Forenza, Chiara (2024) Biological activity of N. meningitidis and N. gonorrhoeae-derived OMVs on human monocytes/macrophages and development of cross protection by trained immunity. [Tesi di dottorato]

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Abstract

The pathogenic species N. gonorrhoeae and N. meningitidis share between 80-90% of genome sequence identity. However, they have developed different behaviors regarding infection and disease they caused. Adaptation to different host niches, leads to functional differences in their gene regulatory mechanisms, as observed for homologous regulators FarR and NadR of Ng and Nm respectively. Moreover, recent studies demonstrated that Outer Membrane Vescicles (OMVs) based vaccines against Nm serogroup B induce cross-protection against Ng infection. The work developed around two questions. The first one was focused on identification of factors on Nm and Ng whose interaction with innate immune cells impair cytokines secretion and is based on the evidence that NadR and FarR regulated-genes impair the cytokines secretion by human monocytes and macrophages in vitro. The second investigates the possibility that innate immune system could have a role in the observed cross-protection of Nm vaccine against gonococcus infection by induction of innate immune memory, as already observed with other vaccinations. Using a mass spectrometry approach on OMVs proteome, I found that Ng FarR regulator represses expression of α-Carbonic Anhydrase, an enzyme involved in bacterial metabolism and pathogen survival. However, remain to explore α-CA putative role in observed impairment of cytokines secretion. Besides, using the innate immune memory model in vitro, the study demonstrates that OMVs from Nm and Ng can induce innate immune memory in macrophages in intra- and inter-species manner. Prospective in vivo studies could analyze the effects of innate memory induction at organism’s level.

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