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HUMAN GENETIC VARIATION REGULATING SALMONELLA HOST-PATHOGEN INTERACTIONS AND DISEASE SUSCEPTIBILITY

Award Number: R01AI118903
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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HUMAN GENETIC VARIATION REGULATING SALMONELLA HOST-PATHOGEN INTERACTIONS AND DISEASE SUSCEPTIBILITY - Salmonellae cause an estimated 150 million cases of gastroenteritis and 25 million cases of invasive disease (enteric fever and non-typhoidal bacteremia), leading to 300,000 deaths per year. Findings based on inbred mouse strains and rare human mutations indicate that the clinical presentations and outcomes of salmonellosis are influenced by the host’s genetic makeup. However, we do not understand the impact of common, naturally occurring human genetic differences on Salmonella infections. Our long-term goal is to leverage high- throughput cellular phenotyping of infection and natural genetic diversity to define molecular parameters of susceptibility to human infectious diseases. While genome-wide association studies (GWAS) of enteric fever and bacteremia identified genetic differences regulating susceptibility, such studies are limited by high variability in patient exposure, pathogen genetic diversity, and a limited understanding of the pathophysiology of identified variants. We developed a complementary cellular GWAS approach (Hi-HOST: High-throughput Human in vitrO Susceptibility Testing; http://h2p2.oit.duke.edu) to perform high resolution analysis of human genetic differences that impact host-pathogen traits while enabling experimental dissection of these traits. In the previous funding period, we focused on human genetic variants that regulate Salmonella invasion of host cells. We identified a regulatory variant in VAC14 that modulates levels of plasma membrane cholesterol and thus limits the docking of the Salmonella SPI-1 type III secretion system to host cells. Humans with the high-invasion allele of VAC14 have increased risk of typhoid fever and bacteremia. The objectives of this application are to define and characterize human genetic differences that alter the full spectrum of Salmonella host-pathogen interactions and assess their impact on disease. Building from our unique resource of Hi-HOST cellular GWAS of Salmonella invasion, replication, and host cytokine levels, we have identified SNPs mediating susceptibility to infection phenotypes that will undergo experimental validation and mechanistic studies. We will determine how regulatory SNPs affecting ARHGEF26 and MCOLN2 expression impact Salmonella invasion and replication and the role these genes play during infection in mice. For ARHGEF26, a Rho GEF that stimulates Salmonella-induced membrane ruffling, our association data and experimental evidence indicate SNPs regulate ARHGEF26 expression to increase invasion dependent on the Salmonella effector sopB. For MCOLN2, we hypothesize that this divalent cation channel is a novel factor that regulates intracellular replication by modulating nutrient access, metal toxicity, and/or immune cell polarization. Using Arhgef26 and Mcoln2 mice, we will elucidate how altered expression of these genes regulates bacterial burden and immune response during infection. Finally, we will test whether SNPs identified by Hi-HOST are associated with enteric fever and bacteremia in humans. Revealing these mechanisms could lead to new therapeutic strategies for salmonellosis and other diseases impacted by the same genetic variants.


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: 2024 ( Subtotal = $453,579 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	10	5/13/2024	NON-COMPETING CONTINUATION	$453,579
														Subtotal = $453,579

Issue Date FY: 2023 ( Subtotal = $453,579 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	9	5/11/2023	NON-COMPETING CONTINUATION	$453,579
														Subtotal = $453,579

Issue Date FY: 2022 ( Subtotal = $489,425 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	8	5/13/2022	NON-COMPETING CONTINUATION	$489,425
														Subtotal = $489,425

Issue Date FY: 2021 ( Subtotal = $504,675 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	7	5/18/2021	NON-COMPETING CONTINUATION	$504,675
2021	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	002	6	6/14/2021	COMPETING CONTINUATION	$67,138
2021	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	001	5	6/14/2021	NON-COMPETING CONTINUATION	-$67,138
														Subtotal = $504,675

Issue Date FY: 2020 ( Subtotal = $467,079 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	001	6	5/30/2020	COMPETING CONTINUATION	$467,079
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	002	6	9/16/2020	COMPETING CONTINUATION	$0
2020	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	5	5/30/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $467,079

Issue Date FY: 2019 ( Subtotal = $428,645 )
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	5	1/17/2019	NON-COMPETING CONTINUATION	$428,645
														Subtotal = $428,645

Issue Date FY: 2018 ( Subtotal = $428,645 )
2018	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	4	1/8/2018	NON-COMPETING CONTINUATION	$428,645
														Subtotal = $428,645

Issue Date FY: 2017 ( Subtotal = $433,415 )
2017	2017	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	3	1/17/2017	NON-COMPETING CONTINUATION	$433,415
														Subtotal = $433,415

Issue Date FY: 2016 ( Subtotal = $360,782 )
2016	2016	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	2	1/13/2016	NON-COMPETING CONTINUATION	$360,782
														Subtotal = $360,782

Issue Date FY: 2015 ( Subtotal = $182,778 )
2015	2015	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	1	7/30/2015	NEW	$182,778
														Subtotal = $182,778

Grand Total All Awards = $4,202,602

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HUMAN GENETIC VARIATION REGULATING SALMONELLA HOST-PATHOGEN INTERACTIONS AND DISEASE SUSCEPTIBILITY

Award Number: R01AI118903

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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