# Host-Pathogen Interaction in Leptospirosis

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $2,463,023

## Abstract

Abstract: Overall Component
Leptospirosis is a widespread and frequently fatal human health problem that disproportionately impacts low
resource settings. Research on host-pathogen dynamics in leptospirosis are significant because little is known
about leptospiral virulence factors or host response to leptospirosis. The proposed studies will involve highly
synergistic collaborations between program project investigators who are leaders in studies of leptospiral
virulence genes (Haake and Picardeau), endothelial interactions (Coburn), inflammasome pathways
(Sutterwala), and field studies of acute febrile illness (Reller and Woods). With the description of many new
leptospiral genomes, a striking pattern of massive species diversity has emerged leading to central hypothesis
#1, which is that a core set of leptospiral virulence factors have evolved with roles in survival in mammalian host
phagocytes, translocation, and dissemination, which are upregulated in response to the host microenvironment.
Central hypothesis #1 will be tested by correlating genome-scale leptospiral evolutionary changes with virulence
phenotypes, examining the roles of transcriptional regulators and non-coding small RNAs in adaptation to and
survival within host phagocytes, and translocation across endothelial barriers. The correlation of inflammatory
markers such as IL-1β levels with disease severity leads to central hypothesis #2, which is that human
inflammatory response pathways drive disease outcomes. Central hypothesis #2 will be tested in vitro
(interactions with macrophages and endothelial cells), in animal models (infections in hamsters and mice), and
in human field studies in Tanzania, Nicaragua, and Sri Lanka. Specifically, we will follow up on our innovative
discovery of a striking dichotomy between the high level of inflammasome activation in human macrophages
and the low level in macrophages from mice, which are reservoir hosts and do not exhibit disease. We will also
follow up on our innovative discovery of dramatic disruption of endothelial VE-cadherins by pathogenic
leptospires in terms of the role of intercellular invasion in dissemination. Animal model studies will provide
longitudinal host response data in support of human studies that will have a positive impact through
development and validation of rapid biomarker diagnostic and triage tools to identify serious infections at an
early stage when antibiotics and other interventions can prevent and/or treat critical illness including fatal
hepatorenal failure.

## Key facts

- **NIH application ID:** 10643286
- **Project number:** 1P01AI168148-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** DAVID A HAAKE
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $2,463,023
- **Award type:** 1
- **Project period:** 2023-05-16 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10643286

## Citation

> US National Institutes of Health, RePORTER application 10643286, Host-Pathogen Interaction in Leptospirosis (1P01AI168148-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10643286. Licensed CC0.

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