Proinflammatory cytokines are expressed in vivo during infection with the sexually transmitted disease pathogen Neisseria gonorrhoeae and contribute to disease pathology. The activation of proinflammatory cytokines is directed by pattern recognition receptors (PRRs). PRRs can be classified as transmembrane molecules such at the Toll-like receptors (TLRs), or cytosolic molecules including Nod- like receptors (NLRs). TLR2 and TLR4 function as receptors for Neisseria ligands. However, nothing is known about cytosolic molecules that respond to intracellular N. gonorrhoeae. We recently demonstrated that blocking signaling through TLRs using antagonistic antibodies only partially reduced the production of proinflammatory cytokines following N. gonorrhoeae infection of epithelial cells suggesting that intracellular NLRs may be employed for N. gonorrhoeae induced proinflammatory cytokines. We also demonstrated that infection of epithelial cells with N. gonorrhoeae induced the expression of NLRs including Nodi and a protein recently implicated in intracellular immune recognition, inhibitor of apoptosis protein (clAP-2), as well as the receptor interacting serine-threonine kinase 2 (R1P2), a key mediator of innate immune signaling. Furthermore, we established that N. gonorrhoeae stimulates proinflammatory cytokine responses through Nod1 and Nod 2 in an over expression system. Based on these observations we propose that N. gonorrhoeae employs specific intracellular signaling receptors that respond to intracellular gonococci and or their ligands, resulting in proinflammatory responses that contribute to N. gonorrhoeae induced inflammation in vivo. To test this hypothesis we propose the following aims: 1. To define the role of NLR signaling receptors (clAP2, N0D1, and N0D2) in N. gonorrhoeae induction of proinflammatory cytokines in human epithelial cells and macrophages;2. To define the role of NLR signaling receptors (clAP2, N0D1, and N0D2) in N. gonorrhoeae induction of proinflammatory cytokines in murine epithelial cells and macrophages;and 3. To define the role of NLRs in N. gonorrhoeae induced inflammatory responses in a mouse model.

Public Health Relevance

There are gaps in our knowledge regarding specific details of the interactions between N. gonorrhoeae and the innate immune response that results in inflammatory disease. This study will use novel in vitro and in vivo approaches to define the mechanisms that control host signaling in response to N. gonorrhoeae Improved understanding of the mechanisms driving innate immune recognition of pathogens and the roles of specific cytokines and the factors that trigger their expression will provide a promising avenue for novel therapies for this bacterially induced inflammatory disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-MMT-M)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Massachusetts Medical School Worcester
United States
Zip Code
Shaughnessy, Jutamas; Gulati, Sunita; Agarwal, Sarika et al. (2016) A Novel Factor H-Fc Chimeric Immunotherapeutic Molecule against Neisseria gonorrhoeae. J Immunol 196:1732-40
Nudel, Kathleen; Massari, Paola; Genco, Caroline A (2015) Neisseria gonorrhoeae Modulates Cell Death in Human Endocervical Epithelial Cells through Export of Exosome-Associated cIAP2. Infect Immun 83:3410-7
Ayehunie, Seyoum; Islam, Ayesha; Cannon, Chris et al. (2015) Characterization of a Hormone-Responsive Organotypic Human Vaginal Tissue Model: Morphologic and Immunologic Effects. Reprod Sci 22:980-90
Gulati, Sunita; Mu, Xin; Zheng, Bo et al. (2015) Antibody to reduction modifiable protein increases the bacterial burden and the duration of gonococcal infection in a mouse model. J Infect Dis 212:311-5
Lewis, Lisa A; Gulati, Sunita; Burrowes, Elizabeth et al. (2015) α-2,3-sialyltransferase expression level impacts the kinetics of lipooligosaccharide sialylation, complement resistance, and the ability of Neisseria gonorrhoeae to colonize the murine genital tract. MBio 6:
McClure, Ryan; Nudel, Kathleen; Massari, Paola et al. (2015) The Gonococcal Transcriptome during Infection of the Lower Genital Tract in Women. PLoS One 10:e0133982
Su, Xiao-Hong; Wang, Bao-Xi; Le, Wen-Jing et al. (2015) Multidrug-Resistant Neisseria gonorrhoeae Isolates from Nanjing, China, Are Sensitive to Killing by a Novel DNA Gyrase Inhibitor, ETX0914 (AZD0914). Antimicrob Agents Chemother 60:621-3
Mavrogiorgos, Nikolaos; Mekasha, Samrawit; Yang, Yibin et al. (2014) Activation of NOD receptors by Neisseria gonorrhoeae modulates the innate immune response. Innate Immun 20:377-89
Agarwal, Sarika; Vasudhev, Shreekant; DeOliveira, Rosane B et al. (2014) Inhibition of the classical pathway of complement by meningococcal capsular polysaccharides. J Immunol 193:1855-63
Li, Sai; Su, Xiao-Hong; Le, Wen-Jing et al. (2014) Antimicrobial susceptibility of Neisseria gonorrhoeae isolates from symptomatic men attending the Nanjing sexually transmitted diseases clinic (2011-2012): genetic characteristics of isolates with reduced sensitivity to ceftriaxone. BMC Infect Dis 14:622

Showing the most recent 10 out of 39 publications