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Survival of Neisseria gonorrhoeae after primary human neutrophil challenge

Award Number: R01AI097312
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: 07/01/2012
PERIOD OF PERFORMANCE END DATE: 10/31/2029

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Survival of Neisseria gonorrhoeae after primary human neutrophil challenge - PROJECT SUMMARY/ABSTRACT The bacterium Neisseria gonorrhoeae (Gc) causes the sexually transmitted infection gonorrhea. With over 82 million cases of gonorrhea estimated worldwide and growing resistance to all clinically recommended antibiotics, the CDC and WHO have labeled Gc an urgent threat “superbug.” The consequences of repeated, untreated, or untreatable Gc infections include infertility, chronic pelvic pain, and ectopic pregnancy. The clinical hallmark of acute gonorrhea is the recruitment of neutrophils to sites of infection. Despite neutrophils’ robust phagocytic and antimicrobial activities, infectious Gc are recovered from neutrophil-rich gonorrheal secretions. Our overarching hypothesis is that Gc possesses mechanisms to evade and subvert the antimicrobial functions of neutrophils, ensuring its persistence in its obligate human host. To test this hypothesis, we model human mucosal infection ex vivo using primary human neutrophils that are adherent and treated with the neutrophil chemoattractant interleukin-8, and we analyze neutrophil-rich specimens from individuals with gonorrhea. In the previous renewal period, we examined how different routes of phagocytosis affect survival of Gc from neutrophils, particularly for bacterial variants in the opacity-associated (Opa) proteins that promote nonopsonic interaction of Gc with neutrophils. We measured a nonstandard distribution of Gc associated with neutrophils ex vivo and in human gonorrheal specimens, where some neutrophils contain numerous Gc and others none. During these studies, we discovered that Gc co-opts C4b-binding protein (C4BP) and sialic acid addition to its lipooligosaccharide to enhance the survival of Opa+ bacteria from neutrophils. C4BP and sialic acid are well-known for conferring resistance of Gc to complement, but our results are complement-independent, instead thwarting CEACAM3- mediated interactions with Opa+ Gc. Along with new ways to modulate Opa expression and abundance, we now have the tools to dissect how Opa+ Gc thwarts CEACAM3-dependent neutrophil activation. In Aim 1 of this renewal application, we will define how C4BP binding to Gc blocks CEACAM3-dependent phagocytosis of Opa+ Gc. In Aim 2, we will delineate how sialylated Gc exploits interaction with sialic acid-binding immunoglobulin-like lectins (Siglecs) to inhibit neutrophil activation. Aim 3 will define heterogeneity in mature human neutrophils’ functions and gene expression profiles, to test the hypotheses that a subset of neutrophils infected with Gc support bacterial survival, with the infecting Gc for each subset correspondingly varying their gene expression profiles. This Aim will integrate multispectral flow cytometric profiling of primary neutrophils, dual RNAseq on infected neutrophils that are flow-sorted and stratified by bacterial load, and neutrophil single-cell RNAseq with targeted functional analysis of bacterial and human gene products. Our multidisciplinary approach combines expertise in Gc pathogenesis, mass spectrometry, complement inhibition, bioinformatics, and clinical infectious diseases. Through these ongoing studies on how Gc subverts neutrophil attack, new host or bacterial targets for therapeutics can be identified, to combat the global public health burden of drug-resistant gonorrhea.


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 = $546,940 )
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	11	11/18/2024	COMPETING CONTINUATION	$546,940
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	001	11	12/18/2024	COMPETING CONTINUATION	$0
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	003	11	5/1/2025	COMPETING CONTINUATION	$22,202
2025	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	002	10	5/1/2025	NON-COMPETING CONTINUATION	-$22,202
														Subtotal = $546,940

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	10	9/13/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $425,607 )
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	10	10/14/2021	NON-COMPETING CONTINUATION	$425,607
														Subtotal = $425,607

Issue Date FY: 2021 ( Subtotal = $536,335 )
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	9	10/22/2020	NON-COMPETING CONTINUATION	$536,335
														Subtotal = $536,335

Issue Date FY: 2020 ( Subtotal = $551,645 )
2020	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	8	11/6/2019	NON-COMPETING CONTINUATION	$551,645
														Subtotal = $551,645

Issue Date FY: 2019 ( Subtotal = $537,926 )
2019	2019	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	001	7	4/19/2019	SUPPLEMENT FOR EXPANSION	$44,361
2019	2019	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	7	10/25/2018	NON-COMPETING CONTINUATION	$493,565
														Subtotal = $537,926

Issue Date FY: 2018 ( Subtotal = $424,741 )
2018	2018	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	001	6	11/22/2017	COMPETING CONTINUATION	$424,741
2018	2018	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	002	6	2/1/2018	COMPETING CONTINUATION	$0
2018	2016	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	5	11/21/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
2018	2016	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	003	5	7/13/2018	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $424,741

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2015	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	4	11/16/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $392,158 )
2016	2016	UNIVERSITY OF VIRGINIA	P.O. BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	5	6/10/2016	EXTENSION WITH OR WITHOUT FUNDS	$392,158
														Subtotal = $392,158

Issue Date FY: 2015 ( Subtotal = $442,851 )
2015	2015	UNIVERSITY OF VIRGINIA	P.O. BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	4	6/16/2015	NON-COMPETING CONTINUATION	$442,851
														Subtotal = $442,851

Issue Date FY: 2014 ( Subtotal = $518,425 )
2014	2014	UNIVERSITY OF VIRGINIA	P.O. BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	001	3	6/11/2014	NON-COMPETING CONTINUATION	$480,638
2014	2014	UNIVERSITY OF VIRGINIA	P.O. BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	2	2/21/2014	SUPPLEMENT FOR EXPANSION	$37,787
														Subtotal = $518,425

Issue Date FY: 2013 ( Subtotal = $368,629 )
2013	2013	UNIVERSITY OF VIRGINIA	P.O. BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	2	6/27/2013	NON-COMPETING CONTINUATION	$368,629
														Subtotal = $368,629

Issue Date FY: 2012 ( Subtotal = $392,158 )
2012	2012	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	002	1	8/10/2012	NEW	$0
2012	2012	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	001	1	7/26/2012	NEW	$0
2012	2012	UNIVERSITY OF VIRGINIA	P.O. BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	1	4/26/2012	NEW	$392,158
														Subtotal = $392,158

Grand Total All Awards = $5,137,415

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Survival of Neisseria gonorrhoeae after primary human neutrophil challenge

Award Number: R01AI097312

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: 07/01/2012

PERIOD OF PERFORMANCE END DATE: 10/31/2029

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