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In this review, we compare the mechanisms by which bacterial pathogens reach the CNS and infect the brain. In particular, we focus on recent data regarding mechanisms of bacterial translocation from the nasal mucosa to the brain, which represents a little explored pathway of bacterial invasion but has been proposed as being particularly important in explaining how infection with Burkholderia pseudomallei can result in melioidosis encephalomyelitis.
Microbial infection involving the central nervous system CNS is an important and relatively common presentation. CNS infections are frequently caused by viruses, such as the enteroviruses, which cause the majority of cases of aseptic meningitis and meningoencephalitis 1 , — 3.
Other neurotropic viruses, such as human cytomegalovirus, herpes simplex viruses, varicella-zoster virus, and the emerging viruses West Nile virus, henipaviruses, Japanese encephalitis virus, chikungunya virus, Ebola virus, and rabies virus, may also cause CNS infections 4 , — 7.
There are many bacterial pathogens that are associated with CNS invasion. Rapid detection of a bacterial agent in such presentations and the initiation of appropriate antibiotic therapy influence morbidity and mortality 8 , — The clinical presentations of bacterial CNS infection range from meningitis and meningoencephalitis to focal CNS syndromes.
Meningitis, or inflammation of the meninges, is usually acute but can also be subacute and most frequently presents with headache, fever, and neck stiffness Meningitis can be pyogenic pus forming , which is associated with common bacterial etiologies described below , or aseptic, in which pyogenic bacteria are not isolated from the cerebrospinal fluid CSF and the causative agent may be viral or mycobacterial or there is a noninfective etiology.
A prospective, laboratory-based surveillance study in defined the epidemiology of bacterial meningitis in a population of 34 million in the United States This study reported an average of 6.
Staphylococcus aureus and Escherichia coli are also important causes of bacterial meningitis 15 , and Streptococcus suis is emerging as a zoonotic etiology of meningitis 16 ; however, it must be noted that meningitis can be caused by a plethora of different bacteria The most common alternative bacterial cause of meningitis is Mycobacterium tuberculosis , which is recognized particularly in pediatric populations of the developing world 18 , These infections involve a clinical onset that is usually insidious, with hydrocephalus being a prominent feature.
Bacterial meningitis is usually preceded by nasopharyngeal or middle ear colonization, followed by i microbial invasion of the tissue and intravascular space and ii bacteremia.
Meningeal invasion occurs following penetration of the cellular barriers of the CNS. High-level bacteremia was shown to be necessary for the development of meningitis in experimental animal models 20 , 21 , which is consistent with clinical observations in humans 22 , — Several species-specific factors that promote bacterial survival in blood, resistance to complement, and survival within phagocytes have been identified 25 , — Bacterial meningitis resulting from nonhematogenous spread is less common and is a consequence of infection preexisting in an adjacent intracranial site.
Such infections include mastoiditis, frontal sinusitis, and rupture of an intracerebral abscess into the ventricles of the brain and may occur following head trauma or neurosurgical procedures.
There are no specific distinguishing clinical features of pneumococcal meningitis. While a rash is uncommon, it is occasionally seen in splenectomized patients with overwhelming sepsis.
There is a close correlation between bacteremic and meningitic serotypes of S. After the introduction of the 7-valent pneumococcal conjugate vaccine which contains serotype antigens 4, 6B, 9V, 14, 18C, 19F, and 23F in the United States, the incidence of pneumococcal meningitis declined by Across all age groups, the number of meningitis cases caused by S.
Similar reductions in invasive pneumococcal disease caused by 7-valent serotypes have also been reported in Australia, England, and Wales 33 , — 35 ; however, this has led to a replacement phenomenon, in which the rates of disease caused by nonvalent S.
The serotypes most commonly implicated are A, B, C, W, and Y 14 , 36 , — 38 , and meningitis without shock is the most common presentation The predominant clinical feature, which can distinguish N.
It can rapidly become purpuric, which in the presence of meningitis or sepsis strongly implicates N. These lesions are a consequence of meningococci adhering to the endothelial cells of the capillaries and small veins in the skin, thereby altering the antithrombotic surface of the endothelium.
This results in the formation of clots and the extravasion of erythrocytes, which appear as skin hemorrhages. The United Kingdom was the first country to introduce routine immunization with a monovalent serotype C conjugate vaccine, in Meningococcal serotype C vaccination programs in Australia have also led to a marked decrease in disease due to N.
In New Zealand, the introduction of an outer membrane vesicle vaccine against an epidemic N. As a cause of meningitis, H. The signs and symptoms of L.
Listeriosis is associated with the consumption of contaminated food, implicating the gastrointestinal tract as the portal of entry to the bloodstream.
Group B streptococcus and E. Gram-negative aerobic bacteria, such as Klebsiella pneumoniae , Serratia marcescens , Salmonella spp. Tuberculosis meningitis occurs following hematogenous spread of bacilli from the lungs and the establishment of a caseating Rich focus tuberculous granuloma in the brain cortex, meninges, or choroid plexus.
Bacteria are subsequently released from the foci and enter the subarachnoid space In certain circumstances, acute meningitis can be clinically indistinguishable from acute encephalitis, which refers to inflammation of the brain parenchyma in association with neurologic dysfunction Encephalitis is typically characterized by headache with an acute confusional state, with or without seizures.
The California Encephalitis Program identified the clinical profiles and etiologies of encephalitis in a large cohort of immunocompetent patients from to 7.
A confirmed or probable etiology was identified in only Herpes simplex virus is the most common cause of encephalitis in Western countries 6 , 53 , Enteroviruses, varicella-zoster virus, Epstein-Barr virus, measles virus, and arboviruses, such as Japanese encephalitis virus, West Nile virus, and Murray Valley encephalitis virus, have also been implicated as causes of encephalitis 6 , 7 , 54 , Beckham and Tyler provided a comprehensive list of other important and emerging viral causes of encephalitis Fevers are usually a prominent feature, and headaches are common, but neck stiffness is usually mild or absent.
The computed tomography CT scan is often normal, but dramatic changes are seen on magnetic resonance imaging, most notably a diffusely increased T 2 -weighted signal in the midbrain, brain stem, and spinal cord, with variable symmetry and enhancement with gadolinium.
CSF shows high protein, normal or slightly decreased glucose, and, most notably, a pleocytosis with lymphocytes usually predominant. Bulbar palsy and decreased respiratory drive often necessitate ventilation, which may be required for many weeks 56 , 59 , — In northern Australia, patients infected with the flavivirus Murray Valley encephalitis virus can present with clinical features indistinguishable from those seen with melioidosis encephalomyelitis.
Neurologic melioidosis is occasionally seen outside Australia, although it appears to be less common in melioidosis patients in Southeast Asia than in Australia.
Frank meningitis is rarely seen in melioidosis. A recent report described the first case of neurological melioidosis in the United States, in a year-old male who presented with low-grade fever, nausea, vomiting, headaches, diplopia, left-sided ptosis, and transient episodes of marked somnolence, after recent travel to Cambodia CSF demonstrated increased levels of glucose, protein, and lymphocytes; however, microbiological investigation consistently showed no organisms by Gram stain and failed to detect any organisms on culture medium.
The range of focal CNS infections includes brain abscesses, subdural empyema, and epidural abscesses. Brain abscess refers to an intracerebral infection that usually begins as localized cerebritis, which develops into a collection of pus that is surrounded by a well-vascularized capsule The clinical presentations of brain abscesses are variable and depend on the anatomical area of the brain that is compressed or affected.
Brain abscesses commonly originate from a contiguous focus of infection, such as the middle ear, mastoid cells, or paranasal sinuses.
Brain abscesses may also occur following i hematogenous spread of bacteria from a distant focus of infection or ii brain trauma or neurosurgery A recent systematic review and meta-analysis of brain abscess studies reported between and demonstrated that Streptococcus and Staphylococcus spp.
Gram-negative enteric bacteria were responsible for Other, less common causative agents include anaerobic bacteria Bacteroides spp. Subdural empyema refers to a collection of pus in the subdural space, which is located between the dura mater and arachnoid mater layers of the meninges see Barriers of the CNS, below.
In contrast, epidural abscesses are defined as a collection of pus between the dura mater and the skull or vertebral column The etiologies of subdural empyema and epidural abscesses are similar to those of brain abscesses; however, due to the anatomical location of these infections, bacteria do not need to penetrate the blood-brain barrier BBB to establish disease.
The CNS is physically protected from injury by bony structures, such as the vertebrae and the cranium, and is also enveloped by the meninges and surrounded by CSF.
The meninges comprise three layers: The arachnoid mater and pia mater are separated by the subarachnoid space, which is filled with CSF that is produced by the choroid plexus in the ventricles of the brain Fig.
The CSF provides mechanical support, regulates ion composition, and maintains chemical stability. Once it has circulated through the ventricles of the brain, the CSF enters the subarachnoid space and drains into the blood through arachnoid villi and granulations.
CSF also drains through the cribriform plate into the lymphatics within the nasal mucosa 71 , — Anatomical locations and organizations of the blood-brain and blood-cerebrospinal fluid barriers and the olfactory portal.
The skull and the meninges, which consist of the dura mater, arachnoid mater, and pia mater, protect the brain. The arachnoid mater and pia mater are connected by strands of connective tissue called arachnoid trabeculae, which course through the CSF-containing subarachnoid space.
The BBB is formed by tight junctions between endothelial cells lining cerebral microvessels, in addition to pericytes and astrocytes.
The BCSFB is formed by tight junctions between i epithelial cells at the choroid plexus, ii endothelial cells of the veins and venules within the subarachnoid space, and iii the epithelial cells of the arachnoid mater.
The olfactory system bypasses the cellular barriers of the CNS and provides a direct portal from the nasal cavity to the olfactory bulb within the brain.
The complex functions of the brain are dependent on homeostatic mechanisms that regulate the ionic composition of the interstitial fluid that surrounds neurons in the parenchyma This homeostasis is maintained by two cellular barriers which separate the CNS from the systemic circulation: These barriers protect the brain from abrupt changes in blood biochemistry while at the same time allowing delivery of nutrients and removal of metabolites.
Importantly, these barriers also protect the CNS from invasion by microbes that may be present within the blood. The BBB is composed of endothelial cells that line cerebral microvessels in association with pericytes, astrocytes, and the basement membrane collectively referred to as a neurovascular unit, in association with neurons, microglia, and peripheral immune cells.
Pericytes are attached to the abluminal surface of the endothelium and, together with the astrocytic end feet, form a contiguous membrane barrier.
A physical barrier is formed at the interendothelial cleft by complex junctions that regulate the flux of ions, polar molecules, and macromolecules from the systemic circulation 74 , At the interendothelial cleft, two types of junctions comprise the BBB: These junctions block the transport of a wide range of molecules, restricting paracellular permeability across the BBB In addition, endothelial cells forming the BBB lack fenestrations in their plasma membranes and have a reduced number of pinocytotic vesicles compared to endothelial cells in other tissues, which restricts transcellular flux The transcellular and paracellular routes of entry to the CNS are highly relevant for microbial pathogens.
Tight junctions between the epithelial cells of the arachnoid mater also contribute to the BCSFB by forming a barrier between the subarachnoid space and the leaky fenestrated blood vessels of the dura mater.
Of these BCSFB locations, the choroid plexus has a large vascular surface area and represents the major interface between fenestrated blood vessels and CSF.
Thus, the choroid plexus BCSFB may be more vulnerable to microbial penetration via paracellular mechanisms. The BCSFB at the arachnoid mater has a smaller total surface area than those of other barriers of the CNS and is not thought to be an important route for the entry of solutes into the brain The brain parenchyma and spinal cord are populated throughout by resident immune cells, the microglia, which are highly specialized tissue macrophages that are maintained through in situ self-renewal without reconstitution from the bone marrow 81 , — Microglia continuously survey the brain parenchyma by sampling their microenvironment with highly motile processes and protrusions Recent data have also revealed that cells expressing CD11c are localized within the juxtavascular parenchyma of the healthy mouse brain and extend processes to the glia limitans astrocytic foot processes at the parenchymal basement membrane, surrounding the brain under the pia mater In agreement with a previous study 86 , this raises the possibility that dendritic cells, which are characterized by high-level CD11c expression, may reside within the brain parenchyma.
However, a range of cells of the myeloid lineage including activated microglia also express CD11c, albeit at lower levels.
Thus, the CD11c-expressing cells described within the brain parenchyma may also represent a subpopulation of microglia Other resident immune cells of the CNS include perivascular macrophages in addition to small populations of blood-derived dendritic cells and macrophages within the choroid plexus and meninges.
Normal CNS immune surveillance occurs when central memory T cells migrate from the blood across the choroid plexus epithelium, enter the CSF, and scan the subarachnoid space.
In the absence of recognizing ligands presented by local antigen-presenting cells, T cells exit the subarachnoid space and drain to the secondary lymphoid organs via the nasal mucosa 90 , In contrast, recognition of presented antigens results in the formation of immunological synapses and is accompanied by cellular signaling that results in the recruitment of peripheral inflammatory cells to the CNS via paracellular or transcellular diapedesis In bacterial meningitis, neuronal injury also occurs due to the direct effects of bacterial toxins and virulence factors 96 , — A recent study of human bacterial meningitis cases demonstrated that the profile of pro- and anti-inflammatory cytokines and matrix metalloproteinases within the CSF is dependent upon the causative pathogen The sequelae of bacterial meningitis and the associated neuroinflammation include vasculitis and cerebral venous thrombosis, which can lead to cerebral ischemia.
An increase in CSF outflow resistance in combination with interstitial edema results in raised intracranial pressure, which causes hypoxic brain damage and may lead to death Peripheral nerves other than the olfactory and trigeminal cranial nerves have also been implicated as routes of entry for some viruses, but these are not reviewed here.
In contrast to a diverse group of neurotropic viruses for which mechanisms are described for invasion of the brain via the olfactory sensory nerves, bacterial infection via the olfactory epithelium and the olfactory nerve bundles has been described infrequently.
Even less well understood is the fact that, in addition to the olfactory nerve, the trigeminal nerve may also present a potential pathway to the brain.
Much of our understanding of the mechanisms of microbial CNS invasion has been obtained from in vivo and in vitro studies.
Mice and rats are the most common animals used to model CNS infections. These animal models have been used to investigate the sites of microbial entry 20 , , — and the roles of virulence determinants in CNS invasion and pathogenesis , — Despite clear differences in the size and complexity of mouse and human brains, comparative transcriptomic studies between mice and humans have demonstrated that gene expression profiles of the healthy brain and choroid epithelium are highly conserved between the species , — There are, however, several important differences between the mouse and human CNS that are relevant to microbial invasion studies.
In mice, the leptomeninges comprising the arachnoid mater and pia mater are significantly thinner and less vascular than the case in humans Additionally, the human choroid plexus epithelium has more abundant fibrovascular stroma along the vascular channels and a relatively larger surface area than those of the mouse choroid epithelium.
Mice also possess very large olfactory bulbs compared to humans , which may result in a higher incidence of CNS invasion via the olfactory route than the case in humans.
Furthermore, mice lack several anatomically defined subclasses of astrocytes that are present in humans These combined anatomical differences may influence the initial site of microbial attachment and subsequent CNS invasion.
In vitro cell culture systems have been used to model the BBB and to elucidate the cellular and molecular mechanisms of microbial CNS invasion.
Primary human, rodent, and bovine brain microvascular endothelial cells have been used in some studies 97 , , — ; however, the isolation of these cells is technically demanding, and in vitro culture dramatically alters the transcriptome, leading to downregulation of genes involved in BBB function , Human umbilical vein endothelial cells HUVECs , — , Caco-2 cells, and Madin-Darby canine kidney cells have been used as surrogate models of the BBB, although the noncerebral origin of these cells may limit their relevance.
When grown on Transwell membranes, HBMECs i form tight junctions, as measured by transendothelial electrical resistance; ii express the adherens junction and tight junction proteins zonula occludens-1, junctional adhesion molecule A, claudin-5, occludin, and vascular endothelial cadherin; and iii demonstrate negligible paracellular permeability , — It must be noted that brain microvascular endothelial cells grown in static monocultures represent a surrogate model for the human BBB, as they lack other components of the neurovascular unit that are required for the development of true BBB properties.
Studies using pericyte-deficient mice have shown that pericytes Fig. Compared to wild-type mice, pericyte-deficient mice demonstrated an accumulation of water and tracer dyes within the brain, structural abnormalities in cerebral endothelial tight junctions, and increased expression of genes known to increase vascular permeability, endothelial vesicle trafficking, and immune cell recruitment , — Astrocytes also play a key role in regulating the BBB , — , and as such, a range of coculture systems have been developed to more closely model the BBB properties of the neurovascular unit , — Choroid plexus epithelial cell lines that display the characteristic properties of the BCSFB have been described , ; however, the majority of in vitro microbial invasion studies have been performed using monocultures of brain microvascular endothelial cells.
Classical bacterial meningeal pathogens may potentially enter the CSF by penetrating the BBB of cerebral microvessels and entering the extracellular fluid of the brain, which is continuous with the CSF.
The highly vascularized choroid plexus has been favored as a major site of bacterial entry to the CSF due to lower electrical resistances between choroid epithelial cells.
Autopsies of neonates who died from bacterial meningitis demonstrated that meningitis was frequently Ventriculitis preceding meningitis would support the role of the choroid plexus as the initial site of bacterial invasion; however, ventriculitis frequently occurs as a complication of meningitis, and the site of bacterial CNS invasion remains incompletely understood.
In experimentally infected rhesus macaques, the choroid plexus was the site where the earliest histopathologic lesions were observed in H. Following intranasal inoculation, H.
In 5- to 7-week-old pigs, S. Interestingly, autopsy of a 2-month-old infant who died of fulminant meningococcemia prior to the onset of meningitis revealed adherent bacteria within the capillaries of the choroid plexus and, to a much lesser extent, the capillaries within the meninges This would appear to support the choroid plexus as the preferential site of N.
In contrast, a study of autopsy material from symptomatic patients with meningococcal disease revealed the presence of N. Neonatal rat models of E.
Similar findings were reported by Zelmer et al. In contrast, Kim et al. Remarkably, pneumococci could be detected in the choroid plexus only at 8 h postinfection, suggesting that this is not the site of initial entry to the CSF.
Transcellular penetration occurs following bacterial adhesion to endothelial or epithelial cells. Bacteria are subsequently translocated across these barriers by pinocytosis or receptor-mediated mechanisms.
Microorganisms may exploit more than one of these mechanisms to access the CNS. Mechanisms of blood-cerebrospinal fluid penetration by bacterial pathogens.
There has been significant research into the host-pathogen interactions that occur prior to bacterial invasion of brain microvascular endothelial cells Table 1 , including the identification of host receptors that mediate these interactions.
The kDa laminin receptor is a precursor for the mature, kDa laminin receptor, which binds laminin-1 within the basement membrane on the abluminal surface of eukaryotic cells In an in vivo model, Orihuela et al.
Several bacterial meningeal pathogens have been shown to bind host glycoproteins, such as fibrinogen, vitronectin, fibronectin, laminin, and collagen, which may act as bridging molecules between the bacterium and HBMECs , , — In addition, the heat shock protein gp96 and a gp96 homologue act as receptors for the surface-expressed virulence protein Vip of L.
Known bacterial ligands and their host receptors for adhesion to and invasion of the blood-brain barrier a. Transcellular penetration of brain microvascular endothelial cells, mainly via receptor-mediated mechanisms Fig.
Electron microscopy studies have demonstrated that E. Both early early endosome antigen 1 and transferrin receptor and late Ras-related protein 7 and lysosome-associated membrane protein 1 endosomal markers were recruited to vacuoles containing E.
However, the lysosomal hydrolytic enzyme cathespin D did not accumulate within the vacuoles, demonstrating that lysosomal fusion was prevented.
This was found to occur in a capsule-dependent manner This is associated with a CNFmediated recruitment of focal adhesion kinase and the cytoskeletal protein paxillin to the kDa laminin receptor, which forms clusters that colocalize with adherent E.
The activity of focal adhesion kinase and its autophosphorylation site, tyrosine , were shown to be essential for E. Furthermore, the Src kinase-dependent activation of phosphatidylinositol 3-kinase and its interaction with focal adhesion kinase were required for E.
In an independent mechanism, E. The activation of cytosolic phospholipase A 2 generated arachidonic acid metabolites, induced host actin cytoskeletal rearrangements, and was essential for E.
Notably, OmpA is highly conserved between Gram-negative bacteria and may play a role in CNS invasion by those whose mechanisms of entry are unknown.
The attachment of N. This initial attachment is inhibited by high cerebral microcirculation shear stress levels; however, once attached, N.
CD46 was previously identified as the receptor for type IV pili ; however, this was not corroborated by additional studies, and it is likely that the type IV pilus attaches to host cells independently of CD46 Furthermore, studies with human bronchial epithelial cells show that the meningococcal type IV pilus binds to the platelet activating factor PAF receptor and that synergy between a pilin-linked glycan and phosphorylcholine decorating moieties is required for pili to efficiently engage the receptor Following initial bacterial attachment, the meningococcal minor pilin protein, PilV, triggers a cellular response in which endothelial cells form protrusions around N.
These cellular projections further protect the bacterial microcolony from the mechanical stresses associated with high-velocity blood flow and also lead to the engulfment and internalization of N.
The host signaling events that contribute to these interactions have been elucidated. Following type IV pilus-mediated attachment, N.
Several host proteins, including ezrin and moesin, which regulate the cortical cytoskeleton through F-actin-binding sites, are then recruited to the site of bacterial attachment and accumulate in honeycombed molecular complexes, referred to as cortical plaques, underneath the meningococcal microcolonies , , Cortical actin is then polymerized in a Rho GTPase- and Cdcdependent manner, which leads to the formation of cell membrane protrusions Once internalized, the membrane-bound vesicles containing meningococci associate with transferrin receptor and lysosome-associated membrane protein 1 endosomal markers It is likely that lysosomal fusion is subverted, as live meningococci have been shown to translocate from the basolateral side to the apical side in a Transwell BCSFB invasion model In vitro studies have demonstrated that capsular polysaccharide inhibits the invasion of N.
This interaction results in the activation of mitogen-activated protein kinase c-Jun N-terminal kinase 1 [JNK1], JNK2, and p38 and protein tyrosine kinase signal transduction pathways Furthermore, the use of Opc-deficient mutant strains demonstrated that JNK signaling, but not p38 signaling, was mediated by Opc expression A more recent study identified that Opc preferentially binds to activated vitronectin within human serum and that this interaction promotes N.
In vitro , the enhanced invasion of nonencapsulated N. This uptake does not involve the formation of cellular membrane protrusions as discussed for N.
Following initial attachment, the laminin G-like domain of NanA initiates chemokine signaling and inflammatory activation of endothelial cells The activation of endothelial cells results in the increased expression of PAF receptor—the receptor for pneumococcal phosphorylcholine, which is a component of the cell wall and acts as a molecular mimic of the chemokine PAF In contrast, transparent pneumococci may undergo some recycling back to the apical surface; however, by 5 h postinfection in a Transwell system, the majority of bacteria had translocated to the basolateral chamber This interaction also stimulates mitogen-activated protein kinase signaling, which is required for pneumococcal uptake The small number of pneumococcus-containing vacuoles that underwent recycling to the apical surface demonstrated colocalization with Ras-related protein 11, which regulates endosome recycling.
The hypervirulent group B streptococcus adhesin HvgA was identified as a sequence type 17 ST -specific virulence factor which is anchored to the group B streptococcal cell wall by sortase A Therefore, it was proposed that HvgA expression may contribute to the hypervirulence of ST Furthermore, in a murine model of hematogenous meningitis, HvgA was required for CNS invasion, although it had no effect on the levels of bacteremia The group B streptococcal pilus tip adhesin PilA and the recently identified streptococcal fibronectin-binding protein A SfbA bind immobilized collagen and fibronectin, respectively.
The collagen and fibronectin then associate with HBMECs via integrins, and these interactions facilitate the entry of group B streptococcus , The fibrinogen-binding protein FbsA also mediates group B streptococcal adherence to HBMECs, by binding immobilized fibrinogen , although it is unknown if this interaction also occurs via a dock, latch, and lock mechanism.
Electron microscopy studies have demonstrated that in vitro , group B streptococcus associates closely with the cell membrane of HBMECs and is enveloped by microvillous structures Group B streptococci are internalized within membrane-bound vesicles and translocate from the apical side to the basolateral side of HBMECs without a marked change in transendothelial electrical resistance.
Internalized group B streptococci did not undergo significant replication and survived within HBMECs for up to 20 h Intracellular survival of group B streptococcus may be promoted by the CiaR-CiaH two-component regulatory system, which regulates several genes associated with stress tolerance and the subversion of host defenses A serotype III strain that was deficient in the CiaR response regulator demonstrated adhesion and invasion levels similar to those of the wild-type group B streptococcus in HBMECs but was associated with a significant decrease in intracellular survival.
Broth inhibition assays demonstrated that CiaR conferred resistance to antimicrobial peptides, lysozyme, and reactive oxygen species The host signal transduction pathways that are involved in the uptake of group B streptococcus by HBMECs are similar to those discussed for E.
It has also been demonstrated that group B streptococcus invasion occurs via cytoskeletal rearrangements that are induced following the activation of RhoA and Rac1 Furthermore, group B streptococcus induces serine phosphorylation of host cytosolic phospholipase A 2 , which leads to the release of arachidonic acid metabolites, including cysteinyl leukotrienes In vitro pharmacological inhibition studies demonstrated that the activation of cytosolic phospholipase A 2 was required for efficient group B streptococcal invasion of HBMECs.
In addition, brain colonization by group B streptococcus was significantly reduced in mice deficient in cytosolic phospholipase A 2 compared to wild-type animals in a model of hematogenous meningitis.
The zoonotic pathogen S. In contrast, invasion of porcine brain microvascular endothelial cells has been observed for this swine pathogen.
Inhibition studies demonstrated that S. Electron microscopy studies showed that S. Unlike the case of group B streptococci, following internalization within membrane-bound vacuoles, the number of viable intracellular S.
However, similar to the case with S. Pretreatment of porcine brain microvascular endothelial cells with S. These genes were characterized as encoding proteins belonging to the following groups: However, the roles of these genes in S.
As discussed above, the choroid plexus may be the site of entry to the CNS for S. In order to study the interactions between S.
These findings were also replicated in a human choroid plexus epithelial cell inverted Transwell model This suggested that S. The translocation of S.
The invasion of L. Following escape into the cytoplasm, L. In an epithelial cell line or a murine macrophage-like cell line, cell-to-cell spread then occurs by cell fusion, with the formation of multinucleated giant cells, in a type VI secretion-dependent process.
BimA, which is necessary for actin-mediated motility, and Fla2, which is thought to mediate intracellular motility, are also required and are considered to mediate cell-to-cell contact prior to cell fusion , — To our knowledge, the ability of B.
Interestingly, a recent study investigated the variable virulence factors of B. Patients that were infected with B.
Several studies have shown that internalin B InlB is required for L. It was suggested that these inconsistent findings may be attributable to differences in experimental conditions, especially involving the addition of normal human serum, which markedly affects InlB-mediated invasion due to the presence of anti- Listeria antibodies In this model, L.
Vip is a surface-expressed protein that is absent from nonpathogenic Listeria and binds to gp96 on host cells A vip allelic replacement mutant was shown to be significantly less invasive than wild-type L.
Similarly, IspC was also shown to contribute to L. Interestingly, the deletion of IspC did not affect the ability of L. In vitro , M. Antibiotic protection assays demonstrated that M.
The mechanisms and host-pathogen interactions involved in CNS invasion by M. In an in vitro BBB model consisting of bovine brain microvascular endothelial cells BBMECs cocultured with rat astrocytes, the addition of purified recombinant heparin-binding hemagglutinin adhesin rHBHA induced actin filament rearrangement Furthermore, gene expression profiling of M.
In vivo screening of transposon mutant libraries has also been employed to identify potential M. In vitro studies confirmed that these mutants invaded HBMECs at significantly reduced levels compared to that of a negative-control transposon mutant Rvc also known as pknD encodes a serine-threonine protein kinase and was also identified as a key microbial factor required for brain infection in a guinea pig model of hematogenous meningitis, from a library of mutants When studied independently in a mouse model of infection, the pknD mutant was associated with significant reductions in bacterial loads within the brain but not the lungs.
Microspheres coated with pknD adhered to HBMECs at significantly higher levels than those of microspheres coated with bovine serum albumin, and it was proposed that pknD binds to HBMECs via interactions with laminin within the extracellular matrix Early studies in intracisternally infected rats demonstrated that E.
Further experiments with H. This suggests that bacterial meningeal pathogens may open a paracellular route of CNS entry, although these data should be interpreted cautiously, as intracisternal inoculation cannot be used to model the physiological events that occur during hematogenous meningitis because the inoculum is injected directly into the cisternal spaces between the arachnoid mater and pia mater.
From these studies reviewed below for specific pathogens , it appears that microbes may initially attach to and transcellularly invade brain microvascular endothelial cells and that these host-pathogen interactions may lead to a subsequent increase in barrier permeability and a loss of tight junctions.
Thus, it is likely that both transcellular and paracellular mechanisms of CNS entry are exploited by bacterial pathogens.
In addition to triggering the internalization of E. Immunofluorescence experiments demonstrated that vascular endothelial cadherin was redistributed from the intercellular junctions to the sites of bacterial attachment This resulted in a significant increase in HBMEC permeability to horseradish peroxidase and a parallel decrease in transendothelial electrical resistance Furthermore, the activation of host cytosolic phospholipase A 2 by E.
This was associated with a significant decrease in transendothelial electrical resistance and a dramatic detachment of pericytes from the Transwell membrane.
These effects were not observed when the pericyte vascular endothelial growth factor receptor 1 was blocked using a polyclonal antibody. These findings suggest that the vascular endothelial growth factor released by brain endothelial cells may bind to the vascular endothelial growth factor receptor 1 on adjacent pericytes and trigger ablation of the pericytes from the basal membrane, potentially opening a paracellular route In vitro studies using the mouse brain microvascular endothelial cell line Bend.
B5 in inducing BBB permeability. These signaling events were associated with a decrease in the expression of the tight junction proteins claudin-5 and zonula occludens-1 and a reduction in transendothelial electrical resistance.
LPS also induced changes in F-actin organization, leading to paracellular gaps and stress fiber formation In Shiga toxin-producing E.
LPS may mediate these effects , Using this intracisternal inoculation model, the role of H. In leukopenic rats, no increases in BBB permeability and CSF leukocyte counts were observed following LOS or outer membrane vesicle challenge, suggesting that the decrease in BBB integrity is mediated by the intact host leukocyte response , In contrast, Tunkel et al.
Peptidoglycan within the H. Intracisternally inoculated peptidoglycan induced an increase in BBB permeability to I-albumin , as well as CSF leukocytosis , although the CSF leukocytosis was attenuated compared to that in animals challenged with LOS Access to detailed statistics of competitions, atheletes, horses and events.
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