# Host-pathogen interactions in experimental cholera

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $597,530

## Abstract

Project Summary
Cholera is a severe dehydrating diarrheal disease caused by Vibrio cholerae. This Gram-negative rod has
the unusual capacity to colonize the small intestine and to cause explosive epidemics. Here we will address
fundamental questions in V. cholerae-host interactions, leveraging many of the approaches and tools we
have created in the past decades. V. cholerae O1, the cause of pandemic cholera, is divided into Ogawa
and Inaba serotypes, which differ only by the presence or absence of methylation of the terminal O-antigen
sugar respectively. Switching of the Ogawa and Inaba serotypes during cholera epidemics has been
recognized for over a century, but the consequences of serotype conversion on pathogen fitness are not
clear. We discovered that the Ogawa serotype has greater in vivo fitness than the Inaba serotype and that
the two serotypes rely on distinct metabolic process for growth in vivo. Thus, there are unexpected direct or
indirect phenotypic and physiological consequences of O-antigen methylation on V. cholerae growth in vivo.
The consequences and mechanisms that underlie the in vivo fitness differences of the V. cholerae serotypes
will be determined in Aim 1. Cholera toxin (CT) triggers the intestinal fluid secretion that largely accounts for
choleric diarrhea. We found that CT also leads to the secretion of hundreds of host proteins identified in
diarrheal fluid and re-models the intestinal epithelial transcriptional response to V. cholerae. Many of these
proteins and transcripts are linked to innate immune responses and we found that one of these proteins,
surfactant protein D (SP-D), restricts V. cholerae growth in the intestine. In Aim 2, we will analyze the
protective mechanisms mediated by SP-D and investigate the roles of additional V. cholerae-induced
secreted host proteins in impeding the pathogen’s colonization, to uncover host innate axes that protect
against V. cholerae infection. Cholera epidemics often spread extremely rapidly, and host passaging
increases V. cholerae infectivity, but the V. cholerae and host genes that govern cholera transmission are
largely unknown. In Aim 3, we will leverage our experience with pathogen barcoding and a new computational
framework to extend analyses developed in Aims 1 and 2, examining the roles of serotype and CT in
modulating host-priming of infectivity. Additional pathogen pathways and host processes that control V.
cholerae infectivity will also be elucidated, to deepen understanding of cholera transmission. Collectively, the
proposed research will yield new understanding of the interconnected processes that govern V. cholerae
intestinal colonization and infectivity as well as the host factors and mechanisms that limit colonization and
control transmission. This work will provide new perspectives on the biology of the two V. cholerae serotypes,
and on the actions of cholera toxin in stimulating innate host defense responses against the pathogen. Our
findings will also hav...

## Key facts

- **NIH application ID:** 10836413
- **Project number:** 5R01AI042347-29
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Matthew K WALDOR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $597,530
- **Award type:** 5
- **Project period:** 1998-01-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10836413

## Citation

> US National Institutes of Health, RePORTER application 10836413, Host-pathogen interactions in experimental cholera (5R01AI042347-29). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10836413. Licensed CC0.

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