REVIEWS Pathogenic neisseriae: surface modulation, pathogenesis and infection control Mumtaz Virji Abstract | Although renowned as a lethal pathogen, Neisseria meningitidis has adapted to be a commensal of the human nasopharynx. It shares extensive genetic and antigenic similarities with the urogenital pathogen Neisseria gonorrhoeae but displays a distinct lifestyle and niche preference. Together, they pose a considerable challenge for vaccine development as they modulate their surface structures with remarkable speed. Nonetheless, their host-cell attachment and invasion capacity is maintained, a property that could be exploited to combat tissue infiltration. With the primary focus on N. meningitidis, this Review examines the known mechanisms used by these pathogens for niche establishment and the challenges such mechanisms pose for infection control. Neisseria meningitidis (meningococcus) and Neisseria surface variation also poses a substantial problem in gonorrhoeae (gonococcus), the well known agents of developing effective vaccines against several strains of epidemic meningitis and gonorrhoea, respectively, are N. meningitidis and against N. gonorrhoeae. Although related Gram-negative bacteria that specifically infect multicomponent vaccines are being developed, the humans; both pathogens prefer to inhabit distinct available vaccines fall short of combating all virulent human mucosal niches and cause markedly different strains7,8. diseases (FIG. 1). One important difference between the An array of molecules is produced by bacteria pathogens is that almost all clinically important N. men- to enable them to colonize and/or infect the host, ingitidis strains are encapsulated, whereas N. gonorrhoeae including adhesins, which are key factors that are strains lack capsule biosynthetic genes. N. meningitidis required for initial colonization of human mucosal is a frequent asymptomatic colonizer of the human sites. Characteristically, pathogens can modulate the upper respiratory tract, and most adults are resistant expression and structure of adhesins and still main- to infection through acquired immunity. However, tain the ability to bind to mucosal epithelial cells for in susceptible individuals N. meningitidis can cause colonization. This might suggest some degree of struc- serious blood and brain infections that are usually tural conservation, a property that could be exploited manifested as meningitis and septicaemia. It also for the prevention of infection. To achieve this aim, seems that meningococcal strains vary in their abil- a thorough understanding of the range of host tar- ity to cause sporadic or epidemic outbreaks. The out- geting strategies of the pathogens and of host factors comes of meningococcal infection may be devastating that increase susceptibility to infection is needed. This and, in the absence of timely intervention, can lead Review describes the scale of the problem, focusing to neurological disorders and death1. N. gonorrhoeae on our current understanding of key aspects of the is a sexually transmitted pathogen that primarily pathogenic tactics of Neisseria spp., particularly cellu- infects the urogenital tract, giving rise to intense local lar adhesion and invasion mechanisms. I also discuss inflammation and a range of clinical manifestations2. the relationship between colonization and immune Department of Cellular and A signature property of the two pathogens is their evasion strategies and address host susceptibility in Molecular Medicine, School ability to modulate their surface antigenic make up the context of adhesion receptors. As carriage is itself of Medical Sciences, with remarkable speed. This is the basis of their suc- considered an immunizing event that helps maintain University Walk, University of Bristol, Bristol, BS8 1TD, UK. cess as human-specific pathogens, as constant surface long-term memory, the approaches that could con- 3–5 6 e-mail: [email protected] modulation and point mutations enable the bacte- trol infection without eliminating colonization are doi:10.1038/nrmicro2097 ria to evade human immune mechanisms. Extensive also discussed. 274 | APRIL 2009 | VOLUME 7 www.nature.com/reviews/micro © 2009 Macmillan Publishers Limited. All rights reserved REVIEWS a N. meningitidis Meningitis Nasopharyngeal ECM Blood epithelium vessel Phagocyte Meninges Transmission Nasopharynx Tissue and meningeal infiltration Acquisition LPS Cilia TNF Vascular damage Septicaemia skin rash Figure 1 | Stages in the pathogenesis of N. meningitidis and N. gonorrhoeae. a | Neisseria meningitidis may be b N. gonorrhoeae acquired through the inhalation of respiratory droplets. The organism establishes intimate contact with non-ciliated Transmission mucosal epithelial cells of the upper respiratory tract, where Gonorrhoea it may enter the cells briefly before migrating back to the Acquisition apical surfaces of the cells for transmission to a new host. PMN-rich Asymptomatic carriage is common in healthy adults in exudate which bacteria that enter the body by crossing the epithelial barrier are eliminated. Besides transcytosis, N. meningitidis can cross the epithelium either directly following damage Urethral or to the monolayer integrity or through phagocytes in a vaginal epithelium Microvilli ‘Trojan horse’ manner. In susceptible individuals, once inside the blood, N. meningitidis may survive, multiply rapidly and disseminate throughout the body and the brain. Meningococcal passage across the brain vascular Cell endothelium (or the epithelium of the choroid plexus) may damage then occur, resulting in infection of the meninges and the cerebrospinal fluid124. b | Neisseria gonorrhoeae is acquired through sexual contact and establishes infection in the ECM urogenital tracts by interacting with non-ciliated epithelial cells; this results in cellular invasion. Although different molecular mechanisms are involved during the establishment of gonococci on the mucosal surfaces of males and females, infection often leads to inflammation Macrophage LPS and polymorphonuclear leukocyte (PMN) influx. However, PMN infection of the lower female genital tract is typically asymptomatic. N. gonorrhoeae engulfed by PMN are TNF secreted in PMN-rich exudate. Both tumour necrosis factor (TNF) from phagocytes and gonococcal products, such as Bacterial peptidoglycan and lipopolysaccharide (LPS), also cause killing toxic damage to ciliated epithelial cells of mucosal surfaces (reviewed in REF. 2 ). ECM, extracellular matrix. Nature Reviews | Microbiology Antigenic relatedness and carriage childhood and has been associated with the development Together with 17 other species, N. meningitidis and of a cross-protective immunity against N. meningitidis10. N. gonorrhoeae belong to the genus Neisseria9. Most Meningococcal carriage rate increases gradually after species within the genus are classified as true human birth and reaches a peak in teenagers, with the average commensal bacteria and have negligible infection carriage rate being about 10% of the population in the rates. The best recognized species of this group is United Kingdom1. Carriage rates tend to be high in insti- Commensal bacterium A bacterium that inhabits a Neisseria lactamica, which shares the human respira- tutional settings, for example, in military recruits and 11 host without apparent adverse tory niche and antigenic structures with N. meningitidis. university students . Thus, nasopharyngeal coloniza- effects to the host. The highest carriage rate of N. lactamica occurs in early tion with N. lactamica or other non-pathogenic Neisseria NATURE REVIEWS | MICROBIOLOGY VOLUME 7 | APRIL 2009 | 275 © 2009 Macmillan Publishers Limited. All rights reserved REVIEWS a involved. Gonococcal infections are usually localized and G elicit an intense inflammatory response that gives rise to Capsule b Pili V purulent discharge in male patients, a hallmark of gonor- rhoea. In females, the different embryological origin of LPS the urogenital tract results in a different mode of infec- tion, which is often asymptomatic (reviewed in REF. 2 ). Virulence genes of neisseriae OM Complete nucleotide sequences of several pathogenic Neisseria strains and of N. lactamica (some of which have been available for almost a decade) have facilitated Pilus cross-section the identification of numerous previously unknown 14–16 Opa putative adhesins and virulence factors (also see the Sanger Institute Neisseria lactamica website and the University of Oklahoma Neisseria gonorrhoeae Genome Sequencing Strain FA website). A number of islands of Opc horizontally transferred DNA have been found in the Figure 2 | Prominent outer-membrane components of N. meningitidis that genome of N. meningitidis. However, no classic organized Nature Reviews | Microbiology influence bacterial interactions with host cells. a | Pili traverse the capsule and are the pathogenicity islands are present that define the viru- 17 most prominent adhesins of encapsulated Neisseria meningitidis. In addition, the integral lent behaviour of the organisms . Instead, the N. men- outer membrane (OM) adhesins, Opa and Opc, are known to mediate interactions with ingitidis genome has ‘genetic islands’ with identifiable specific host-cell receptors in appropriate phenotypes83. Lipopolysaccharide may genes that differ in their GC content and codon usage, interfere with the adhesion functions of OM proteins, but can also contribute to cellular which have been acquired through horizontal exchange interactions by interacting with various cellular