# Genetic Dissection of Mycobacterial Pathogenesis During Eicosanoid-Mediated Immunity

> **NIH NIH F31** · DUKE UNIVERSITY · 2022 · $39,058

## Abstract

ABSTRACT
Mycobacterium tuberculosis (Mtb) one of the most successful pathogen in the world due to its long-standing,
ancient partnership with humans. Despite decades of effort put towards prevention and treatment, Mtb was the
number one cause of death by any single infectious agent in 2019. An important regulator of mycobacterial
infections are eicosanoids: host-produced, lipid signaling molecules that can drive both inflammatory and anti-
inflammatory signaling cascades. Using a zebrafish-Mycobacterium marinum infection model that recapitulates
important aspects of mycobacterial pathogenesis, the balance of specific pro- and anti-inflammatory eicosanoids
was found to be critical to control of infection. Disruption of eicosanoid synthesis, through a mutation in
leukotriene A4 hydrolase-deficient (lta4h-/-), results in altered granuloma structure. The granuloma is the central
feature of Mtb infection and is an aggregation of immune cells coordinating to restrict bacterial growth. This is
the principal site of host-pathogen interactions. Although the granuloma is a key part of tuberculosis
pathogenesis, host-pathogen signaling programs that govern granuloma biology remain elusive. Our lack of
understanding of granuloma formation and signaling is due to the difficulty in studying the granuloma because
the complex cell organization can only be formed and observed in vivo. The zebrafish-Mycobacterium marinum
model, with conserved virulence loci and host-pathogen genetic programs, is used to study the genetics of
mycobacterial infection and granuloma structure. This proposal will use genetic approaches in both the zebrafish-
M.marinum granuloma model and the mouse-Mtb model of infection to test the hypothesis that there are key
differences in eicosanoid-mediated immunity and bacterial response that are integral to overall
granuloma biology. To this end, the first single-cell map of mycobacterial granulomas, in an experimentally
tractable system was assembled from wildtype and lta4h-/- zebrafish granuloma cells. The findings from this
dataset informed the following approaches to interrogate the effects of host eicosanoid signaling on granuloma
structure and mycobacterial response. Aim 1 will define the functional role of a previously undefined population
of granuloma cells that are dependent on lta4h expression. Aim 2 will use Mtb TnSeq approaches to the examine
the genetic requirements of Mtb in mice that lack key components of eicosanoid signaling. Together, these aims
will enhance our understanding of granuloma biology and mycobacterial response and can help guide
therapeutic approaches to treating tuberculosis.

## Key facts

- **NIH application ID:** 10480764
- **Project number:** 5F31AI157405-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Erika Joy Hughes
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $39,058
- **Award type:** 5
- **Project period:** 2021-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10480764

## Citation

> US National Institutes of Health, RePORTER application 10480764, Genetic Dissection of Mycobacterial Pathogenesis During Eicosanoid-Mediated Immunity (5F31AI157405-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10480764. Licensed CC0.

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