Immune modulation of macrophages by the meningococcal surface protein NhhA

Abstract: Functional immune modulation of macrophages play important role during bacterial infection. Neisseria meningitidis, a gram-negative diplococcal bacterium, is the leading cause of bacterial meningitis and fatal septic shock. However, it is also a commensal bacterium that colonizes the nasopharynx of healthy individuals asymptomatically. In this thesis, we studied the immunomodulatory role of a meningococcal adhesin, NhhA (Neisseria hia/hsf homologue), in inducing inflammatory activation of macrophages through both Toll-like receptor 4-dependent and -independent pathways in Paper I. Monocytes are precursors of both macrophages and dendritic cells. In paper II, we demonstrated that NhhA orchestrated monocyte differentiation into CD200RhiiNOS+ macrophages through TLR1/ TLR2 activation via endogenously produced IL-10 and TNF-α. These NhhA-induced macrophages were tolerant to meningococcal stimulation but were competent at bacterial elimination. In vivo experiments using a murine model verified the in vitro findings and mice pre-treated with NhhA survived meningococcal infection. We further identified that NhhA-induced immune tolerance contributed to bacterial persistence at nasopharynx when mice were challenged intranasally with N. meningitidis, unravelling a previously undescribed strategy adopted by the bacteria for keeping their commensal lifecycle at the nasopharyngeal mucosa.