Alternative sulfur acquisition pathways in Neisseria gonorrhoeae

Neisseria gonorrhoeae is an obligate human pathogen responsible for the sexually transmitted infection, gonorrhoea. Its success as a pathogen is partly due to robust defence mechanisms that provide protection against oxidative stress encountered during infection. Reduced sulfur compounds such as glutathione, cysteine and methionine are integral to this response and pathogenic growth. Due to a large genomic deletion and pseudogenes, N. gonorrhoeae is incapable of sulfur acquisition via traditional routes and therefore cannot grow when sulfate is the sole sulfur source. However, N. gonorrhoeae can grow in the presence of thiosulfate but lacks the ability to reduce thiosulfate via the conventional thiosulfate reduction pathway. This raises questions of how N. gonorrhoeae acquires sulfur for cysteine biosynthesis? We have identified two sulfurtransferase enzymes (Str and PspE) in N. gonorrhoeae that we hypothesise provide sulfur in the form needed for cysteine synthesis. We show these enzymes have thiosulfate-thiol sulfurtransferase activity and, importantly, produce sulfide that could be utilised for cysteine biosynthesis. Furthermore, we demonstrate that Str is a promiscuous enzyme with respect to thiol acceptor substrates and, intriguingly, is capable of cyanide detoxification. Our N. gonorrhoeae sulfurtransferase deletion strain has a reduced ability to grow when thiosulfate is the only available sulfur source, supporting our hypothesis that Str utilises exogenous inorganic thiosulfate. However, due to functional redundancy provided by the presence of the second sulfurtransferase, PspE, construction of a double knockout strain is essential in understanding the full effect of these enzymes in relation to pathogenicity. Our proposed energetically favourable pathway of thiosulfate reduction via sulfurtransferase enzymes could be pivotal in advancing our understanding of how pathogens fulfil their sulfur requirements. However, much is to be elucidated regarding the role of these ubiquitous enzymes in bacterial pathogens. Herein, this thesis offers insight into the versatility, function, and formal mechanisms of sulfurtransferases within N. gonorrhoeae

Mechanisms of host manipulation by Neisseria gonorrhoeae

Neisseria gonorrhoeae (also known as gonococcus) has been causing gonorrhoea in humans since ancient Egyptian times. Today, global gonorrhoea infections are rising at an alarming rate, in concert with an increasing number of antimicrobial-resistant strains. The gonococcus has concurrently evolved several intricate mechanisms that promote pathogenesis by evading both host immunity and defeating common therapeutic interventions. Central to these adaptations is the ability of the gonococcus to manipulate various host microenvironments upon infection. For example, the gonococcus can survive within neutrophils through direct regulation of both the oxidative burst response and maturation of the phagosome; a concerning trait given the important role neutrophils have in defending against invading pathogens. Hence, a detailed understanding of how N. gonorrhoeae exploits the human host to establish and maintain infection is crucial for combating this pathogen. This review summarizes the mechanisms behind host manipulation, with a central focus on the exploitation of host epithelial cell signaling to promote colonization and invasion of the epithelial lining, the modulation of the host immune response to evade both innate and adaptive defenses, and the manipulation of host cell death pathways to both assist colonization and combat antimicrobial activities of innate immune cells. Collectively, these pathways act in concert to enable N. gonorrhoeae to colonize and invade a wide array of host tissues, both establishing and disseminating gonococcal infection