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• W2972296982 abstract "CNS infections continue to rise in incidence in conjunction with increases in immunocompromised populations or conditions that contribute to the emergence of pathogens, such as global travel, climate change, and human encroachment on animal territories. The severity and complexity of these diseases is impacted by the diversity of etiologic agents and their routes of neuroinvasion. In this review, we present historical, clinical, and molecular concepts regarding the mechanisms of pathogen invasion of the CNS. We also discuss the structural components of CNS compartments that influence pathogen entry and recent discoveries of the pathways exploited by pathogens to facilitate CNS infections. Advances in our understanding of the CNS invasion mechanisms of different neurotropic pathogens may enable the development of strategies to control their entry and deliver drugs to mitigate established infections. CNS infections continue to rise in incidence in conjunction with increases in immunocompromised populations or conditions that contribute to the emergence of pathogens, such as global travel, climate change, and human encroachment on animal territories. The severity and complexity of these diseases is impacted by the diversity of etiologic agents and their routes of neuroinvasion. In this review, we present historical, clinical, and molecular concepts regarding the mechanisms of pathogen invasion of the CNS. We also discuss the structural components of CNS compartments that influence pathogen entry and recent discoveries of the pathways exploited by pathogens to facilitate CNS infections. Advances in our understanding of the CNS invasion mechanisms of different neurotropic pathogens may enable the development of strategies to control their entry and deliver drugs to mitigate established infections. Neuroinfectious diseases are among the most devastating illnesses, in some cases leading to up to 100% mortality, depending on the agent and age and immune status of the infected host. More than 1.2 million people globally are affected by meningitis each year, with bacterial meningitis responsible for approximately 120,000 deaths (http://www.comomeningitis.org). Many types of infectious agents, including those within the broad categories of bacteria, viruses, fungi, and parasites, cause CNS infections of the meningeal or parenchymal compartments. Infection of the meninges leads to meningitis, an inflammatory response in the cerebrospinal fluid (CSF) compartment, in which affected individuals present clinically with fever, headache, nuchal rigidity, and photophobia. Bacterial, fungal, and parasitic meningitides are medical emergencies requiring immediate treatment to prevent complications and death (Thigpen et al., 2011Thigpen M.C. Whitney C.G. Messonnier N.E. Zell E.R. Lynfield R. Hadler J.L. Harrison L.H. Farley M.M. Reingold A. Bennett N.M. et al.Emerging Infections Programs NetworkBacterial meningitis in the United States, 1998-2007.N. Engl. J. Med. 2011; 364: 2016-2025Crossref PubMed Scopus (520) Google Scholar). Infection of the CNS parenchyma causes encephalitis, which presents with fever, altered mental status ranging from delirium to coma, and focal neurologic symptoms or seizures (Salimi et al., 2016Salimi H. Cain M.D. Klein R.S. Encephalitic arboviruses: emergence, clinical presentation, and neuropathogenesis.Neurotherapeutics. 2016; 13: 514-534Crossref PubMed Scopus (24) Google Scholar). Pathogens invading the brain parenchyma can infect multiple neural cell types, leading to inflammation with dysfunction of neural networks and excitotoxicity, regional damage, and cell death. Additionally, pathogens may cause meningoencephalitis, which results from simultaneous inflammation and/or infection of both meningeal and parenchymal compartments. Conversely, CNS infection may be a localized result in focal lesions or abscesses, which more likely occur in immunocompromised patients (Deigendesch et al., 2017Deigendesch N. Costa Nunez J. Stenzel W. Parasitic and fungal infections.Handb. Clin. Neurol. 2017; 145: 245-262Crossref PubMed Scopus (3) Google Scholar). Symptoms resulting from focal CNS infections are influenced by the specific site(s) of the lesion. Historically, the demonstration of neurotropic pathogens dates back to the early 1900s with examination of CNS tissues infected with rabies (Negri, 1903Negri A. Contributo allo studio dell'eziologia della rabia.Bol. Soc. Med. Chir. Pavia. 1903; 1903: 88-114Google Scholar, Williams, 1905Williams A.W. Negri bodies, special reference to diagnosis.Proc. NY. Path. Soc. 1905; V: 155-162Google Scholar). A few years later, scientists showed that poliovirus (PV) infection of the CNS could be contracted by intranasal introduction of nasopharyngeal secretions from paralyzed animals (Flexner and Lewis, 1910Flexner S. Lewis P.A. Experimental epidemic poliomyelitis in monkeys: characteristic alterations of the cerebrospinal fluid and its early infectivity; infection from human mesenteric lymph node.JAMA. 1910; 14: 1140Crossref Scopus (2) Google Scholar). This study demonstrated that pathogens could enter the CNS after a natural route of infection, which includes mucosal surfaces (nasopharynx and respiratory and gastrointestinal tracts) and the skin. Pathogens gaining access to the CNS after traversing mucosal or cutaneous barriers may do so via direct entry into peripheral nerves or through indirect pathways that require hematogenous dissemination. The term “blood-brain barrier (BBB)” was coined in 1912 to describe the finding that systemically administered dyes are excluded from the developing mammalian brain (Battelli and Stern, 1912Battelli F. Stern L. Die oxydationsfermente.Ergeb. Physiol. 1912; 12: 96-268Crossref Scopus (8) Google Scholar). Since then, the BBB has been shown to limit entry of molecules, immune cells, and pathogens into the CNS (Barker and Widner, 2004Barker R.A. Widner H. Immune problems in central nervous system cell therapy.NeuroRx. 2004; 1: 472-481Crossref PubMed Scopus (146) Google Scholar, Medawar, 1948Medawar P.B. Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye.Br. J. Exp. Pathol. 1948; 29: 58-69PubMed Google Scholar, Wilson et al., 2010Wilson E.H. Weninger W. Hunter C.A. Trafficking of immune cells in the central nervous system.J. Clin. Invest. 2010; 120: 1368-1379Crossref PubMed Scopus (274) Google Scholar). Invasion of pathogens via transneuronal routes bypasses the BBB, which normally protects the CNS from infectious diseases. In contrast, other pathogens use hematogenous routes to gain access to the CSF compartment or cross the BBB and invade the CNS parenchyma. This review discusses our current knowledge of the mechanisms by which neurotropic pathogens gain access into the CNS (Table 1). Each section introduces core principles that dictate potential routes of pathogen neuroinvasion and provide descriptions of cellular and molecular structures that are exploited by individual microbes of all categories of pathogens. We also include technologies that have led to new discoveries regarding mechanisms of pathogen entry into the CNS.Table 1Mechanisms of Neuroinvasion by Neurotropic PathogensEntry PathwayBacteriaVirusesParasitesFungiPrionsTransendothelial entry within CSF compartmentL. monocytogenes (Dinner et al., 2017Dinner S. Kaltschmidt J. Stump-Guthier C. Hetjens S. Ishikawa H. Tenenbaum T. Schroten H. Schwerk C. Mitogen-activated protein kinases are required for effective infection of human choroid plexus epithelial cells by Listeria monocytogenes.Microbes Infect. 2017; 19: 18-33Crossref PubMed Scopus (1) Google Scholar), N. meningitidis (Schwerk et al., 2012Schwerk C. Papandreou T. Schuhmann D. Nickol L. Borkowski J. Steinmann U. Quednau N. Stump C. Weiss C. Berger J. et al.Polar invasion and translocation of Neisseria meningitidis and Streptococcus suis in a novel human model of the blood-cerebrospinal fluid barrier.PLoS ONE. 2012; 7: e30069Crossref PubMed Scopus (0) Google Scholar)Coxsackievirus (Bozym et al., 2010Bozym R.A. Morosky S.A. Kim K.S. Cherry S. Coyne C.B. Release of intracellular calcium stores facilitates coxsackievirus entry into polarized endothelial cells.PLoS Pathog. 2010; 6: e1001135Crossref PubMed Scopus (0) Google Scholar), Echovirus (Morosky et al., 2019Morosky S. Wells A.I. Lemon K. Evans A.S. Schamus S. Bakkenist C.J. Coyne C.B. The neonatal Fc receptor is a pan-echovirus receptor.Proc. Natl. Acad. Sci. USA. 2019; 116: 3758-3763Crossref PubMed Scopus (0) Google Scholar), Mumps (Wright et al., 2019Wright W.F. Pinto C.N. Palisoc K. Baghli S. Viral (aseptic) meningitis: a review.J. Neurol. Sci. 2019; 398: 176-183Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar), LCMV (Kim et al., 2009Kim J.V. Kang S.S. Dustin M.L. McGavern D.B. Myelomonocytic cell recruitment causes fatal CNS vascular injury during acute viral meningitis.Nature. 2009; 457: 191-195Crossref PubMed Scopus (228) Google Scholar)UnknownUnknownUnknownInfection or damage of brain endotheliumS. pneumoniae (Zysk et al., 2001Zysk G. Schneider-Wald B.K. Hwang J.H. Bejo L. Kim K.S. Mitchell T.J. Hakenbeck R. Heinz H.P. Pneumolysin is the main inducer of cytotoxicity to brain microvascular endothelial cells caused by Streptococcus pneumoniae.Infect. Immun. 2001; 69: 845-852Crossref PubMed Scopus (0) Google Scholar)NiV (Wong et al., 2002Wong K.T. Shieh W.J. Kumar S. Norain K. Abdullah W. Guarner J. Goldsmith C.S. Chua K.B. Lam S.K. Tan C.T. et al.Nipah Virus Pathology Working GroupNipah virus infection: pathology and pathogenesis of an emerging paramyxoviral zoonosis.Am. J. Pathol. 2002; 161: 2153-2167Abstract Full Text Full Text PDF PubMed Google Scholar)Toxoplasma gondii (Konradt et al., 2016Konradt C. Ueno N. Christian D.A. Delong J.H. Pritchard G.H. Herz J. Bzik D.J. Koshy A.A. McGavern D.B. Lodoen M.B. Hunter C.A. Endothelial cells are a replicative niche for entry of Toxoplasma gondii to the central nervous system.Nat. Microbiol. 2016; 1: 16001Crossref PubMed Google Scholar)UnknownUnknownTranscytosis across the BBBS. pneumoniae (Iovino et al., 2013Iovino F. Orihuela C.J. Moorlag H.E. Molema G. Bijlsma J.J. Interactions between blood-borne Streptococcus pneumoniae and the blood-brain barrier preceding meningitis.PLoS ONE. 2013; 8: e68408Crossref PubMed Scopus (0) Google Scholar, Iovino et al., 2017Iovino F. Engelen-Lee J.Y. Brouwer M. van de Beek D. van der Ende A. Valls Seron M. Mellroth P. Muschiol S. Bergstrand J. Widengren J. Henriques-Normark B. pIgR and PECAM-1 bind to pneumococcal adhesins RrgA and PspC mediating bacterial brain invasion.J. Exp. Med. 2017; 214: 1619-1630Crossref PubMed Scopus (20) Google Scholar)WNV (Hasebe et al., 2010Hasebe R. Suzuki T. Makino Y. Igarashi M. Yamanouchi S. Maeda A. Horiuchi M. Sawa H. Kimura T. Transcellular transport of West Nile virus-like particles across human endothelial cells depends on residues 156 and 159 of envelope protein.BMC Microbiol. 2010; 10: 165Crossref PubMed Scopus (0) Google Scholar), JEV (Liou and Hsu, 1998Liou M.L. Hsu C.Y. Japanese encephalitis virus is transported across the cerebral blood vessels by endocytosis in mouse brain.Cell Tissue Res. 1998; 293: 389-394Crossref PubMed Scopus (75) Google Scholar), ZIKV (Papa et al., 2017Papa M.P. Meuren L.M. Coelho S.V.A. Lucas C.G.O. Mustafá Y.M. Lemos Matassoli F. Silveira P.P. Frost P.S. Pezzuto P. Ribeiro M.R. et al.Zika virus infects, activates, and crosses brain microvascular endothelial cells, without barrier disruption.Front. Microbiol. 2017; 8: 2557Crossref PubMed Scopus (26) Google Scholar)UnknownC. Neoformans (Chang et al., 2004Chang Y.C. Stins M.F. McCaffery M.J. Miller G.F. Pare D.R. Dam T. Paul-Satyaseela M. Kim K.S. Kwon-Chung K.J. Cryptococcal yeast cells invade the central nervous system via transcellular penetration of the blood-brain barrier.Infect. Immun. 2004; 72: 4985-4995Crossref PubMed Scopus (0) Google Scholar), S. cerevisiae (Na Pombejra et al., 2018Na Pombejra S. Jamklang M. Uhrig J.P. Vu K. Gelli A. The structure-function analysis of the Mpr1 metalloprotease determinants of activity during migration of fungal cells across the blood-brain barrier.PLoS ONE. 2018; 13: e0203020Crossref PubMed Scopus (3) Google Scholar)UnknownTrojan horse via infected leukocytesL. monocytogenes (Drevets et al., 2004Drevets D.A. Dillon M.J. Schawang J.S. Van Rooijen N. Ehrchen J. Sunderkötter C. Leenen P.J. The Ly-6Chigh monocyte subpopulation transports Listeria monocytogenes into the brain during systemic infection of mice.J. Immunol. 2004; 172: 4418-4424Crossref PubMed Google Scholar)WNV (Bai et al., 2010Bai F. Kong K.F. Dai J. Qian F. Zhang L. Brown C.R. Fikrig E. Montgomery R.R. A paradoxical role for neutrophils in the pathogenesis of West Nile virus.J. Infect. Dis. 2010; 202: 1804-1812Crossref PubMed Scopus (0) Google Scholar), NiV (Tiong et al., 2018Tiong V. Shu M.H. Wong W.F. AbuBakar S. Chang L.Y. Nipah virus infection of immature dendritic cells increases its transendothelial migration across human brain microvascular endothelial cells.Front. Microbiol. 2018; 9: 2747Crossref PubMed Scopus (2) Google Scholar)Toxoplasma gondii (Courret et al., 2006Courret N. Darche S. Sonigo P. Milon G. Buzoni-Gâtel D. Tardieux I. CD11c- and CD11b-expressing mouse leukocytes transport single Toxoplasma gondii tachyzoites to the brain.Blood. 2006; 107: 309-316Crossref PubMed Scopus (225) Google Scholar, Ueno et al., 2014Ueno N. Harker K.S. Clarke E.V. McWhorter F.Y. Liu W.F. Tenner A.J. Lodoen M.B. Real-time imaging of Toxoplasma-infected human monocytes under fluidic shear stress reveals rapid translocation of intracellular parasites across endothelial barriers.Cell. Microbiol. 2014; 16: 580-595Crossref PubMed Scopus (27) Google Scholar)C. Neoformans (Kaufman-Francis et al., 2018Kaufman-Francis K. Djordjevic J.T. Juillard P.G. Lev S. Desmarini D. Grau G.E.R. Sorrell T.C. The early innate immune response to, and phagocyte-dependent entry of, Cryptococcus neoformans map to the perivascular space of cortical post-capillary venules in neurocryptococcosis.Am. J. Pathol. 2018; 188: 1653-1665Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Santiago-Tirado et al., 2017Santiago-Tirado F.H. Onken M.D. Cooper J.A. Klein R.S. Doering T.L. Trojan horse transit contributes to blood-brain barrier crossing of a eukaryotic pathogen.MBio. 2017; 8 (e02183-16)Crossref PubMed Scopus (49) Google Scholar)UnknownParacellular entryB. anthracis (Ebrahimi et al., 2009Ebrahimi C.M. Kern J.W. Sheen T.R. Ebrahimi-Fardooee M.A. van Sorge N.M. Schneewind O. Doran K.S. Penetration of the blood-brain barrier by Bacillus anthracis requires the pXO1-encoded BslA protein.J. Bacteriol. 2009; 191: 7165-7173Crossref PubMed Scopus (19) Google Scholar)WNV (Daniels et al., 2014Daniels B.P. Holman D.W. Cruz-Orengo L. Jujjavarapu H. Durrant D.M. Klein R.S. Viral pathogen-associated molecular patterns regulate blood-brain barrier integrity via competing innate cytokine signals.MBio. 2014; 5 (e01476-14)Crossref Scopus (66) Google Scholar, Wang et al., 2008Wang P. Dai J. Bai F. Kong K.F. Wong S.J. Montgomery R.R. Madri J.A. Fikrig E. Matrix metalloproteinase 9 facilitates West Nile virus entry into the brain.J. Virol. 2008; 82: 8978-8985Crossref PubMed Scopus (102) Google Scholar)A. castellanii (Alsam et al., 2005Alsam S. Sissons J. Jayasekera S. Khan N.A. Extracellular proteases of Acanthamoeba castellanii (encephalitis isolate belonging to T1 genotype) contribute to increased permeability in an in vitro model of the human blood-brain barrier.J. Infect. 2005; 51: 150-156Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar)UnknownUnknownAxonal transportL. monocytogenes (Dramsi et al., 1998Dramsi S. Lévi S. Triller A. Cossart P. Entry of Listeria monocytogenes into neurons occurs by cell-to-cell spread: an in vitro study.Infect. Immun. 1998; 66: 4461-4468Crossref PubMed Google Scholar)PRV (Antinone and Smith, 2010Antinone S.E. Smith G.A. Retrograde axon transport of herpes simplex virus and pseudorabies virus: a live-cell comparative analysis.J. Virol. 2010; 84: 1504-1512Crossref PubMed Scopus (94) Google Scholar), HSV-1 (Miranda-Saksena et al., 2018Miranda-Saksena M. Denes C.E. Diefenbach R.J. Cunningham A.L. Infection and transport of hrpes simplex virus type 1 in neurons: role of the cytoskeleton.Viruses. 2018; 10: E92Crossref PubMed Scopus (10) Google Scholar), WNV (Samuel et al., 2007Samuel M.A. Wang H. Siddharthan V. Morrey J.D. Diamond M.S. 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Transsynaptic tracing with vesicular stomatitis virus reveals novel retinal circuitry.J. Neurosci. 2013; 33: 35-51Crossref PubMed Scopus (32) Google Scholar)UnknownUnknownPrions (Encalada et al., 2011Encalada S.E. Szpankowski L. Xia C.H. Goldstein L.S. Stable kinesin and dynein assemblies drive the axonal transport of mammalian prion protein vesicles.Cell. 2011; 144: 551-565Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, Glatzel et al., 2001Glatzel M. Heppner F.L. Albers K.M. Aguzzi A. Sympathetic innervation of lymphoreticular organs is rate limiting for prion neuroinvasion.Neuron. 2001; 31: 25-34Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar) Open table in a new tab The CSF compartment is located between the meningeal arachnoid and pia mater membranes and includes both the subarachnoid space (SAS) and the ventricular system (Figure 1A). The arachnoid barrier consists of the multilayer epithelium of the arachnoid and separates the CSF compartment from the fenestrated blood vessels within the dura mater (Brøchner et al., 2015Brøchner C.B. Holst C.B. Møllgård K. Outer brain barriers in rat and human development.Front. Neurosci. 2015; 9: 75Crossref PubMed Scopus (20) Google Scholar). The microvasculature with the SAS represents an additional blood-CSF barrier. These vessels are capable of restricting diffusion of plasma proteins by expression of claudin-5-positive tight junctions (TJs) (Møllgård et al., 2017Møllgård K. Dziegielewska K.M. Holst C.B. Habgood M.D. Saunders N.R. Brain barriers and functional interfaces with sequential appearance of ABC efflux transporters during human development.Sci. Rep. 2017; 7: 11603Crossref PubMed Scopus (9) Google Scholar). Pial microvessels differ from the BBB in TJ arrangement and in the absence of astrocyte ensheathment (Allt and Lawrenson, 1997Allt G. Lawrenson J.G. Is the pial microvessel a good model for blood-brain barrier studies?.Brain Res. Brain Res. Rev. 1997; 24: 67-76Crossref PubMed Scopus (0) Google Scholar). The capillaries within the SAS therefore represent a site where pathogens and immune cells can exit the blood and migrate along ablumenal (brain-facing) surfaces into perivascular spaces within the brain parenchyma at sites with BBB specializations. The choroid plexus (CP), a network of microvessels with modified ependymal cells in the ventricular system, provides a barrier between its fenestrated capillaries and the CSF compartment via junctional complexes similar to the BBB (reviewed in Engelhardt et al., 2016Engelhardt B. Carare R.O. Bechmann I. Flügel A. Laman J.D. Weller R.O. Vascular, glial, and lymphatic immune gateways of the central nervous system.Acta Neuropathol. 2016; 132: 317-338Crossref PubMed Scopus (119) Google Scholar). The CP connects with lymphatics that provide mechanisms for leukocyte egress from the CNS (Aspelund et al., 2015Aspelund A. Antila S. Proulx S.T. Karlsen T.V. Karaman S. Detmar M. Wiig H. Alitalo K. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules.J. Exp. Med. 2015; 212: 991-999Crossref PubMed Google Scholar, Louveau et al., 2015Louveau A. Smirnov I. Keyes T.J. Eccles J.D. Rouhani S.J. Peske J.D. Derecki N.C. Castle D. Mandell J.W. Lee K.S. et al.Structural and functional features of central nervous system lymphatic vessels.Nature. 2015; 523: 337-341Crossref PubMed Scopus (1364) Google Scholar). Cells of the CP also are the main producers of CSF, which circulates via a combination of directed bulk flow and both pulsatile and continuous bidirectional movement at the BBB and at the borders between CSF and CNS interstitial spaces (reviewed in Brinker et al., 2014Brinker T. Stopa E. Morrison J. Klinge P. A new look at cerebrospinal fluid circulation.Fluids Barriers CNS. 2014; 11: 10Crossref PubMed Scopus (294) Google Scholar). Whether CSF circulation contributes to pathogen dissemination in the CNS is unknown. Several bacteria, including Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitides, gain access to the blood and CSF after initial colonization within the nasopharynx. There are over 90 serotypes of S. pneumoniae, which differ in virulence and drug susceptibility. H. influenzae was a leading cause of childhood meningitis until its near eradication through the introduction of an effective conjugate H. influenza type b (HiB) vaccine (Scheifele, 2001Scheifele D. Hib conjugate vaccines: lessons learned.Int. J. Clin. Pract. Suppl. 2001; : 8-9PubMed Google Scholar). N. meningitides and S. pneumoniae can cause fulminant bacteremia and sepsis, especially in young children and the elderly, with spread to multiple organs, including the CNS (Oordt-Speets et al., 2018Oordt-Speets A.M. Bolijn R. van Hoorn R.C. Bhavsar A. Kyaw M.H. Global etiology of bacterial meningitis: a systematic review and meta-analysis.PLoS ONE. 2018; 13: e0198772Crossref PubMed Scopus (7) Google Scholar). Listeria monocytogenes is an intracellular bacterium that is more effective at invading the CNS than other neuroinvasive bacteria (Drevets et al., 2004Drevets D.A. Dillon M.J. Schawang J.S. Van Rooijen N. Ehrchen J. Sunderkötter C. Leenen P.J. The Ly-6Chigh monocyte subpopulation transports Listeria monocytogenes into the brain during systemic infection of mice.J. Immunol. 2004; 172: 4418-4424Crossref PubMed Google Scholar). L. monocytogenes spreads hematogenously from the gastrointestinal tract after consumption of contaminated food and enters the CNS parenchyma through invasion of meningeal endothelium, transport across the BBB within infected macrophages, or retrograde migration along cranial nerve axons (Drevets et al., 2004Drevets D.A. Dillon M.J. Schawang J.S. Van Rooijen N. Ehrchen J. Sunderkötter C. Leenen P.J. The Ly-6Chigh monocyte subpopulation transports Listeria monocytogenes into the brain during systemic infection of mice.J. Immunol. 2004; 172: 4418-4424Crossref PubMed Google Scholar). Bacillus anthracis, a spore-forming bacterium, causes three clinical forms of anthrax: cutaneous; inhalational; and gastrointestinal (Inglesby et al., 2002Inglesby T.V. O’Toole T. Henderson D.A. Bartlett J.G. Ascher M.S. Eitzen E. Friedlander A.M. Gerberding J. Hauer J. Hughes J. et al.Working Group on Civilian BiodefenseAnthrax as a biological weapon, 2002: updated recommendations for management.JAMA. 2002; 287: 2236-2252Crossref PubMed Google Scholar). Both inhalational and gastrointestinal forms may disseminate to the CNS, causing fatal hemorrhagic meningitis. Bacterial infections within the CNS generally cause meningitis, which is limited to the CSF compartment. Host inflammatory responses and, in some cases, pathogens or their virulence factors may lead to subsequent BBB disruption with invasion of the CNS parenchyma. Within the subarachnoid space, bacteria can adhere to the endothelium via interactions between bacterial and host proteins. The classes of proteins exploited by bacteria are diverse, including adhesion molecules and other cell surface receptors (Figure 1B). The major adhesion protein of S. pneumoniae pilus-1, RrgA, binds the polymeric immunoglobulin receptor (pIgR) and/or platelet-associated cell adhesion molecule (PECAM)-1 on endothelial cells, whereas the bacterial choline binding protein (PspC) binds only pIgR (Iovino et al., 2017Iovino F. Engelen-Lee J.Y. Brouwer M. van de Beek D. van der Ende A. Valls Seron M. Mellroth P. Muschiol S. Bergstrand J. Widengren J. Henriques-Normark B. pIgR and PECAM-1 bind to pneumococcal adhesins RrgA and PspC mediating bacterial brain invasion.J. Exp. Med. 2017; 214: 1619-1630Crossref PubMed Scopus (20) Google Scholar). H. influenzae pili can interact with platelet activating factor receptor (PAFR) on brain microvascular endothelial cells (BMECs) (Al-Obaidi and Desa, 2018Al-Obaidi M.M.J. Desa M.N.M. Mechanisms of blood brain barrier disruption by different types of bacteria, and bacterial-host interactions facilitate the bacterial pathogen invading the brain.Cell. Mol. Neurobiol. 2018; 38: 1349-1368Crossref PubMed Scopus (3) Google Scholar, Orihuela et al., 2009Orihuela C.J. Mahdavi J. Thornton J. Mann B. Wooldridge K.G. Abouseada N. Oldfield N.J. Self T. Ala’Aldeen D.A. Tuomanen E.I. Laminin receptor initiates bacterial contact with the blood brain barrier in experimental meningitis models.J. Clin. Invest. 2009; 119: 1638-1646Crossref PubMed Scopus (0) Google Scholar). N. meningitides type IV pili (PilE and PilV) facilitate adhesion to brain endothelial cells through interaction with CD147 (Bernard et al., 2014Bernard S.C. Simpson N. Join-Lambert O. Federici C. Laran-Chich M.P. Maïssa N. Bouzinba-Ségard H. Morand P.C. Chretien F. Taouji S. et al.Pathogenic Neisseria meningitidis utilizes CD147 for vascular colonization.Nat. Med. 2014; 20: 725-731Crossref PubMed Google Scholar). Subsequent interaction of CD147 with β2-adrenoreceptor triggers signaling events that facilitate crossing of the endothelial barrier (Coureuil et al., 2010Coureuil M. Lécuyer H. Scott M.G. Boularan C. Enslen H. Soyer M. Mikaty G. Bourdoulous S. Nassif X. Marullo S. Meningococcus Hijacks a β2-adrenoceptor/β-Arrestin pathway to cross brain microvasculature endothelium.Cell. 2010; 143: 1149-1160Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, Maïssa et al., 2017Maïssa N. Covarelli V. Janel S. Durel B. Simpson N. Bernard S.C. Pardo-Lopez L. Bouzinba-Ségard H. Faure C. Scott M.G.H. et al.Strength of Neisseria meningitidis binding to endothelial cells requires highly-ordered CD147/β2-adrenoceptor clusters assembled by alpha-actinin-4.Nat. Commun. 2017; 8: 15764Crossref PubMed Scopus (9) Google Scholar). The N. meningitides cysteine transport system (CTS) also is a determinant of BMEC invasion (Takahashi et al., 2018Takahashi H. Watanabe H. Kim K.S. Yokoyama S. Yanagisawa T. The meningococcal cysteine transport system plays a crucial role in Neisseria meningitidis survival in human brain microvascular endothelial cells.MBio. 2018; 9 (e02332-18)Crossref PubMed Scopus (1) Google Scholar). Listeria internalin (InlA and InlB) proteins interact with host receptors E-cadherin and the Met receptor tyrosine kinase, which are expressed by CP epithelium and brain endothelium, respectively (Gründler et al., 2013Gründler T. Quednau N. Stump C. Orian-Rousseau V. Ishikawa H. Wolburg H. Schroten H. Tenenbaum T. Schwerk C. The surface proteins InlA and InlB are interdependently required for polar basolateral invasion by Listeria monocytogenes in a human model of the blood-cerebrospinal fluid barrier.Microbes Infect. 2013; 15: 291-301Crossref PubMed Scopus (29) Google Scholar). 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Mahdavi J. Thornton J. Mann B. Wooldridge K.G. Abouseada N. Oldfield N.J. Self T. Ala’Aldeen D.A. Tuomanen E.I. Laminin receptor initiates bacterial contact with the blood brain barrier in experimental meningitis models.J. Clin. Invest. 2009; 119: 1638-1646Crossref PubMed Scopus (0) Google Scholar); these binding events can facilitate formation of bacterial microcolonies on the lumenal (blood-facing) surface of the endothelium (Iovino et al., 2013Iovino F. Orihuela C.J. Moorlag H.E. Molema G. Bijlsma J.J. Interactions between blood-borne Streptococcus pneumoniae and the blood-brain barrier preceding meningitis.PLoS ONE. 2013; 8: e68408Crossref PubMed Scopus (0) Google Scholar, Schw" @default.
• W2972296982 created "2019-09-12" @default.
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• W2972296982 date "2019-09-01" @default.
• W2972296982 modified "2023-10-16" @default.
• W2972296982 title "Mechanisms of Pathogen Invasion into the Central Nervous System" @default.
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