Christopher N. LaRock

Assistant Professor

Emory University School of Medicine

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Biography

Dr. LaRock received his Ph.D. from the University of Washington for his work with Drs. Carleen Collins and Brad Cookson examining the virulence mechanisms of Yersinia pestis, cause of bubonic plague. His postdoctoral work with Dr. Victor Nizet at the University of California, San Diego focused on the pathogenesis of group A Streptococcus (GAS) and other Gram-positive pathogens. In 2017 Dr. LaRock joined the Department of Microbiology and Immunology as an Assistant Professor.

Research

Pathogens must successfully prevent restriction by our formidable immune defenses in order to infect. This is often promoted by virulence factors specifically adapted to intercept key immune regulators. The LaRock laboratory examines this host-microbe interaction using a number of biochemical, genetic, and pharmacologic tools with a major focus on how inflammation combats infection. Our work is revealing new mechanisms of microbial pathogenesis, infection risks associated with immunotherapy, and new drug targets for the treatment of infectious and autoinflammatory diseases. A long-term goal is to devise rational treatment strategies that enable effective immune clearance of an infecting pathogen without the dysbiosis or evolution of resistance that can occur with conventional antibiotics.

We previously identified pharmacological inhibition of the pro-inflammatory cytokine IL-1β was associated with elevated incidence of invasive GAS infections. This occurs in part because GAS hyperactivates IL-1β, independently of the canonical host caspase regulator, via the proteolytic toxin SpeB acting as a ‘bacterial caspase’ (LaRock et al. Science Immunology 2016). This mechanism explains why GAS isolated from sepsis and necrotizing fasciitis infections frequently have mutations inactivating SpeB; these mutations are pathoadaptions that limit IL-1β activation, thereby permitting GAS to escape restriction by inflammation. We are now are examining how IL-1β and other inflammatory pathways contribute to the biology of GAS infections, with on eye on the pathogen's population structure, host immune coordination, and interactions with resident species of the microbiome.

In addition to SpeB, we have discovered IL-1β-activating proteases in other medically important pathogens including Enterococcus faecalisPseudomonas aeruginosa, and Candida albicans, and are detailing their roles in pathogenesis. The preponderance of this activity indicates this is not a nuance of GAS infection, but rather, that IL-1β is an innate immune sensor of aberrant proteolysis. We are further exploring this model with a detailed genetic and molecular analysis of IL-1β cleavage sites and their signaling impact, examination of IL-1β human polymorphisms and its evolutionary history across vertebrates, and finally translating these findings toward the study of other proteolytically regulated cytokines.

We are also analyzing the infection risk in ‘pharmacological knockout’ humans. This allows discoveries unforeseen by basic or clinical research such as the high importance for appropriate IL-1β signaling for protection against GAS; IL-1β-knockout mice were expected to have uniform susceptibility to pathogens, conversely, human infection risk remained unrealized due to clinical trial sizes. Our ongoing analysis incorporates electronic medical records and FDA post-marketing drug surveillance to provide high-resolution rates of disease to allow detection of infection risks resulting from preexisting disease or its treatment. These data hint at plasticity in the host-pathogen interaction not fully anticipated by classic ‘Molecular Koch’s postulates’ strategies that use mutant bacteria or knockout mice.

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