Study of Neisseria gonorrhoeae adaptability to impact microbial survival and host response inside human neutrophil phagosomes

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Neisseria gonorrhoeae (Ng) is an intracellular and exclusively human pathogen that causes the sexually transmitted disease gonorrhea. A hallmark of gonorrhea is the exuberant inflammation secondary to recruitment of human polymorphonuclear leukocytes (hPMN). Under normal circumstances, hPMN ingest and kill invading microbes inside hPMN phagosomes, after which spent hPMN undergo phagocytosis-induced cell death (PICD) as part of the programmed resolution of inflammation (1, 2). As a successful pathogen, Ng not only survives and replicates inside hPMN phagosomes, but also delay PICD of hPMN (3, 4). How Ng undermines normal hPMN-mediated host defense by surviving hPMN killing and delaying PICD of hPMN has not been elucidated. The candidate’s objective is to understand the mechanisms underpinning the adaptability of Ng inside hPMN phagosomes. The candidate’s hypotheses are that (1) that acetylation is one of the post-translational modifications of neisserial proteins that is critical to Ng survival and (2) that the Ng escape from phagosomes and modification of hPMN signaling pathways delay programmed cell death of hPMN that normally follows phagocytosis. To test these hypotheses, the candidate has created two specific aims: Aim 1: To determine the role of Ne-lysine acetylation as a regulatory determinant for the survival of Ng inside hPMN phagosomes. Aim 2: To determine the effect of NGAG00012 on hPMN phagosomes and subsequent cell fate of hPMN fed Ng. This proposal is innovative because the candidate uses biased (mutagenesis and mass spectrometry) and unbiased (transcriptome analysis) approach to elucidate Ng biology within the phagosomes of hPMN, a clinically relevant context. The rise in resistance of Ng to antibiotics has made effective treatment for gonorrhea nearly impossible, thus making it imperative to understand Ng’s behavior inside hPMN. This proposal is significant in that its discoveries will provide better understanding of how Ng inside hPMN phagosomes survives and thus a rational for novel therapeutic intervention for gonorrhea.