# Redox defenses and evasion of reactive oxygen species mediated host immunity in Mycobacterium tuberculosis

> **NIH NIH F31** · WASHINGTON UNIVERSITY · 2021 · $31,970

## Abstract

Project 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. We will test our
hypothesis by characterizing the ΔcpsA mutant within different myeloid cells in vivo using flow-assisted cell
sorting (FACS) and in mice that are deficient in alveolar macrophages, neutrophils, or monocyte-derived
macrophages, as well as in mice that fail to mount an adaptive immune response against Mtb or that have cell
type specific defects in LAP. KatG is a catalase-peroxidase that is also important in ROS defense in Mtb. We
will test whether CpsA and KatG cooperate in virulence by charactering a ΔcpsA ΔkatG double mutant. We
hypothesize that the ΔcpsA ΔkatG mutant will be more attenuated than either single mutant due to disinhibited
ROS production by the host and reduced ROS detoxifying activity by 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. This proposal is the topic of Steven Grigsby’s PhD thesis in Molecular Microbiology &
Microbial Pathogenesis in the Medical Scientist Training Program at Washington University School of Medicine
(WUSM). The strength at WUSM in microbial pathogenesis and immunology makes it a perfect fit for the studies
proposed by Steven Grigsby....

## Key facts

- **NIH application ID:** 10140849
- **Project number:** 1F31AI152321-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Steven Joseph Grigsby
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $31,970
- **Award type:** 1
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140849

## Citation

> US National Institutes of Health, RePORTER application 10140849, Redox defenses and evasion of reactive oxygen species mediated host immunity in Mycobacterium tuberculosis (1F31AI152321-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10140849. Licensed CC0.

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