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Molecular mechanisms driving the coevolution of clinical isolates of phages and epidemic Vibrio cholerae

Award Number: R01AI153303
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Molecular mechanisms driving the coevolution of clinical isolates of phages and epidemic Vibrio cholerae - Illness and death caused by infectious diarrheal disease agents, like Vibrio cholerae, are major threats to public health and significant barriers to socioeconomic development worldwide. Natural disasters and continuing conflict in some depressed regions threaten to exacerbate the already rising incidence of cholera globally. Comparative genomics of V. cholerae isolated over the last century reveal recurring episodes of novel genetic variants with new repertoires of mobile genetic elements (MGEs) spreading globally from where they initially emerged in the Bay of Bengal. For unknown reasons, a hallmark of this pattern is that previously prevalent strains completely disappear when new variants emerge. The arms race between viruses and their host organisms is a key driving force in the evolution of all cellular life. Successful strains of epidemic V. cholerae must defend against the ubiquitous threat of predatory phages in aquatic reservoirs and the intestinal tract during human disease. In collaboration with the icddr,b, we have established a longitudinal collection of clinical phages and V. cholerae isolates to serve as a tractable, clinically relevant platform to study mechanisms driving reciprocal adaptations in ongoing phage-bacterial conflict. Using this platform, we discovered fluctuating MGEs in epidemic V. cholerae that provide robust protection against co-circulating phages. One such family of anti-phage MGEs, called PLEs, provides exquisitely specific protection against ICP1, the predominant phage in cholera patient stool samples. We discovered novel mechanisms that ICP1 evolved to counter PLEs and other V. cholerae defenses. Although we have made critical advances in understanding mechanisms underpinning reciprocal adaptations that contribute to some of the observed diversification and dynamics of PLEs and ICP1 in nature, many observations from our extensive collection of contemporary clinical isolates remain unexplained. To reveal molecular mechanisms contributing to the selection of emergent phage and epidemic V. cholerae genotypes, we will pursue the following specific aims: 1) We will examine how a novel PLE variant blocks phage despite phage-mediated degradation of PLE. 2) We will interrogate barriers limiting the acquisition and maintenance of co-resident PLEs in V. cholerae, and 3) We will define the array of defenses and counter-defenses in a clinical collection of V. cholerae and phage. The proposed studies will advance the understanding of factors influencing population shifts in epidemic V. cholerae and reveal novel mechanisms underpinning phage-bacterial coevolution. This knowledge will further enhance our understanding of phage-mediated perturbations to microbial populations in healthy and diseased states and advance our capacity to manipulate these communities for therapeutic or prophylactic benefit.


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 = $603,693 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	6	4/29/2025	COMPETING CONTINUATION	$603,693
														Subtotal = $603,693

Issue Date FY: 2024 ( Subtotal = $629,003 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	5	5/21/2024	NON-COMPETING CONTINUATION	$629,003
														Subtotal = $629,003

Issue Date FY: 2023 ( Subtotal = $626,714 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	4	4/26/2023	NON-COMPETING CONTINUATION	$626,714
														Subtotal = $626,714

Issue Date FY: 2022 ( Subtotal = $636,929 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	3	5/19/2022	NON-COMPETING CONTINUATION	$636,929
														Subtotal = $636,929

Issue Date FY: 2021 ( Subtotal = $631,676 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	2	5/4/2021	NON-COMPETING CONTINUATION	$631,676
														Subtotal = $631,676

Issue Date FY: 2020 ( Subtotal = $612,764 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	1	6/1/2020	NEW	$612,764
														Subtotal = $612,764

Grand Total All Awards = $3,740,779

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Molecular mechanisms driving the coevolution of clinical isolates of phages and epidemic Vibrio cholerae

Award Number: R01AI153303

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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