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 recognifion 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 funcfion 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 antagonisfic anfibodies only partially reduced the producfion of proinflammatory cytokines following N. gonorrhoeae infection of epithelial cells suggesfing 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 recognifion, inhibitor of apoptosis protein (clAP-2), as well as the receptorinteracfing serine-threonine kinase 2 (R1P2), a key mediator of innate immune signaling. Furthermore, we established that N. gonorrhoeae sfimulates proinflammatory cytokine responses through Nodi and Nod 2 in an over expression system. Based on these observafions we propose that N. gonorrhoeae employs specific intracellular signaling receptors that respond to intracellular gonococci and or their ligands, resulfing 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 inducfion of proinfiammatory 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 infiammatory responses in a mouse model.
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 infiammatory disease.
|Andrade, Warrison A; Agarwal, Sarika; Mo, Shunyan et al. (2016) Type I Interferon Induction by Neisseria gonorrhoeae: Dual Requirement of Cyclic GMP-AMP Synthase and Toll-like Receptor 4. Cell Rep 15:2438-48|
|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|
|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) ?-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:|
|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|
|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|
|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|
|Lewis, Lisa A; Ram, Sanjay (2014) Meningococcal disease and the complement system. Virulence 5:98-126|
|Del Tordello, Elena; Vacca, Irene; Ram, Sanjay et al. (2014) Neisseria meningitidis NalP cleaves human complement C3, facilitating degradation of C3b and survival in human serum. Proc Natl Acad Sci U S A 111:427-32|
|Rice, Peter A (2014) Editorial commentary: The shifting sands of gonococcal antimicrobial resistance. Clin Infect Dis 59:1092-4|
Showing the most recent 10 out of 39 publications