberculosis

“…This also leaves pathogens coated with cleaved Fab fragments and camouflaged from the immune system. IgA1 proteases disable this important defense immune molecule allowing for direct escape of the invading pathogen from host immunity (Woof and Russell, 2011;Marshall et al, 2017). This communication/crosstalk involving the gut microbiota from the CNS encompasses several channels along various neural, enteric and immune systems.…”

We Are Not Alone: The iMOP Initiative and Its Roles in a Biology- and Disease-Driven Human Proteome Project

“…While both the genetic and proteomic background of the host are important, it is equally important to consider this information for the microorganism. During infections, the proteomic repertoire of the infectant can vary from proteases that aid the manipulation of a hosts defense 33 to mechanisms that enable it to subvert the hosts biology for its own purpose 34 In recent years, there has been a steady increase in knowledge around how human life and wellbeing are dependent on microorganisms 3 . Complex microbial communities are found throughout the human body from our skin to our intestinal tracts 35 .…”

Predicted salivary human protease activity in experimental gingivitis revealed by endoProteo‐FASP approach

“…The induction of an inflammatory response requires proteases to facilitate access of leukocytes to the site of infection. The protease network is crucial for effective responses against infection, where swift deactivation of microbial proteins or activation of host proteins by proteases can be critical, but it also has a key role in wound healing (17). Proteases are essential instigators and executioners of responses, and dysregulation may lead to excessive or non‐resolving inflammation.…”