# Pathogen-induced immune and stress responses mediated by bZIP transcription factors

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2024 · $388,750

## Abstract

Project Description
The mitis group streptococci are ubiquitous microorganisms that colonize the human oropharynx. In susceptible
hosts, these organisms are important opportunistic pathogens and they have shown to cause a wide range of
infectious complications in humans, which includes bacteremia, orbital cellulitis, septic arthritis, and infective
endocarditis. However, despite the clinical significances of these infections, the mechanisms of pathogenesis
and the pathophysiology are poorly understood. Hydrogen peroxide (H2O2) produced by these microorganisms
has been identified as an important virulence factor. Furthermore, H2O2 produced by members of this group such
as Streptococcus oralis and Streptococcus mitis induced epithelial cell and macrophage death, while H2O2
produced by Streptococcus pneumoniae had a profound effect on the activation of cellular stress pathways in
lung epithelial cells. The genetically tractable model organism Caenorhabditis elegans provides an opportunity
to characterize the pathophysiology in context of the whole organism and to elucidate how non-immune cells
facilitate innate immune and stress responses. In this study, we propose to elucidate mechanisms of activation
of pathogen-induced immune and stress responses by the mitis group streptococci. Our central hypothesis is
that immune and oxidative stress responses are mediated by the bZIP transcription factors ZIP-2 and ZIP-10 via
pathogen-derived H2O2. To address our hypothesis the following aims will be tested; Specific Aim #1. To
elucidate the mechanism how the bZIP transcription factor, ZIP-2 mediates the effector-triggered immune
response in C. elegans against streptococcal-derived H2O2. Specific Aim #2. We will determine the mechanisms
of activation of an immune and oxidative stress response via the bZIP transcription factor ZIP-10 in response to
the pathogen-derived H2O2 in the worm. Specific Aim #3. To demonstrate the conservation of these
mechanisms identified in aims 1 and 2 in human gingival fibroblasts. The proposed study is significant because
we will identify how H2O2 produced by the mitis group streptococci causes pathogen-associated disruption of
cellular processes and in turn the activation of protective mechanisms. Elucidating the protective mechanisms
will help identify novel therapeutic strategies to combat these pathogens.

## Key facts

- **NIH application ID:** 10901920
- **Project number:** 7R01AI158429-04
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Ransome van der Hoeven
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $388,750
- **Award type:** 7
- **Project period:** 2021-09-23 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10901920

## Citation

> US National Institutes of Health, RePORTER application 10901920, Pathogen-induced immune and stress responses mediated by bZIP transcription factors (7R01AI158429-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10901920. Licensed CC0.

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