Key Points
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The pathogenic Neisseria species, Neisseria gonorrhoeae and Neisseria meningitidis, are obligate human bacteria that share many properties and virulence factors but inhabit distinct anatomical sites and cause distinct diseases. They differ from the commensal Neisseria spp. that also inhabit humans in that they elicit inflammatory responses driven mainly by neutrophils.
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Interactions between the pathogenic Neisseria spp. and neutrophils are central to the progression of both gonorrhoea and meningococcal meningitis. Neutrophils are major cells of the innate immune system that elaborate oxidative (reactive oxygen species (ROS)) and non-oxidative antibacterial activities, but there is strong evidence that pathogenic neisseriae survive inside and outside neutrophils.
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Pathogenic neisseriae can partially resist phagocytosis by neutrophils through capsule production (for N. meningitidis), sialylation of surface components, inhibition of the complement cascade and variation of surface antigens. However, some bacteria are killed by unknown extracellular, non-oxidative mechanisms.
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Despite mechanisms for avoiding phagocytosis, neutrophils internalize pathogenic neisseriae by opsonic and non-opsonic means. Bacteria expressing the subset of opacity-associated (Opa) proteins that interact with CEACAM receptors are efficiently phagocytosed by neutrophils without opsonization.
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Pathogenic neisseriae have the ability to inhibit apoptosis of neutrophils and extend the lifespan of these terminally differentiated myeloid cells. Some, if not all, of the anti-apoptotic activity is attributed to the bacterial porins.
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Pathogenic neisseriae produce many factors that promote bacterial survival in the presence of ROS, and some of these antioxidant factors are upregulated in response to oxidative stress. Under certain conditions the pathogenic neisseriae also inhibit production of ROS by neutrophils, but some Opa proteins can induce ROS production.
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In vitro, neutrophils exclusively direct ROS-independent antibacterial mechanisms against pathogenic neisseriae, but a significant percentage of bacteria survive neutrophil exposure. Neisserial defences that protect against the cationic antimicrobial peptides, proteases and other degradative enzymes that are produced by neutrophils are likely to contribute to bacterial survival after neutrophil challenge.
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It is likely that the recruitment of neutrophils to the sites of neisserial infection is essential to the pathogenic programmes of these bacteria, as these immune cells may facilitate nutrient acquisition, create an intracellular protective niche for the bacteria, aid dissemination of the bacteria from the site of infection to secondary locations within the host, and enable transmission of the bacteria between hosts.
Abstract
Neisseria gonorrhoeae and Neisseria meningitidis are Gram-negative bacterial pathogens that are exquisitely adapted for growth at human mucosal surfaces and for efficient transmission between hosts. One factor that is essential to neisserial pathogenesis is the interaction between the bacteria and neutrophils, which are recruited in high numbers during infection. Although this vigorous host response could simply reflect effective immune recognition of the bacteria, there is mounting evidence that in fact these obligate human pathogens manipulate the innate immune response to promote infectious processes. This Review summarizes the mechanisms used by pathogenic neisseriae to resist and modulate the antimicrobial activities of neutrophils. It also details some of the major outstanding questions about the Neisseria–neutrophil relationship and proposes potential benefits of this relationship for the pathogen.
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References
Schielke, S., Frosch, M. & Kurzai, O. Virulence determinants involved in differential host niche adaptation of Neisseria meningitidis and Neisseria gonorrhoeae. Med. Microbiol. Immunol. 199, 185–196 (2010).
Marri, P. R. et al. Genome sequencing reveals widespread virulence gene exchange among human Neisseria species. PLoS ONE 5, e11835 (2010). In this investigation, the authors sequence the genomes of multiple commensal and pathogenic neisseriae to show that supposed 'virulence' genes are present in many commensal species.
Wiesner, P. J. & Thompson, S. E. 3rd. Gonococcal diseases. Dis. Mon. 26, 1–44 (1980).
Stephens, D. S. Biology and pathogenesis of the evolutionarily successful, obligate human bacterium Neisseria meningitidis. Vaccine 27 (Suppl. 2), B71–B77 (2009).
Burg, N. D. & Pillinger, M. H. The neutrophil: function and regulation in innate and humoral immunity. Clin. Immunol. 99, 7–17 (2001).
Urban, C. F., Lourido, S. & Zychlinsky, A. How do microbes evade neutrophil killing? Cell. Microbiol. 8, 1687–1696 (2006). An excellent overview of the methods used by neutrophils to kill intracellular and extracellular microorganisms.
Edwards, J. L. & Apicella, M. A. The molecular mechanisms used by Neisseria gonorrhoeae to initiate infection differ between men and women. Clin. Microbiol. Rev. 17, 965–981 (2004).
Merz, A. J. & So, M. Interactions of pathogenic Neisseriae with epithelial cell membranes. Annu. Rev. Cell Dev. Biol. 16, 423–457 (2000).
Kellogg, D. S. Jr, Peacock, W. L. Jr, Deacon, W. E., Brown, L. & Pirkle, D. I. Neisseria gonorrhoeae. I. Virulence genetically linked to clonal variation. J. Bacteriol. 85, 1274–1279 (1963).
Swanson, J. et al. Gonococcal pilin variants in experimental gonorrhea. J. Exp. Med. 165, 1344–1357 (1987).
James, J. F. & Swanson, J. Studies on gonococcus infection. XIII. Occurrence of color/opacity colonial variants in clinical cultures. Infect. Immun. 19, 332–340 (1978).
Swanson, J., Barrera, O., Sola, J. & Boslego, J. Expression of outer membrane protein II by gonococci in experimental gonorrhea. J. Exp. Med. 168, 2121–2129 (1988).
Jerse, A. E. et al. Multiple gonococcal opacity proteins are expressed during experimental urethral infection in the male. J. Exp. Med. 179, 911–920 (1994).
Spence, J. M. & Clark, V. L. Role of ribosomal protein L12 in gonococcal invasion of Hec1B cells. Infect. Immun. 68, 5002–5010 (2000).
Harvey, H. A., Jennings, M. P., Campbell, C. A., Williams, R. & Apicella, M. A. Receptor-mediated endocytosis of Neisseria gonorrhoeae into primary human urethral epithelial cells: the role of the asialoglycoprotein receptor. Mol. Microbiol. 42, 659–672 (2001).
Edwards, J. L. & Apicella, M. A. The role of lipooligosaccharide in Neisseria gonorrhoeae pathogenesis of cervical epithelia: lipid A serves as a C3 acceptor molecule. Cell. Microbiol. 4, 585–598 (2002).
Edwards, J. L. et al. A co-operative interaction between Neisseria gonorrhoeae and complement receptor 3 mediates infection of primary cervical epithelial cells. Cell. Microbiol. 4, 571–584 (2002).
Virji, M. et al. Expression of the Opc protein correlates with invasion of epithelial and endothelial cells by Neisseria meningitidis. Mol. Microbiol. 6, 2785–2795 (1992).
Capecchi, B. et al. Neisseria meningitidis NadA is a new invasin which promotes bacterial adhesion to and penetration into human epithelial cells. Mol. Microbiol. 55, 687–698 (2005).
Makepeace, B. L., Watt, P. J., Heckels, J. E. & Christodoulides, M. Interactions of Neisseria gonorrhoeae with mature human macrophage opacity proteins influence production of proinflammatory cytokines. Infect. Immun. 69, 1909–1913 (2001).
Kurzai, O. et al. Carbohydrate composition of meningococcal lipopolysaccharide modulates the interaction of Neisseria meningitidis with human dendritic cells. Cell. Microbiol. 7, 1319–1334 (2005).
Feinen, B., Jerse, A. E., Gaffen, S. L. & Russell, M. W. Critical role of Th17 responses in a murine model of Neisseria gonorrhoeae genital infection. Mucosal Immunol. 3, 312–321 (2010).
Geddes, K., Magalhaes, J. G. & Girardin, S. E. Unleashing the therapeutic potential of NOD-like receptors. Nature Rev. Drug Discov. 8, 465–479 (2009).
Kumar, H., Kawai, T. & Akira, S. Toll-like receptors and innate immunity. Biochem. Biophys. Res. Commun. 388, 621–625 (2009).
Massari, P. et al. Cutting edge: immune stimulation by neisserial porins is Toll-like receptor 2 and MyD88 dependent. J. Immunol. 168, 1533–1537 (2002).
Fisette, P. L., Ram, S., Andersen, J. M., Guo, W. & Ingalls, R. R. The Lip lipoprotein from Neisseria gonorrhoeae stimulates cytokine release and NF-κB activation in epithelial cells in a Toll-like receptor 2-dependent manner. J. Biol. Chem. 278, 46252–46260 (2003).
Zughaier, S. M. et al. Neisseria meningitidis lipooligosaccharide structure-dependent activation of the macrophage CD14/Toll-like receptor 4 pathway. Infect. Immun. 72, 371–380 (2004).
Kaparakis, M. et al. Bacterial membrane vesicles deliver peptidoglycan to NOD1 in epithelial cells. Cell. Microbiol. 12, 372–385 (2010). References 25–28 identify the products of pathogenic neisseriae that activate human TLR and NLR family receptors to modulate immune activation.
Waage, A. et al. Local production of tumor necrosis factor α, interleukin 1, and interleukin 6 in meningococcal meningitis. Relation to the inflammatory response. J. Exp. Med. 170, 1859–1867 (1989).
Ramsey, K. H. et al. Inflammatory cytokines produced in response to experimental human gonorrhea. J. Infect. Dis. 172, 186–191 (1995). References 29 and 30 identify the cytokines released during human infection with pathogenic neisseriae, including cytokines that coordinate neutrophil influx.
Fichorova, R. N., Desai, P. J., Gibson, F. C. 3rd & Genco, C. A. Distinct proinflammatory host responses to Neisseria gonorrhoeae infection in immortalized human cervical and vaginal epithelial cells. Infect. Immun. 69, 5840–5848 (2001).
Christodoulides, M. et al. Interaction of Neisseria meningitidis with human meningeal cells induces the secretion of a distinct group of chemotactic, proinflammatory, and growth-factor cytokines. Infect. Immun. 70, 4035–4044 (2002).
Chen, A. & Seifert, H. S. Neisseria gonorrhoeae-mediated inhibition of apoptotic signalling in polymorphonuclear leukocytes. Infect. Immun. 79, 4447–4458 (2011).
Chin, A. C. & Parkos, C. A. Pathobiology of neutrophil transepithelial migration: implications in mediating epithelial injury. Annu. Rev. Pathol. 2, 111–143 (2007).
Seifert, H. S., Wright, C. J., Jerse, A. E., Cohen, M. S. & Cannon, J. G. Multiple gonococcal pilin antigenic variants are produced during experimental human infections. J. Clin. Invest. 93, 2744–2749 (1994). This article and reference 13 report the timing and numbers of neutrophils recruited to the male urethra in response to experimental N. gonorrhoeae infection.
Jerse, A. E. Experimental gonococcal genital tract infection and opacity protein expression in estradiol-treated mice. Infect. Immun. 67, 5699–5708 (1999). This groundbreaking study describes the development of a genetically tractable model system for examining infection by the pathogenic Neisseria spp.: genital infection of female mice by N. gonorrhoeae.
Lacy, P. & Eitzen, G. Control of granule exocytosis in neutrophils. Front. Biosci. 13, 5559–5570 (2008).
Criss, A. K., Katz, B. Z. & Seifert, H. S. Resistance of Neisseria gonorrhoeae to non-oxidative killing by adherent human polymorphonuclear leucocytes. Cell. Microbiol. 11, 1074–1087 (2009). This report shows that ROS do not participate in the antibacterial activity of human neutrophils against N. gonorrhoeae , and that up to 50% of phagocytosed bacteria seem to be viable inside neutrophils.
Stohl, E. A., Criss, A. K. & Seifert, H. S. The transcriptome response of Neisseria gonorrhoeae to hydrogen peroxide reveals genes with previously uncharacterized roles in oxidative damage protection. Mol. Microbiol. 58, 520–532 (2005). This article identifies the first N. gonorrhoeae gene products that protect the bacterium from killing by human neutrophils.
Jarvis, G. A. & Vedros, N. A. Sialic acid of group B Neisseria meningitidis regulates alternative complement pathway activation. Infect. Immun. 55, 174–180 (1987).
Frosch, M. & Vogel, U. in Handbook of Meningococcal Disease: Infection Biology, Vaccination, Clinical Management (eds Frosch, M. & Maiden, M. C. J.) 145–162 (Wiley-VCH, Weinheim, 2006).
Spinosa, M. R. et al. The Neisseria meningitidis capsule is important for intracellular survival in human cells. Infect. Immun. 75, 3594–3603 (2007).
Thongthai, C. & Sawyer, W. D. Studies on the virulence of Neisseria gonorrhoeae. I. Relation of colonial morphology and resistance to phagocytosis by polymorphonuclear leukocytes. Infect. Immun. 7, 373–379 (1973).
King, G., James, J. F. & Swanson, J. Studies on gonococcus infection. XI. Comparison of in vivo and vitro association of Neisseria gonorrhoeae with human neutrophils. J. Infect. Dis. 137, 38–43 (1978). This historic work compares neutrophils in urethral gonorrhoeal secretions with peripheral neutrophils from the same individuals to show that both cell populations ingest N. gonorrhoeae . The work also shows that both piliated and non-piliated bacteria are phagocytosed by neutrophils.
Virji, M. & Heckels, J. E. The effect of protein II and pili on the interaction of Neisseria gonorrhoeae with human polymorphonuclear leucocytes. J. Gen. Microbiol. 132, 503–512 (1986).
Jack, D. L. et al. Activation of complement by mannose-binding lectin on isogenic mutants of Neisseria meningitidis serogroup B. J. Immunol. 160, 1346–1353 (1998).
Kahler, C. M. et al. The (α2→8)-linked polysialic acid capsule and lipooligosaccharide structure both contribute to the ability of serogroup B Neisseria meningitidis to resist the bactericidal activity of normal human serum. Infect. Immun. 66, 5939–5947 (1998).
Gilbert, M. et al. Cloning of the lipooligosaccharide α-2,3-sialyltransferase from the bacterial pathogens Neisseria meningitidis and Neisseria gonorrhoeae. J. Biol. Chem. 271, 28271–28276 (1996).
Nairn, C. A. et al. Cytidine 5′-monophospho-N-acetylneuraminic acid or a related compound is the low Mr factor from human red blood cells which induces gonococcal resistance to killing by human serum. J. Gen. Microbiol. 134, 3295–3306 (1988).
Wu, H. & Jerse, A. E. α-2,3-sialyltransferase enhances Neisseria gonorrhoeae survival during experimental murine genital tract infection. Infect. Immun. 74, 4094–4103 (2006).
Smith, H., Parsons, N. J. & Cole, J. A. Sialylation of neisserial lipopolysaccharide: a major influence on pathogenicity. Microb. Pathog. 19, 365–377 (1995).
Ram, S. et al. Binding of complement factor H to loop 5 of porin protein 1A: a molecular mechanism of serum resistance of nonsialylated Neisseria gonorrhoeae. J. Exp. Med. 188, 671–680 (1998).
Ram, S. et al. A novel sialic acid binding site on factor H mediates serum resistance of sialylated Neisseria gonorrhoeae. J. Exp. Med. 187, 743–752 (1998).
Madico, G. et al. The meningococcal vaccine candidate GNA1870 binds the complement regulatory protein factor H and enhances serum resistance. J. Immunol. 177, 501–510 (2006).
Lewis, L. A. et al. The meningococcal vaccine candidate neisserial surface protein A (NspA) binds to factor H and enhances meningococcal resistance to complement. PLoS Pathog. 6, e1001027 (2010).
Ram, S. et al. Binding of C4b-binding protein to porin: a molecular mechanism of serum resistance of Neisseria gonorrhoeae. J. Exp. Med. 193, 281–295 (2001).
Jarva, H., Ram, S., Vogel, U., Blom, A. M. & Meri, S. Binding of the complement inhibitor C4bp to serogroup B Neisseria meningitidis. J. Immunol. 174, 6299–6307 (2005).
Davila, S. et al. Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease. Nature Genet. 42, 772–776 (2010).
Virji, M. Pathogenic neisseriae: surface modulation, pathogenesis and infection control. Nature Rev. Microbiol. 7, 274–286 (2009). An excellent review on the virulence-associated, antigenically variable surface structures of the pathogenic neisseriae.
Lee, W. L., Harrison, R. E. & Grinstein, S. Phagocytosis by neutrophils. Microbes Infect. 5, 1299–1306 (2003).
Lewis, L. A. et al. Defining targets for complement components C4b and C3b on the pathogenic neisseriae. Infect. Immun. 76, 339–350 (2008).
Dempsey, J. A., Litaker, W., Madhure, A., Snodgrass, T. L. & Cannon, J. G. Physical map of the chromosome of Neisseria gonorrhoeae FA1090 with locations of genetic markers, including opa and pil genes. J. Bacteriol. 173, 5476–5486 (1991).
Aho, E. L., Dempsey, J. A., Hobbs, M. M., Klapper, D. G. & Cannon, J. G. Characterization of the opa (class 5) gene family of Neisseria meningitidis. Mol. Microbiol. 5, 1429–1437 (1991).
Bhat, K. S. et al. The opacity proteins of Neisseria gonorrhoeae strain MS11 are encoded by a family of 11 complete genes. Mol. Microbiol. 5, 1889–1901 (1991).
Murphy, G. L., Connell, T. D., Barritt, D. S., Koomey, M. & Cannon, J. G. Phase variation of gonococcal protein II: regulation of gene expression by slipped-strand mispairing of a repetitive DNA sequence. Cell 56, 539–547 (1989).
Sadarangani, M., Pollard, A. J. & Gray-Owen, S. D. Opa proteins & CEACAMs: pathways of immune engagement for pathogenic Neisseria. FEMS Microbiol. Rev. 35, 498–514 (2011).
King, G. J. & Swanson, J. Studies on gonococcus infection. XV. Identification of surface proteins of Neisseria gonorrhoeae correlated with leukocyte association. Infect. Immun. 21, 575–584 (1978). This study is the first to identify outer-membrane proteins — later found to be Opa proteins — that mediate interaction of N. gonorrhoeae with neutrophils.
Rest, R. F., Fischer, S. H., Ingham, Z. Z. & Jones, J. F. Interactions of Neisseria gonorrhoeae with human neutrophils: effects of serum and gonococcal opacity on phagocyte killing and chemiluminescence. Infect. Immun. 36, 737–744 (1982). The authors of this report use human neutrophils infected with N. gonorrhoeae expressing defined Opa proteins to correlate the Opa–neutrophil interaction with reduced bacterial survival and enhanced ROS production.
Fischer, S. H. & Rest, R. F. Gonococci possessing only certain P.II outer membrane proteins interact with human neutrophils. Infect. Immun. 56, 1574–1579 (1988).
Kupsch, E. M., Knepper, B., Kuroki, T., Heuer, I. & Meyer, T. F. Variable opacity (Opa) outer membrane proteins account for the cell tropisms displayed by Neisseria gonorrhoeae for human leukocytes and epithelial cells. EMBO J. 12, 641–650 (1993).
Belland, R. J., Chen, T., Swanson, J. & Fischer, S. H. Human neutrophil response to recombinant Neisserial Opa proteins. Mol. Microbiol. 6, 1729–1737 (1992).
Naids, F. L., Belisle, B., Lee, N. & Rest, R. F. Interactions of Neisseria gonorrhoeae with human neutrophils: studies with purified PII (Opa) outer membrane proteins and synthetic Opa peptides. Infect. Immun. 59, 4628–4635 (1991).
Kuespert, K., Pils, S. & Hauck, C. R. CEACAMs: their role in physiology and pathophysiology. Curr. Opin. Cell Biol. 18, 565–571 (2006).
Billker, O. et al. Distinct mechanisms of internalization of Neisseria gonorrhoeae by members of the CEACAM receptor family involving Rac1- and Cdc42-dependent and -independent pathways. EMBO J. 21, 560–571 (2002).
Schmitter, T., Agerer, F., Peterson, L., Munzner, P. & Hauck, C. R. Granulocyte CEACAM3 is a phagocytic receptor of the innate immune system that mediates recognition and elimination of human-specific pathogens. J. Exp. Med. 199, 35–46 (2004).
Pils, S., Gerrard, D. T., Meyer, A. & Hauck, C. R. CEACAM3: an innate immune receptor directed against human-restricted bacterial pathogens. Int. J. Med. Microbiol. 298, 553–560 (2008). References 74–76 describe and support the concept that CEACAM3 evolved as a granulocyte receptor for engulfment and killing of human-specific bacteria such as the pathogenic neisseriae.
Chen, T. & Gotschlich, E. C. CGM1a antigen of neutrophils, a receptor of gonococcal opacity proteins. Proc. Natl Acad. Sci. USA 93, 14851–14856 (1996).
Chen, T., Grunert, F., Medina-Marino, A. & Gotschlich, E. C. Several carcinoembryonic antigens (CD66) serve as receptors for gonococcal opacity proteins. J. Exp. Med. 185, 1557–1564 (1997).
Gray-Owen, S. D., Dehio, C., Haude, A., Grunert, F. & Meyer, T. F. CD66 carcinoembryonic antigens mediate interactions between Opa-expressing Neisseria gonorrhoeae and human polymorphonuclear phagocytes. EMBO J. 16, 3435–3445 (1997).
Virji, M., Makepeace, K., Ferguson, D. J. & Watt, S. M. Carcinoembryonic antigens (CD66) on epithelial cells and neutrophils are receptors for Opa proteins of pathogenic Neisseriae. Mol. Microbiol. 22, 941–950 (1996).
Bos, M. P., Grunert, F. & Belland, R. J. Differential recognition of members of the carcinoembryonic antigen family by Opa variants of Neisseria gonorrhoeae. Infect. Immun. 65, 2353–2361 (1997). References 77–81 identify members of the CEACAM family of receptors as the proteins (on neutrophils and other cells) that act as binding partners for a subset of neisserial Opa proteins.
Bos, M. P., Kuroki, M., Krop-Watorek, A., Hogan, D. & Belland, R. J. CD66 receptor specificity exhibited by Neisserial Opa variants is controlled by protein determinants in CD66 N-domains. Proc. Natl Acad. Sci. USA 95, 9584–9589 (1998).
Virji, M., Watt, S. M., Barker, S., Makepeace, K. & Doyonnas, R. The N-domain of the human CD66a adhesion molecule is a target for Opa proteins of Neisseria meningitidis and Neisseria gonorrhoeae. Mol. Microbiol. 22, 929–939 (1996).
Gray-Owen, S. D. & Blumberg, R. S. CEACAM1: contact-dependent control of immunity. Nature Rev. Immunol. 6, 433–446 (2006).
Hauck, C. R., Meyer, T. F., Lang, F. & Gulbins, E. CD66-mediated phagocytosis of Opa52 Neisseria gonorrhoeae requires a Src-like tyrosine kinase- and Rac1-dependent signalling pathway. EMBO J. 17, 443–454 (1998).
Booth, J. W. et al. Phosphatidylinositol 3-kinases in carcinoembryonic antigen-related cellular adhesion molecule-mediated internalization of Neisseria gonorrhoeae. J. Biol. Chem. 278, 14037–14045 (2003).
Sarantis, H. & Gray-Owen, S. D. The specific innate immune receptor CEACAM3 triggers neutrophil bactericidal activities via a Syk kinase-dependent pathway. Cell. Microbiol. 9, 2167–2180 (2007).
Sarantis, H. & Gray-Owen, S. D. Defining the roles of human carcinoembryonic antigen-related cell adhesion molecules during neutrophil responses to Neisseria gonorrhoeae. Infect. Immun. 80, 345–358 (2012). The authors of this work express selected CEACAMs, alone or in combination, in mouse promyelocytic cells to show that each receptor initiates different signalling events in response to N. gonorrhoeae . CEACAM1 and CEACAM6 are found to enhance CEACAM3 signals in neutrophils, an unexpected finding given the inhibitory role of CEACAM1 in other cell types.
Gray-Owen, S. D., Lorenzen, D. R., Haude, A., Meyer, T. F. & Dehio, C. Differential Opa specificities for CD66 receptors influence tissue interactions and cellular response to Neisseria gonorrhoeae. Mol. Microbiol. 26, 971–980 (1997).
McCaw, S. E., Liao, E. H. & Gray-Owen, S. D. Engulfment of Neisseria gonorrhoeae: revealing distinct processes of bacterial entry by individual carcinoembryonic antigen-related cellular adhesion molecule family receptors. Infect. Immun. 72, 2742–2752 (2004).
Estabrook, M. M., Zhou, D. & Apicella, M. A. Nonopsonic phagocytosis of group C Neisseria meningitidis by human neutrophils. Infect. Immun. 66, 1028–1036 (1998).
Ovcinnikov, N. M. & Delektorskij, V. V. Electron. microscope studies of gonococci in the urethral secretions of patients with gonorrhoea. Br. J. Vener. Dis. 47, 419–439 (1971).
Farzadegan, H. & Roth, I. L. Scanning electron microscopy and freeze-etching of gonorrhoeal urethral exudate. Br. J. Vener. Dis. 51, 83–91 (1975).
Apicella, M. A. et al. The pathogenesis of gonococcal urethritis in men: confocal and immunoelectron microscopic analysis of urethral exudates from men infected with Neisseria gonorrhoeae. J. Infect. Dis. 173, 636–646 (1996).
Casey, S. G., Veale, D. R. & Smith, H. Demonstration of intracellular growth of gonococci in human phagocytes using spectinomycin to kill extracellular organisms. J. Gen. Microbiol. 113, 395–398 (1979).
Casey, S. G., Veale, D. R. & Smith, H. Intracellular survival of Neisseria gonorrhoeae in human urethral exudate. FEMS Microbiol. Lett. 8, 97–100 (1980).
Casey, S. G., Shafer, W. M. & Spitznagel, J. K. Neisseria gonorrhoeae survive intraleukocytic oxygen-independent antimicrobial capacities of anaerobic and aerobic granulocytes in the presence of pyocin lethal for extracellular gonococci. Infect. Immun. 52, 384–389 (1986). References 95–97 provide the first evidence for N. gonorrhoeae replication inside human neutrophils.
Simons, M. P., Nauseef, W. M. & Apicella, M. A. Interactions of Neisseria gonorrhoeae with adherent polymorphonuclear leukocytes. Infect. Immun. 73, 1971–1977 (2005). The authors of this article develop an in vitro infection assay with N. gonorrhoeae that yields evidence for bacterial survival and replication inside adherent primary human neutrophils.
Binnicker, M. J., Williams, R. D. & Apicella, M. A. Infection of human urethral epithelium with Neisseria gonorrhoeae elicits an upregulation of host anti-apoptotic factors and protects cells from staurosporine-induced apoptosis. Cell. Microbiol. 5, 549–560 (2003).
Deghmane, A. E. et al. Differential modulation of TNF-α–induced apoptosis by Neisseria meningitidis. PLoS Pathog. 5, e1000405 (2009).
Kepp, O. et al. Bim and Bmf synergize to induce apoptosis in Neisseria gonorrhoeae infection. PLoS Pathog. 5, e1000348 (2009).
Massari, P., King, C. A., Ho, A. Y. & Wetzler, L. M. Neisserial PorB is translocated to the mitochondria of HeLa cells infected with Neisseria meningitidis and protects cells from apoptosis. Cell. Microbiol. 5, 99–109 (2003).
Kozjak-Pavlovic, V., Ott, C., Gotz, M. & Rudel, T. Neisserial Omp85 protein is selectively recognized and assembled into functional complexes in the outer membrane of human mitochondria. J. Biol. Chem. 286, 27019–27026 (2011).
Muller, A. et al. Targeting of the pro-apoptotic VDAC-like porin (PorB) of Neisseria gonorrhoeae to mitochondria of infected cells. EMBO J. 19, 5332–5343 (2000).
Simons, M. P., Nauseef, W. M., Griffith, T. S. & Apicella, M. A. Neisseria gonorrhoeae delays the onset of apoptosis in polymorphonuclear leukocytes. Cell. Microbiol. 8, 1780–1790 (2006).
Witko-Sarsat, V., Pederzoli-Ribeil, M., Hirsch, E., Sozzani, S. & Cassatella, M. A. Regulating neutrophil apoptosis: new players enter the game. Trends Immunol. 32, 117–124 (2011).
Roos, D., van Bruggen, R. & Meischl, C. Oxidative killing of microbes by neutrophils. Microbes Infect. 5, 1307–1315 (2003).
Fang, F. C. Antimicrobial reactive oxygen and nitrogen species: concepts and controversies. Nature Rev. Microbiol. 2, 820–832 (2004).
Johnson, S. R., Steiner, B. M., Cruce, D. D., Perkins, G. H. & Arko, R. J. Characterization of a catalase-deficient strain of Neisseria gonorrhoeae: evidence for the significance of catalase in the biology of N. gonorrhoeae. Infect. Immun. 61, 1232–1238 (1993).
Wilks, K. E. et al. Periplasmic superoxide dismutase in meningococcal pathogenicity. Infect. Immun. 66, 213–217 (1998).
Tseng, H. J., Srikhanta, Y., McEwan, A. G. & Jennings, M. P. Accumulation of manganese in Neisseria gonorrhoeae correlates with resistance to oxidative killing by superoxide anion and is independent of superoxide dismutase activity. Mol. Microbiol. 40, 1175–1186 (2001).
Skaar, E. P. et al. The outer membrane localization of the Neisseria gonorrhoeae MsrA/B is involved in survival against reactive oxygen species. Proc. Natl Acad. Sci. USA 99, 10108–10113 (2002).
Seib, K. L., Tseng, H. J., McEwan, A. G., Apicella, M. A. & Jennings, M. P. Defenses against oxidative stress in Neisseria gonorrhoeae and Neisseria meningitidis: distinctive systems for different lifestyles. J. Infect. Dis. 190, 136–147 (2004).
Soler-Garcia, A. A. & Jerse, A. E. A Neisseria gonorrhoeae catalase mutant is more sensitive to hydrogen peroxide and paraquat, an inducer of toxic oxygen radicals. Microb. Pathog. 37, 55–63 (2004).
Davidsen, T., Bjoras, M., Seeberg, E. C. & Tonjum, T. Antimutator role of DNA glycosylase MutY in pathogenic Neisseria species. J. Bacteriol. 187, 2801–2809 (2005).
Stohl, E. A. & Seifert, H. S. Neisseria gonorrhoeae DNA recombination and repair enzymes protect against oxidative damage caused by hydrogen peroxide. J. Bacteriol. 188, 7645–7651 (2006).
LeCuyer, B. E., Criss, A. K. & Seifert, H. S. Genetic characterization of the nucleotide excision repair system of Neisseria gonorrhoeae. J. Bacteriol. 192, 665–673 (2010).
Tala, A. et al. Glutamate utilization promotes meningococcal survival in vivo through avoidance of the neutrophil oxidative burst. Mol. Microbiol. 81, 1330–1342 (2011).
Grifantini, R. et al. Characterization of a novel Neisseria meningitidis Fur and iron-regulated operon required for protection from oxidative stress: utility of DNA microarray in the assignment of the biological role of hypothetical genes. Mol. Microbiol. 54, 962–979 (2004). This study identifies the first N. meningitidis gene products found to protect the bacterium from killing by primary human neutrophils.
Britigan, B. E., Klapper, D., Svendsen, T. & Cohen, M. S. Phagocyte-derived lactate stimulates oxygen consumption by Neisseria gonorrhoeae. An unrecognized aspect of the oxygen metabolism of phagocytosis. J. Clin. Invest. 81, 318–324 (1988).
Criss, A. K. & Seifert, H. S. Neisseria gonorrhoeae suppresses the oxidative burst of human polymorphonuclear leukocytes. Cell. Microbiol. 10, 2257–2270 (2008).
Lorenzen, D. R. et al. Neisseria gonorrhoeae porin modifies the oxidative burst of human professional phagocytes. Infect. Immun. 68, 6215–6222 (2000).
Seib, K. L. et al. Investigation of oxidative stress defenses of Neisseria gonorrhoeae by using a human polymorphonuclear leukocyte survival assay. Infect. Immun. 73, 5269–5272 (2005). This work uses N. gonorrhoeae carrying mutations in multiple antioxidant genes to show that neutrophil-mediated killing of gonococci is independent of ROS.
Frangipane, J. V. & Rest, R. F. Anaerobic growth of gonococci does not alter their Opa-mediated interactions with human neutrophils. Infect. Immun. 60, 1793–1799 (1992).
Wu, H., Soler-Garcia, A. A. & Jerse, A. E. A strain-specific catalase mutation and mutation of the metal-binding transporter gene mntC attenuate Neisseria gonorrhoeae in vivo but not by increasing susceptibility to oxidative killing by phagocytes. Infect. Immun. 77, 1091–1102 (2009).
Seib, K. L. et al. Characterization of the OxyR regulon of Neisseria gonorrhoeae. Mol. Microbiol. 63, 54–68 (2007).
Wu, H. J. et al. Azurin of pathogenic Neisseria spp. is involved in defense against hydrogen peroxide and survival within cervical epithelial cells. Infect. Immun. 73, 8444–8448 (2005).
Muench, D. F. et al. Hydrogen peroxide-producing lactobacilli inhibit gonococci in vitro but not during experimental genital tract infection. J. Infect. Dis. 199, 1369–1378 (2009).
O'Hanlon, D. E., Lanier, B. R., Moench, T. R. & Cone, R. A. Cervicovaginal fluid and semen block the microbicidal activity of hydrogen peroxide produced by vaginal lactobacilli. BMC Infect. Dis. 10, 120 (2010).
Levy, O. Antimicrobial proteins and peptides: anti-infective molecules of mammalian leukocytes. J. Leukoc. Biol. 76, 909–925 (2004).
Kinchen, J. M. & Ravichandran, K. S. Phagosome maturation: going through the acid test. Nature Rev. Mol. Cell Biol. 9, 781–795 (2008).
Shafer, W. M., Qu, X., Waring, A. J. & Lehrer, R. I. Modulation of Neisseria gonorrhoeae susceptibility to vertebrate antibacterial peptides due to a member of the resistance/nodulation/division efflux pump family. Proc. Natl Acad. Sci. USA 95, 1829–1833 (1998). This report describes the cloning and characterization of the gonococcal MtrCDE efflux pump and its crucial role in neisserial defence against cationic antimicrobial peptides.
Lee, E. H. & Shafer, W. M. The farAB-encoded efflux pump mediates resistance of gonococci to long-chained antibacterial fatty acids. Mol. Microbiol. 33, 839–845 (1999).
Jerse, A. E. et al. A gonococcal efflux pump system enhances bacterial survival in a female mouse model of genital tract infection. Infect. Immun. 71, 5576–5582 (2003).
Johnson, C. R. et al. Generation and characterization of a PhoP homologue mutant of Neisseria meningitidis. Mol. Microbiol. 39, 1345–1355 (2001).
Tzeng, Y. L. et al. The MisR/MisS two-component regulatory system influences inner core structure and immunotype of lipooligosaccharide in Neisseria meningitidis. J. Biol. Chem. 279, 35053–35062 (2004).
Newcombe, J. et al. Phenotypic and transcriptional characterization of the meningococcal PhoPQ system, a magnesium-sensing two-component regulatory system that controls genes involved in remodeling the meningococcal cell surface. J. Bacteriol. 187, 4967–4975 (2005).
Lewis, L. A. et al. Phosphoethanolamine substitution of lipid A and resistance of Neisseria gonorrhoeae to cationic antimicrobial peptides and complement-mediated killing by normal human serum. Infect. Immun. 77, 1112–1120 (2009). In this investigation, different modifications of neisserial LOS, including the addition of phosphoethanolamine by LptA, were shown to differentially affect bacterial resistance to complement and cationic antimicrobial peptides.
Frigimelica, E., Bartolini, E., Galli, G., Grandi, G. & Grifantini, R. Identification of 2 hypothetical genes involved in Neisseria meningitidis cathelicidin resistance. J. Infect. Dis. 197, 1124–1132 (2008).
Dillard, J. P. & Hackett, K. T. Mutations affecting peptidoglycan acetylation in Neisseria gonorrhoeae and Neisseria meningitidis. Infect. Immun. 73, 5697–5705 (2005).
Thwaites, G. E. & Gant, V. Are bloodstream leukocytes Trojan Horses for the metastasis of Staphylococcus aureus? Nature Rev. Microbiol. 9, 215–222 (2011).
Rohde, K. H. & Dyer, D. W. Mechanisms of iron acquisition by the human pathogens Neisseria meningitidis and Neisseria gonorrhoeae. Front. Biosci. 8, D1186–D1218 (2003).
Boulton, I. C. & Gray-Owen, S. D. Neisserial binding to CEACAM1 arrests the activation and proliferation of CD4+ T lymphocytes. Nature Immunol. 3, 229–236 (2002).
Pantelic, M. et al. Neisseria gonorrhoeae kills carcinoembryonic antigen-related cellular adhesion molecule 1 (CD66a)-expressing human B cells and inhibits antibody production. Infect. Immun. 73, 4171–4179 (2005).
Merz, A. J., Enns, C. A. & So, M. Type IV pili of pathogenic Neisseriae elicit cortical plaque formation in epithelial cells. Mol. Microbiol. 32, 1316–1332 (1999).
Zen, K. & Parkos, C. A. Leukocyte–epithelial interactions. Curr. Opin. Cell Biol. 15, 557–564 (2003).
Soderholm, N., Vielfort, K., Hultenby, K. & Aro, H. Pathogenic Neisseria hitchhike on the uropod of human neutrophils. PLoS ONE 6, e24353 (2011).
Woodfin, A. et al. The junctional adhesion molecule JAM-C regulates polarized transendothelial migration of neutrophils in vivo. Nature Immunol. 12, 761–769 (2011).
van Ulsen, P. & Tommassen, J. Protein secretion and secreted proteins in pathogenic Neisseriaceae. FEMS Microbiol. Rev. 30, 292–319 (2006).
WHO. Emergence of multi-drug resistant Neisseria gonorrhoeae – Threat of global rise in untreatable sexually transmitted infections. Fact Sheet RHR 11.14. (Geneva, Switzerland, 2011).
Jennings, M. P. et al. The genetic basis of the phase variation repertoire of lipopolysaccharide immunotypes in Neisseria meningitidis. Microbiology 145, 3013–3021 (1999).
Cahoon, L. A. & Seifert, H. S. Focusing homologous recombination: pilin antigenic variation in the pathogenic Neisseria. Mol. Microbiol. 81, 1136–1143 (2011).
Jonsson, A. B., Nyberg, G. & Normark, S. Phase variation of gonococcal pili by frameshift mutation in pilC, a novel gene for pilus assembly. EMBO J. 10, 477–488 (1991).
Blake, M. S. & Swanson, J. Studies on gonococcus infection. XVI. Purification of Neisseria gonorrhoeae immunoglobulin A1 protease. Infect. Immun. 22, 350–358 (1978).
Hauck, C. R. & Meyer, T. F. The lysosomal/phagosomal membrane protein h-lamp-1 is a target of the IgA1 protease of Neisseria gonorrhoeae. FEBS Lett. 405, 86–90 (1997).
Ayala, P., Lin, L., Hopper, S., Fukuda, M. & So, M. Infection of epithelial cells by pathogenic Neisseriae reduces the levels of multiple lysosomal constituents. Infect. Immun. 66, 5001–5007 (1998).
Johannsen, D. B., Johnston, D. M., Koymen, H. O., Cohen, M. S. & Cannon, J. G. A Neisseria gonorrhoeae immunoglobulin A1 protease mutant is infectious in the human challenge model of urethral infection. Infect. Immun. 67, 3009–3013 (1999).
Jones, H. E., Uronen-Hansson, H., Callard, R. E., Klein, N. & Dixon, G. L. The differential response of human dendritic cells to live and killed Neisseria meningitidis. Cell. Microbiol. 9, 2856–2869 (2007).
Acknowledgements
Research in A.K.C.'s laboratory is supported by the US National Institutes of Health (NIH) grant R00 TW008042 and by the Thomas F. and Kate Miller Jeffress Memorial Trust. Work in H.S.S.'s laboratory is supported by NIH grants R37 AI033493 and R01 AI044239.
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Glossary
- Commensal
-
Describing the relationship between two organisms in which one organism benefits while the other is unaffected.
- Phagocytosis
-
A crucial process by which the immune system clears foreign objects, invading microorganisms and dead or dying cells. Phagocytic cells of the immune system include neutrophils and macrophages; dendritic cells can also undergo phagocytosis.
- Phagolysosomes
-
Intracellular compartments that are capable of degrading material ingested by phagocytic cells. In neutrophils, the phagolysosome is formed when the early phagosome fuses with granules that carry antimicrobial products.
- Neutrophil extracellular traps
-
Chromatin-based structures that are coated with granule proteins and are released from neutrophils to entrap microorganisms. There is currently some debate about whether neutrophil extracellular traps are released from dying neutrophils only, or whether live neutrophils can also produce them.
- Apoptosis
-
Programmed cell death of host cells. The rate and extent of apoptosis in neutrophils and other cells can be influenced by bacterial infection.
- Opacity-associated proteins
-
A family of proteins expressed on the surface of pathogenic neisseriae. The assortment of Opa proteins expressed by the bacteria constantly changes owing to phase variation of the opa genes. Opa proteins mediate bacterium–bacterium and bacterium–host cell interactions, and some alter the characteristics of neisserial colonies grown on solid media.
- Adhesins
-
Molecules that are expressed on a cell to mediate adherence to another surface.
- Lipo-oligosaccharide
-
(LOS). The main component of the outer leaflet of the outer membrane of Gram-negative bacteria. LOS is similar to lipopolysaccharide (LPS) but lacks the long sugar chain (the O antigen). Pathogenic neisseriae produce different LOS isotypes owing to phase variation of glucosyltransferases for LOS.
- Pilus
-
A fibre that extends from the bacterial cell surface to mediate adherence to a host cell.
- Porins
-
Bacterial outer-membrane, channel-forming proteins. Neisserial porins have been reported to translocate into human cells and affect mitochondrial membrane potential, cell lifespan and the neutrophil-mediated oxidative burst.
- Pattern recognition receptors
-
A family of proteins that recognize families of foreign objects, including evolutionarily conserved products of microorganisms, such as lipopolysaccharide and peptidoglycan. Common pattern recognition receptors include proteins of the Toll-like receptor family and the NOD-like receptor family.
- Cytokines
-
Secreted proteins that are produced by cells of the immune system and by non-immune cells that can recognize infection, injury or inflammation. Chemokines are a class of chemotactic cytokines which recruit immune cells to specific locations in the body.
- Dysuria
-
Pain while urinating. Common in men with acute gonorrhoea.
- Reactive oxygen species
-
(ROS). A family of chemicals that are oxidized versions of molecular oxygen, including hydrogen peroxide, superoxide and hydroxyl radicals. ROS are produced by neutrophils via the action of NADPH oxidase and exert antimicrobial activities by damaging lipids, carbohydrates, proteins and nucleic acids.
- Opsonic
-
Coating a particle to facilitate its uptake by phagocytes. Common opsonins are immunoglobulins (antibodies) and complement.
- Complement
-
A system of >25 proteins that recognize foreign objects and target them for destruction or phagocytosis. The complement proteins undergo sequential proteolytic events, resulting in activation of the membrane attack complex, a pore that forms on the surface of the foreign object to rupture it. Complement proteins such as C3b and C4b are recognized by complement receptors, and this triggers phagocytosis of the complement-opsonized particle.
- Capsule
-
The polysaccharide coating found on N. meningitidis that alters the bacterial cell surface and its interactions with other cells and molecules.
- CEACAM receptors
-
(Carcinoembryonic antigen-related cell adhesion molecule receptors). A family of host proteins that are expressed on a variety of cell types to mediate intercell communication. They serve as receptors for opacity-associated (Opa) proteins.
- Granulocytes
-
Innate immune cells with a cytoplasm that is morphologically distinguished by the presence of granules. Neutrophils, eosinophils and basophils are all granulocytes.
- Oxidative burst
-
The production of reactive oxygen species (ROS) through the action of the NADPH oxidase enzyme.
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Criss, A., Seifert, H. A bacterial siren song: intimate interactions between Neisseria and neutrophils. Nat Rev Microbiol 10, 178–190 (2012). https://doi.org/10.1038/nrmicro2713
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DOI: https://doi.org/10.1038/nrmicro2713
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