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Cellular mechanisms by which Neisseria gonorrhoeae infects the female reproductive tract

Award Number: R01AI141894
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: 07/05/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Cellular mechanisms by which Neisseria gonorrhoeae infects the female reproductive tract - Project Summary Neisseria gonorrhoeae (GC) infect humans exclusively, primarily the genital tract, causing gonorrhea, which remains a public health crisis due to antibiotic resistance and no vaccines. GC infect both males and females, but women disproportionally suffer from severe complications. However, most female infections are asymptomatic. GC can colonize the vaginocervix asymptomatically for months, which delays treatments and allows infections to silently disseminate and ascend to the upper reproductive tract, leading to pelvic inflammatory disease and predisposing women to infertility and ectopic pregnancy. GC infection has been shown to induce mucosal cytokine secretion into vaginocervical secretions and in epithelial cell lines. However, the mechanism(s) used by GC to actively colonize the cervix without triggering immune detection remains unknown. Whether the local cytokine response plays a role in asymptomatic infection is also unclear. This proposal aims to determine the mechanisms by which GC manipulate the initial local cytokine response to enable asymptomatic colonization of the human cervix. Work supported by this grant has established an ex vivo GC cervical infection model mimicking GC in vivo infection, using human cervical tissue explants. This model gives us a unique opportunity to understand GC asymptomatic colonization at the cervix. Using this model, we have revealed the local IL-10 induction at the cervix as a mechanism for GC to inhibit local immune detection and promote GC colonization, which leads to our hypothesis: GC-epithelial cell interactions, dependent on GC surface structures, result in differential localized production of pro-inflammatory epithelial disrupting and anti-inflammatory epithelial repairing cytokines to interrupt the earliest signals of inflammation. To pursue this hypothesis, we will combine the cervical tissue explant model with isogenic GC strains, cutting- edge Luminex and tissue imaging technologies, and emerging spatial transcriptomic technologies. We will characterize the initial GC-induced cytokine production in the human cervix and the role of GC surface molecules in cytokine induction, determine how GC-induced cytokines promote asymptomatic infection in the cervix, and investigate how GC manipulate transcriptomic programs of cervical cells to induce cytokine production. The proposed studies will significantly advance our understanding of mechanisms underlying asymptomatic infections of GC and other sexually transmitted infections in women, filling critical knowledge gaps and enlightening novel ideas for designing preventatives and vaccines and understanding other challenging women’s health issues.


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: 2026 ( Subtotal = $689,377 )
2026	2026	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	6	4/27/2026	NON-COMPETING CONTINUATION	$689,377
														Subtotal = $689,377

Issue Date FY: 2025 ( Subtotal = $703,373 )
2025	2025	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	001	5	4/28/2025	COMPETING CONTINUATION	$703,377
2025	2022	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	4	2/19/2025	NON-COMPETING CONTINUATION	-$4
														Subtotal = $703,373

Issue Date FY: 2022 ( Subtotal = $565,289 )
2022	2022	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	4	6/6/2022	NON-COMPETING CONTINUATION	$565,289
														Subtotal = $565,289

Issue Date FY: 2021 ( Subtotal = $565,289 )
2021	2021	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	3	6/18/2021	NON-COMPETING CONTINUATION	$565,289
														Subtotal = $565,289

Issue Date FY: 2020 ( Subtotal = $565,289 )
2020	2020	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	2	6/22/2020	NON-COMPETING CONTINUATION	$565,289
2020	2020	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	001	2	6/24/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $565,289

Issue Date FY: 2019 ( Subtotal = $615,289 )
2019	2019	UNIVERSITY OF MARYLAND	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	1	7/5/2019	NEW	$615,289
														Subtotal = $615,289

Grand Total All Awards = $3,703,906

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Cellular mechanisms by which Neisseria gonorrhoeae infects the female reproductive tract

Award Number: R01AI141894

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: 07/05/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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