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Analyzing the Biogeography of Virulence and Transmission Gene Expression during Clostridioides difficile infection

Award Number: R21AI168849
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/19/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Analyzing the Biogeography of Virulence and Transmission Gene Expression during Clostridioides difficile infection - The spore-forming bacterial pathogen Clostridioides difficile caused ~450,000 diarrheal infections and ~30,000 deaths in 2017, making it the leading cause of healthcare-associated infections in the US. C. difficile thrives in the dysbiotic gut because an intact resident microflora antagonizes its growth. As C. difficile grows in the colon, it makes the glucosylating toxins responsible for causing disease pathology and the spores necessary to transmit disease. Recent work has shown that toxin production promotes C. difficile growth in the gut by inducing inflammation, which generates host-derived metabolites that C. difficile specifically exploits. For example, toxin- mediated inflammation stimulates the host to degrade collagen and produce sorbitol. C. difficile then catabolizes the resulting metabolites, allowing it to grow to higher levels in the gut. Since these metabolites are likely concentrated close to the gut epithelium where they are produced, proximity to this cell layer may benefit C. difficile infection. Consistent with this hypothesis, C. difficile chemotaxes towards mucin-derived sugars, and its utilization of these sugars enhances its growth during infection. The mucus layer also impedes toxin binding to target cells, so the growth of C. difficile near the epithelial layer may promote more damage to this layer than luminal bacteria. While these studies suggest that an epithelium-proximal C. difficile sub-population may play key roles during infection, C. difficile is primarily thought of as a gut luminal pathogen. For example, the authors of a previous fluorescent in situ hybridization study directed at localizing C. difficile during murine infection concluded that it rarely associates with the gut epithelium. However, using novel C. difficile constitutive fluorescent reporter strains we find that C. difficile frequently grows in close proximity to the gut epithelium, even though most of the population is luminal. Furthermore, toxin production appears to promote C. difficile growth close to the epithelium. Combined with our finding that gene expression levels in epithelium-associated, but not luminal, C. difficile correlates with disease outcome, we hypothesize that toxin gene expression in the epithelium-proximal sub-population may drive disease prognosis in mice. To test this hypothesis, we are using transcriptional reporter strains to localize C. difficile and quantify its toxin gene expression at the single-cell level during infection of both mice and a colonoid-derived monolayer system. By analyzing these reporters in C. difficile mutants that make varying amounts of toxin or have metabolic defects, we will determine the relationship between epithelium- proximal growth, host metabolite utilization, and damage. Since our preliminary data further suggest that toxin gene expression is inversely regulated with sporulation gene expression, we will also test the hypothesis that C. difficile establishes a “division of labor” during infection between toxin-producing vs. sporulating cells in mutants with altered distributions of these two processes. Collectively, these analyses will fundamentally advance our understanding of how C. difficile establishes infection and may identify novel determinants of disease severity.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	4/14/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $202,350 )
2023	2023	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	12/9/2022	NON-COMPETING CONTINUATION	$202,350
														Subtotal = $202,350

Issue Date FY: 2022 ( Subtotal = $243,600 )
2022	2022	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	1/14/2022	NEW	$243,600
														Subtotal = $243,600

Grand Total All Awards = $445,950

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Analyzing the Biogeography of Virulence and Transmission Gene Expression during Clostridioides difficile infection

Award Number: R21AI168849

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/19/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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