Mechanisms of type I IFN enhanced gonococcal infection

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Project Abstract Infection with Neisseria gonorrhoeae (Ng) remains a major public health issue. Ng gonococci are sexually transmitted between individuals causing inflammation and pelvic inflammatory disease (PID). The emergence of antibiotic-resistant Ng is cause for concern, and Ng strains with antibiotic-resistance to nearly all of the approved therapeutics have developed with cephalosporins being the last remaining effective antibiotic. Understanding the mechanisms that underlie Ng susceptibility will be crucial for the development of new and effective therapeutic options for treating gonococcal disease. We discovered that Ng bacteria trigger innate cytokine gene expression through two separate pathways, the Toll-like receptor 4 (TLR4) pathway and via a recently discovered intracellular DNA sensing pathway. DNA released into the cytosol during infection or introduced by transfection binds to an enzyme cyclic-GMP-AMP synthase (cGAS). DNA-activated cGAS produces a cyclic di-nucleotide (cdN), 2’3’-cGAMP, which acts as a second messenger and triggers a protein stimulator of interferon genes (STING). STING, in turn, activates TANK-binding kinase 1 (TBK-1) leading to interferon regulatory factor 3 (IRF3) activation and type I interferon (IFN) gene expression. Bacteria cdNs can also activate STING and type I IFN expression, another example of immune evasion. Based on our preliminary studies, where we found that type I IFNs greatly enhanced gonococcal infection, we hypothesize that Ng-induced type I IFN is a method of immune evasion that enhances the replication and survival of Ng in host phagocytes. Recently, an estrogen-induced type I IFN (IFN-epsilon) was identified in mice and humans. IFN-epsilon is expressed in the genital tract of both men and women and binds the same receptor as other type I IFNs. Estrogen is also known to promote gonococcal infection of vaginal tissues in humans and in mouse models of Ng infection. The goal of this project is to assess the role of estrogen-induced and immune receptor-induced type I IFN in enhancing Ng infection. We will identify and characterize the molecular pathways that are responsible for controlling Ng infection. In Aim 1, we will!elucidate the role of type I IFNs in enhancing Ng infection. These studies will be performed using several knockout mouse models that our labs have generated and examine the role of type I IFN receptor (IFNAR) signaling in promoting Ng infection. In Aim 2, we will look at the molecular mechanism(s) of immune receptor-driven type I IFN production, particularly the cGAS and STING receptor pathways and the role of outer membrane vesicles, during Ng infection. The goal of these studies is to develop novel strategies for therapeutic interventions that may ameliorate or prevent the damaging sequelae of Ng infection and PID.