Genetic Variation in Toll-Like Receptor 5 and Colonization with Flagellated Bacterial Vaginosis-Associated Bacteria.
Erin J Dela Cruz, Tina L Fiedler, Congzhou Liu, Matthew M Munch, Christina M Kohler, Antoinette R Oot, Jacqueline M Wallis, Junhui Wang, Anna Frishman, Kristina Garcia, Andrew Wiser, Jennifer E Balkus, Sujatha Srinivasan, Jonathan L Golob, Laura K Sycuro, Jeanne M Marrazzo, Thomas R Hawn, David N Fredricks
Author Information
Erin J Dela Cruz: Medical Scientist Training Program, School of Medicine, University of Washington, Seattle, Washington, USA. ORCID
Tina L Fiedler: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Congzhou Liu: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Matthew M Munch: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Christina M Kohler: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Antoinette R Oot: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Jacqueline M Wallis: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Junhui Wang: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Anna Frishman: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Kristina Garcia: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Andrew Wiser: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Jennifer E Balkus: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Sujatha Srinivasan: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Jonathan L Golob: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. ORCID
Laura K Sycuro: Department of Microbiology, Immunology & Infectious Diseases, University of Calgary, Calgary, Alberta, Canada.
Jeanne M Marrazzo: Division of Infectious Diseases, Department of Medicine, University of Alabama School of Medicine, Birmingham, Alabama, USA.
Thomas R Hawn: Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, USA.
David N Fredricks: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA dfredric@fredhutch.org. ORCID
Bacterial vaginosis (BV) is a vaginal dysbiotic condition linked to negative gynecological and reproductive sequelae. Flagellated bacteria have been identified in women with BV, including spp. and BV-associated bacterium-1 (BVAB1), an uncultivated, putatively flagellated species. The host response to flagellin mediated through Toll-like receptor 5 (TLR5) has not been explored in BV. Using independent discovery and validation cohorts, we examined the hypothesis that TLR5 deficiency-defined by a dominant negative stop codon polymorphism, rs5744168-is associated with an increased risk for BV and increased colonization with flagellated bacteria associated with BV (BVAB1, , and ). TLR5 deficiency was not associated with BV status, and TLR5-deficient women had decreased colonization with BVAB1 in both cohorts. We stimulated HEK-hTLR5-overexpressing NF-κB reporter cells with whole, heat-killed or and with partially purified flagellin from these species; as BVAB1 is uncultivated, we used cervicovaginal lavage (CVL) fluid supernatant from women colonized with BVAB1 for stimulation. While heat-killed and CVL fluid from women colonized with BVAB1 stimulate a TLR5-mediated response, heat-killed did not. In contrast, partially purified flagellin from both species stimulated a TLR5-mediated response We observed no correlation between vaginal interleukin 8 (IL-8) and flagellated BVAB concentrations among TLR5-sufficient women. Interspecies variation in accessibility of flagellin recognition domains may be responsible for these observations, as reflected in the potentially novel flagellin products encoded by species versus those encoded by BVAB1.
