Dissemination of Neisseria meningitidis.

Neisseria meningitidis is a major global pathogen that continues to cause endemic and epidemic human disease. Initial exposure typically occurs within the nasopharynx, where the bacteria can invade the mucosal epithelium, cause fulminant sepsis, and disseminate to the central nervous system, causing bacterial meningitis. Recently, Chamot-Rooke and colleagues1 described a unique virulence property of N. meningitidis in which the bacterial surface pili, after contact with host cells, undergo a modification that facilitates both systemic invasion and the spread of colonization to close contacts. Person-to-person spread of N. meningitidis can result in community epidemics of bacterial meningitis, with major consequences for public health. In resource-poor nations, cyclical outbreaks continue to result in high mortality and long-term disability, particularly in sub-Saharan Africa, where access to early diagnosis, antibiotic therapy, and vaccination is limited.2,3 An exclusively human pathogen, N. meningitidis uses several virulence factors to cause disease. Highly charged and hydrophilic capsular polysaccharides protect N. meningitidis from phagocytosis and complement-mediated bactericidal activity of the innate immune system. A family of proteins (called opacity proteins) on the bacterial outer membrane facilitate interactions with both epithelial and endothelial cells. These proteins are phase-variable — that is, the genome of the bacterium encodes related opacity proteins that are variably expressed, depending on environment, allowing the bacterium to adjust to rapidly changing environmental conditions. Lipooligosaccharide, analogous to the lipopolysaccharide of enteric gram-negative bacteria, contains a lipid A moiety with endotoxin activity that promotes the systemic sepsis encountered clinically. However, initial attachment to host cells is primarily mediated by filamentous organelles referred to as type IV pili, which are common to many bacterial pathogens and unique in their ability to undergo both antigenic and phase variation. Within hours of attachment to the host endothelial cell, N. meningitidis induces the formation of protrusions in the plasma membrane of host cells that aggregate the bacteria into microcolonies and facilitate pili-mediated contacts between bacteria and between bacteria and host cells. After attachment and aggregation, N. meningitidis detaches from the aggregates to systemically invade the host, by means of a transcellular pathway that crosses the respiratory epithelium,4 or becomes aerosolized and spreads the colonization of new hosts (Fig. 1). Chamot-Rooke et al. dissected the molecular mechanism underlying this critical step of systemic invasion and person-to-person spread and reported that pathogenesis depends on a unique post-translational modification of the type IV pili. Using whole-protein mass spectroscopy, electron microscopy, and molecular modeling, they showed that the major component of N. meningitidis type IV pili (called PilE or pilin) undergoes an unusual post-translational modification by phosphoglycerol. Expression of pilin phosphotransferase, the enzyme that transfers phosphoglycerol onto pilin, is increased within 4 hours of meningococcus contact with host cells and modifies the serine residue at amino acid position 93 of pilin, altering the charge of the pilin structure and thereby destabilizing the pili bundles, reducing bacterial aggregation, and promoting detachment from the cell surface. Strains of N. meningitidis in which phosphoglycerol modification of pilin occurred had a greatly enhanced ability to cross epithelial monolayers, a finding that supports the view that this virulence property, which causes deaggregation, promotes both transmission to new hosts and systemic invasion. Although this new molecular understanding of N. meningitidis virulence in humans is provoc-