Gonococcal modulation of host immune responses during single and dual infections

Duncan, Joseph A.

Abstract

Neisseria gonorrhoeae and Chlamydia trachomatis are two of the most common sexually transmitted pathogens in the world. N. gonorrhoeae depends on numerous, highly adapted host-pathogen interactions to persist in the human urogenital tract. Uncomplicated gonococcal infection of the urethra or cervix leads to limited, and non- protective, adaptive immune responses. The mechanisms by which N. gonorrhoeae evades host immunity are thought to include both antigenic variation and active manipulation of immune system signaling by the infecting bacteria. Our preliminary data demonstrates that N. gonorrhoeae inhibits the ability of antigen presenting cells to stimulate CD4+ T lymphocyte proliferation. N. gonorrhoeae accomplishes this through the shedding of outer membrane vesicles and anhydrous peptidoglycan fragments from its cell wall. Some C. trachomatis infected individuals appear to develop protective immunity to the infection. In animal models, CD4+ T lymphocytes directed towards chlamydial antigens can mediate protective immuniity in chlamydial infection. Our preliminary data suggest that N. gonorrhoeae is able to cross suppress T lymphocyte proliferation directed towards chlamydial antigens. In this proposal we propose to identify the signaling mechanisms and consequences to the immune response that are activated by N. gonorrheoeae. Further we will determine the impact of N. gonorrhoeae-mediated immune suppression in both N. gonorrhoeae infection and N. gonorrhoeae/Chlamydia co-infection.

Public Health Relevance

Neisseria gonorrhoeae and Chlamydia trachomatis are the most common bacterial sexually transmitted pathogens in the world and are commonly found as co-infecting pathogens. Both have developed mechanisms of immune evasion that aid in their persistence in the genital tract and transmission to sexual partners. This project seeks to determine the mechanisms by which N. gonorrhoeae suppresses the development of host adaptive immunity against both N. gonorrhoeae and C. trachomatis during co- infection.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Allergy and Infectious Diseases (NIAID)
• Type: Research Program--Cooperative Agreements (U19)
• Project #: 1U19AI113170-01
• Application #: 8769567
• Study Section: Special Emphasis Panel (ZAI1)
• Budget Start: 2014-08-01
• Budget End: 2015-07-31
• Support Year: 1
• Fiscal Year: 2014

Institution

• Name: Henry M. Jackson Fdn for the Adv Mil/Med
• City: Bethesda
• State: MD
• Country: United States

Publications

Zheng, Xiaojing; O'Connell, Catherine M; Zhong, Wujuan et al. (2018) Gene Expression Signatures Can Aid Diagnosis of Sexually Transmitted Infection-Induced Endometritis in Women. Front Cell Infect Microbiol 8:307

Kahler, Charlene M; Nawrocki, K L; Anandan, A et al. (2018) Structure-Function Relationships of the Neisserial EptA Enzyme Responsible for Phosphoethanolamine Decoration of Lipid A: Rationale for Drug Targeting. Front Microbiol 9:1922

Zhu, Weiyan; Tomberg, Joshua; Knilans, Kayla J et al. (2018) Properly folded and functional PorB from Neisseria gonorrhoeae inhibits dendritic cell stimulation of CD4+ T cell proliferation. J Biol Chem 293:11218-11229

Zheng, Xiaojing; O'Connell, Catherine M; Zhong, Wujuan et al. (2018) Discovery of Blood Transcriptional Endotypes in Women with Pelvic Inflammatory Disease. J Immunol 200:2941-2956

Rouquette-Loughlin, Corinne E; Dhulipala, Vijaya; Reimche, Jennifer L et al. (2018) cis- and trans-Acting Factors Influence Expression of the norM-Encoded Efflux Pump of Neisseria gonorrhoeae and Levels of Gonococcal Susceptibility to Substrate Antimicrobials. Antimicrob Agents Chemother 62:

Vincent, Leah R; Kerr, Samuel R; Tan, Yang et al. (2018) In Vivo-Selected Compensatory Mutations Restore the Fitness Cost of Mosaic penA Alleles That Confer Ceftriaxone Resistance in Neisseria gonorrhoeae. MBio 9:

Rouquette-Loughlin, Corinne E; Zalucki, Yaramah M; Dhulipala, Vijaya L et al. (2017) Control of gdhR Expression in Neisseria gonorrhoeae via Autoregulation and a Master Repressor (MtrR) of a Drug Efflux Pump Operon. MBio 8:

Rice, Peter A; Shafer, William M; Ram, Sanjay et al. (2017) Neisseria gonorrhoeae: Drug Resistance, Mouse Models, and Vaccine Development. Annu Rev Microbiol 71:665-686

Gangaiah, Dharanesh; Raterman, Erica L; Wu, Hong et al. (2017) Both MisR (CpxR) and MisS (CpxA) Are Required for Neisseria gonorrhoeae Infection in a Murine Model of Lower Genital Tract Infection. Infect Immun 85:

Taylor, Brandie D; Zheng, Xiaojing; Darville, Toni et al. (2017) Whole-Exome Sequencing to Identify Novel Biological Pathways Associated With Infertility After Pelvic Inflammatory Disease. Sex Transm Dis 44:35-41