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Host-pathogen interactions in experimental cholera

Award Number: R01AI042347
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: 01/01/1998
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Host-pathogen interactions in experimental cholera - 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 have important translational implications for design of new cholera therapeutics and vaccines.


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 = $1,195,060 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	30	6/3/2025	EXTENSION WITH OR WITHOUT FUNDS	$1,195,060
2025	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	29	6/3/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,195,060

Issue Date FY: 2024 ( Subtotal = $597,530 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	29	4/24/2024	NON-COMPETING CONTINUATION	$597,530
2024	2022	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	002	27	4/30/2024	COMPETING CONTINUATION	$126,388
2024	2021	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	26	4/30/2024	NON-COMPETING CONTINUATION	-$126,388
														Subtotal = $597,530

Issue Date FY: 2023 ( Subtotal = $597,530 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	28	5/3/2023	NON-COMPETING CONTINUATION	$597,530
														Subtotal = $597,530

Issue Date FY: 2022 ( Subtotal = $597,530 )
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	27	3/15/2022	COMPETING CONTINUATION	$597,530
														Subtotal = $597,530

Issue Date FY: 2021 ( Subtotal = $518,377 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	26	5/19/2021	NON-COMPETING CONTINUATION	$518,377
														Subtotal = $518,377

Issue Date FY: 2020 ( Subtotal = $518,377 )
2020	2020	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	25	4/27/2020	NON-COMPETING CONTINUATION	$518,377
														Subtotal = $518,377

Issue Date FY: 2019 ( Subtotal = $542,379 )
2019	2019	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	24	6/5/2019	NON-COMPETING CONTINUATION	$518,377
2019	2018	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	23	11/30/2018	COMPETING CONTINUATION	$24,002
														Subtotal = $542,379

Issue Date FY: 2018 ( Subtotal = $518,377 )
2018	2018	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	23	5/29/2018	COMPETING CONTINUATION	$518,377
														Subtotal = $518,377

Issue Date FY: 2007 ( Subtotal = $283,189 )
2007	2007	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	12	4/6/2007	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$214,104
2007	2007	TUFTS UNIVERSITY	169 HOLLAND ST, 2ND FLOOR	SOMERVILLE	MA	02144	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	11	12/19/2006	NON-COMPETING CONTINUATION	$69,085
														Subtotal = $283,189

Issue Date FY: 2006 ( Subtotal = $270,857 )
2006	2006	TUFTS UNIVERSITY	169 HOLLAND ST, 2ND FLOOR	SOMERVILLE	MA	02144	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	10	1/6/2006	NON-COMPETING CONTINUATION	$270,857
														Subtotal = $270,857

Issue Date FY: 2005 ( Subtotal = $329,709 )
2005	2005	TUFTS UNIVERSITY	169 HOLLAND ST, 2ND FLOOR	SOMERVILLE	MA	02144	MIDDLESEX	USA	Microbiology and Infectious Diseases Research	000	9	12/29/2004	NON-COMPETING CONTINUATION	$329,709
														Subtotal = $329,709

Issue Date FY: 2004 ( Subtotal = $309,913 )
2004	2004	TUFTS UNIVERSITY	169 HOLLAND ST, 2ND FLOOR	SOMERVILLE	MA	02144	MIDDLESEX	USA	Microbiology and Infectious Diseases Research	000	8	12/5/2003	NON-COMPETING CONTINUATION	$277,375
2004	2004	TUFTS UNIVERSITY	169 HOLLAND ST, 2ND FLOOR	SOMERVILLE	MA	02144	MIDDLESEX	USA	Microbiology and Infectious Diseases Research	001	8	5/15/2004	SUPPLEMENT FOR EXPANSION	$32,538
														Subtotal = $309,913

Issue Date FY: 2003 ( Subtotal = $283,500 )
2003	2003	NEW ENGLAND MEDICAL CENTER HOSPITALS, INC	750 WASHINGTON STREET	BOSTON	MA	02111	SUFFOLK	USA	Microbiology and Infectious Diseases Research	000	6		COMPETING CONTINUATION	$283,500
														Subtotal = $283,500

Issue Date FY: 2002 ( Subtotal = $267,303 )
2002	2002	NEW ENGLAND MEDICAL CENTER HOSPITALS	171 HARRISON AVENUE, BOX 453	BOSTON	MA	02111	SUFFOLK	USA	Microbiology and Infectious Diseases Research	000	5	12/13/2001	NON-COMPETING CONTINUATION	$267,303
														Subtotal = $267,303

Issue Date FY: 2001 ( Subtotal = $259,476 )
2001	2001	NEW ENGLAND MEDICAL CENTER HOSPITALS	171 HARRISON AVENUE, BOX 453	BOSTON	MA	02111	SUFFOLK	USA	Microbiology and Infectious Diseases Research	000	4	1/5/2001	NON-COMPETING CONTINUATION	$259,476
														Subtotal = $259,476

Issue Date FY: 2000 ( Subtotal = $251,957 )
2000	2000	NEW ENGLAND MEDICAL CENTER HOSPITALS	171 HARRISON AVENUE, BOX 453	BOSTON	MA	02111	SUFFOLK	USA	Microbiology and Infectious Diseases Research	000	3	12/22/1999	NON-COMPETING CONTINUATION	$251,957
														Subtotal = $251,957

Issue Date FY: 1999 ( Subtotal = $245,778 )
1999	1999	NEW ENGLAND MEDICAL CENTER HOSPITALS	171 HARRISON AVENUE, BOX 453	BOSTON	MA	02111	SUFFOLK	USA	Microbiology and Infectious Diseases Research	000	2	11/22/1998	NON-COMPETING CONTINUATION	$245,778
														Subtotal = $245,778

Issue Date FY: 1998 ( Subtotal = $177,710 )
1998	1998	NEW ENGLAND MEDICAL CENTER HOSPITALS	171 HARRISON AVENUE, BOX 453	BOSTON	MA	02111	SUFFOLK	USA	Microbiology and Infectious Diseases Research	000	1	12/23/1997	NEW	$177,710
														Subtotal = $177,710

Grand Total All Awards = $7,764,552

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Host-pathogen interactions in experimental cholera

Award Number: R01AI042347

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: 01/01/1998

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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