Steven Grigsby
Program: Molecular Microbiology and Microbial Pathogenesis
Current advisor: Jennifer A. Philips, MD, PhD
Undergraduate university: Washington University
Research summary
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), caused 1.4 million deaths in 2017, more than any other pathogen. TB treatment remains difficult, and an effective vaccine has eluded research efforts for the past century. A major barrier to ending the TB pandemic is a limited understanding of effective host immune responses and Mtb’s immune evasion strategies. Much in vitro work has been done to characterize Mtb infection of macrophages, its predominant cellular niche. Whereas reactive oxygen species (ROS) are an important antimicrobial defense against diverse pathogens, Mtb is resistant to ROS. We recently identified CpsA as a secreted virulence factor that inhibits NADPH oxidase recruitment to the Mtb-containing phagosome, thereby protecting Mtb from an oxidative burst. ROS is also an essential signal for LC3-associated phagocytosis (LAP), a noncanonical form of autophagy. Indeed, the ΔcpsA mutant is rescued in mice defective in the NADPH oxidase and LAP. Interestingly, in mice the ΔcpsA mutant is severely attenuated during the first two weeks of infection and recovers substantially by 6 weeks, suggesting that CpsA is most important during the innate phase of infection before the activation of adaptive immunity. This phenotype coincides with a shift in cell types that are infected and the inflammatory response. Therefore, we hypothesize that CpsA specifically protects Mtb against ROS in the cell types infected and inflammatory environment of the innate immune phase. KatG is a catalase-peroxidase that is also important in ROS defense in Mtb. KatG activates the first-line drug isoniazid (INH), and mutations in katG confer INH resistance. CpsA, therefore, may permit transmission of INH-resistant katG mutants by protecting them against ROS. Investigating the roles of ROS and the diverse myeloid cells involved in Mtb infection will impact strategies for host-directed therapies, targeting drug-resistant bacilli, and novel vaccine design.
Graduate publications
Chandra P, Grigsby SJ, Philips JA. 2022 Immune evasion and provocation by Mycobacterium tuberculosis. Nat Rev Microbiol, ():1-17.
Köster S, Upadhyay S, Chandra P, Papavinasasundaram K, Yang G, Hassan A, Grigsby SJ, Mittal E, Park HS, Jones V, Hsu FF, Jackson M, Sassetti CM, Philips JA. 2017 Mycobacterium tuberculosis is protected from NADPH oxidase and LC3-associated phagocytosisby the LCP protein CpsA. Proc Natl Acad Sci USA, 114(41):E8711-E8720.