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Investigating whether chlamydia trachomatis can increase the infectivity of HPV during genital tract infections

Award Number: R21AI175847
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Although the estimated lifetime risk of human papillomavirus (HPV) infection can be as high as 75% in unvaccinated women, the actual risk of developing cervical cancer is only ~0.68%. This indicates that exposure to HPV alone is insufficient for the development of cervical cancer and that HPV infections likely require the presence of a biological or cellular induced “co-factor” to help trigger oncogenesis. As the most common bacterial sexually transmitted pathogen and because it too is a significant threat to the reproductive health of women, Chlamydia trachomatis (Ct) infections are increasingly being linked to gynecological cancer development as epidemiological reports indicate that co-infections with Ct and HPV are relatively common. Meta-analyses of the epidemiological data and the early investigations into the putative role of Ct in gynecological cancers have implicated the cellular immune response to chlamydial infection as a potential co- factor that can enhance the host’s susceptibility to HPV-induced cervical cancers. We and others have shown that the immune response to Chlamydia infection results in genital tract pathology and our most recent report shows that TLR3 deficiency in HUMAN oviduct epithelial (hOE) cells alters the immune response to Ct infection, resulting in increased chlamydial replication. We also recently reported that Chlamydia infection induces the syntheses of cellular factors that disrupt cell-cell junctions in genital tract tissue and that TLR3 deficiency leads to increased monolayer permeability during Chlamydia infection. Our data support other studies showing that Chlamydia infection can disrupt the protective epithelial barrier function, and we also presented evidence that TLR3 plays a role in maintaining the integrity of the epithelial barrier during genital tract Chlamydia infection. Therefore, we hypothesize that Chlamydia infection disrupts epithelial barrier function (which is in part modulated by TLR3), and the barrier disruption will allow better access to the underlying basal cell layers and thereby can increase the infectivity of HPV. In this proposal, we will test our hypothesis that Ct can serve as a co-factor in HPV-infection-induced cervical cancer by: (1) examining whether Chlamydia infection or secreted products of Chlamydia infection can enhance the attachment and entry of HPV into their target cells, (2) determining if TLR3 signaling modulates the impact that Ct has on increasing HPV infectivity, and (3) ascertaining if genital tract Chlamydia infection will make mice more susceptible to subsequent papillomavirus infections. Confirmation of our hypothesis would reveal novel insight into Ct-HPV coinfection, the role of TLR3 in altering outcomes of coinfection, and implicate TLR3 as a potential target for therapeutic interventions to prevent Ct-triggered oncogenesis in HPV-infected patients.


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 = $168,753 )
2024	2024	MARIAN UNIVERSITY INC	3200 COLD SPRING RD	INDIANAPOLIS	IN	46222	MARION	USA	Allergy and Infectious Diseases Research	001	2	5/21/2024	NON-COMPETING CONTINUATION	$16,875
2024	2024	MARIAN UNIVERSITY INC	3200 COLD SPRING RD	INDIANAPOLIS	IN	46222	MARION	USA	Allergy and Infectious Diseases Research	000	2	2/15/2024	NON-COMPETING CONTINUATION	$151,878
														Subtotal = $168,753

Issue Date FY: 2023 ( Subtotal = $208,893 )
2023	2023	MARIAN UNIVERSITY INC	3200 COLD SPRING RD	INDIANAPOLIS	IN	46222	MARION	USA	Allergy and Infectious Diseases Research	000	1	3/10/2023	NEW	$208,893
														Subtotal = $208,893

Grand Total All Awards = $377,646

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Investigating whether chlamydia trachomatis can increase the infectivity of HPV during genital tract infections

Award Number: R21AI175847

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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