# Leptospiral-Phagocyte Dynamics in Leptospirosis

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $181,540

## Abstract

Abstract: Project 1, University of California, Los Angeles
Leptospirosis is a widespread and frequently fatal human health problem that disproportionately impacts
individuals living in low resource settings. Research on phagocyte interactions in leptospirosis is significant
because little is known about leptospiral virulence factors required for survival within phagocytes or the response
of macrophages to leptospires. The proposed studies will involve collaborations between the PI and co-
investigator Fayyaz Sutterwala, who is a leader in studies of inflammasome activation. Two related but non-
interdependent Aims are proposed. Aim 1 is to examine leptospiral-phagocyte interactions in vitro. We will
examine the murine vs human macrophage responses to L. interrogans in terms of type I interferon and
inflammasome responses and determine the pathways involved in their activation. We will examine whether
leptospiral virulence genes account for lower inflammasome activation in murine relative to human macrophages.
We will examine the time course of leptospiral uptake and survival vs killing of leptospiral species and test the
hypothesis that macrophage survival is a property of the pathogenic, but not the saprophytic, species. We will
identify virulence genes required for survival after exposure to macrophages as a result of phagocytic uptake
and examine the leptospiral response to macrophage uptake. Given the finding that LigB plays a role in
macrophage infection, we are interested in examining macrophage uptake and killing of a ligAligB knock down
mutant that lacks expression of LigA and LigB. Dual RNAseq will be performed with bone marrow-derived
macrophages (BMDMs) and L. interrogans including mutants with impaired intracellular survival to identify genes
potentially involved in leptospiral-phagocyte interactions. Aim 2 is to examine leptospiral-phagocyte interactions
in vivo. We will examine the kinetics of local control vs dissemination after subcutaneous challenge of hamsters
vs mice. We will test the hypothesis that L. interrogans survives within phagocytes during infection of the
subcutaneous space, blood, and liver. We will identify virulence genes required for intracellular survival within
phagocytes after subcutaneous challenge. We are particularly interested in defects in in vivo fitness for local
and disseminated infection of our ligAligB knock-down mutant and other virulence gene candidates. We will
screen our transposon mutant library for mutants with fitness defects in the subcutaneous space and for
dissemination. Using mice with defects in type I interferon response involving cGAS/STING and inflammasome
activation involving NLRP3, we will test the hypothesis that these macrophage responses improve local control
and reduce dissemination after subcutaneous challenge.

## Key facts

- **NIH application ID:** 10842340
- **Project number:** 5P01AI168148-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** DAVID A HAAKE
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $181,540
- **Award type:** 5
- **Project period:** 2023-05-16 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842340

## Citation

> US National Institutes of Health, RePORTER application 10842340, Leptospiral-Phagocyte Dynamics in Leptospirosis (5P01AI168148-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10842340. Licensed CC0.

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