# Novel Therapies Targeting Mitochondrial Pathways in Lung Epithelial Response to S. Pneumoniae Infection

> **NIH VA IK2** · VETERANS HEALTH ADMINISTRATION · 2022 · —

## Abstract

This CDA-2 application proposes a 5-year training program to develop the career of Dr. Nicholas Maurice as
he investigates mechanisms of Streptococcus pneumoniae pathogenicity with a focus on how the interaction
between bacterial virulence factors and host mitochondrial oxidative DNA damage and repair modulates the
innate immune response to pneumococcal infection. His primary mentor, Dr. Ruxana Sadikot, is an
internationally-recognized expert in the field of host defense against bacterial pathogens. His mentorship team
includes other senior investigators at the Atlanta VA and Emory University with complementary areas of
expertise that will contribute to Dr. Maurice’s career development. In addition, Dr. Maurice will benefit from an
excellent training environment at the Atlanta VA Medical Center and Emory University with a proven track
record of success developing the careers of young investigators. Previous published research by Dr. Maurice
identified key virulence factors of the bacterial pathogen, Pseudomonas aeruginosa, that impair innate
immunity through attenuation of host epithelial cell mitochondrial bioenergetic function and mitochondrial
biogenesis. He demonstrated that genetic and pharmacologic strategies that enhanced mitochondrial
biogenesis could promote epithelial host defense. Based on his work investigating mitochondrial biogenesis,
Dr. Maurice began investigating another mitochondrial quality control process namely mitochondrial DNA
repair. He also began focusing on the bacteria S. pneumoniae given the significant health threat it poses to the
veteran population. Preliminary research has identified the novel finding that S. pneumoniae induces oxidative
mitochondrial DNA damage and attenuates expression of the DNA repair enzyme, OGG1, in host epithelial
cells. Additional data suggest that this pathway may have significant consequences on the epithelial host
response to pneumococcal infection. This work has led to the hypothesis that pneumococcal virulence factors
such as pneumolysin, a cholesterol-dependent cytolysin, impair host defense through oxidative mitochondrial
DNA damage, but targeted enhancement of mitochondrial DNA repair can ameliorate cellular dysfunction and
improve the host response to pneumococcal infection. This proposal encompasses three aims. First, the
pneumococcal virulence factors responsible for the induction of oxidative mitochondrial DNA injury and
attenuation of OGG1 expression in host epithelial cells will be identified. Second, the role of reactive oxygen
species-mediated mitochondrial damage and OGG1-mediated mitochondrial DNA repair in the epithelial host
response to S. pneumoniae will be defined. Third, in pre-clinical translational studies, novel therapeutic
strategies targeting mitochondrial OGG1 will be tested in an in vivo model of pneumococcal pneumonia to
determine if enhancing mitochondrial DNA repair reflects an efficacious treatment strategy for S. pneumoniae
infection. These studies will pr...

## Key facts

- **NIH application ID:** 10367976
- **Project number:** 1IK2BX005371-01A2
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Nicholas Michael Maurice
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10367976

## Citation

> US National Institutes of Health, RePORTER application 10367976, Novel Therapies Targeting Mitochondrial Pathways in Lung Epithelial Response to S. Pneumoniae Infection (1IK2BX005371-01A2). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10367976. Licensed CC0.

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