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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 It was subsequently hypothesized that H.

LOS may then augment this response by activating the recruited leukocytes to produce proinflammatory cytokines that further contribute to BBB breakdown ; however, the mechanisms by which this may occur have not been elucidated.

As discussed above, N. Labeling of vascular endothelial cadherin demonstated that N. This depletion of junctional proteins was associated with an increase in barrier permeability to Lucifer yellow and the formation of gaps between cells, thus opening a paracellular route of entry Interestingly, the recruitment of junctional components by N.

In an inflammation-mediated process, N. The cleavage of occludin was prevented in the presence of matrix metalloproteinase-8 inhibitors and in cells transfected with matrix metalloproteinasespecific small interfering RNA siRNA.

Inhibition of matrix metalloproteinase-8 activity also significantly decreased the N. Furthermore, the inhibition of matrix metalloproteinase-8 prevented the caspase-independent detachment of HBMECs from a Matrigel matrix on a solid support following N.

Group B streptococcus, S. In vivo and in vitro studies have shown that group B streptococci, pneumococci, and S. Therefore, the host inflammatory response to group B streptococcus, S.

Using a separate mechanism, group B streptococcus, S. Plasminogen is found in plasma and extracellular fluids, and upon activation is converted to plasmin, which degrades the extracellular matrix and may upregulate matrix metalloproteinases that degrade tight junctions In vitro , plasminogen binds to streptococcal glyceraldehydephosphate dehydrogenase , — Enolase and choline-binding protein E have also been identified as additional pneumococcal plasminogen-binding proteins , Once plasminogen is bound to its binding protein, it becomes activated and is subsequently converted to plasmin by exogenous tissue plasminogen activator and urokinase , , Plasmin bound to the surfaces of group B streptococci enhanced the ability of bacteria to adhere to and invade HBMECs and induced a significant decrease in transendothelial electrical resistance Furthermore, streptococcus-bound plasmin contributed to cellular injury, characterized by human brain microvascular cell detachment and lactate dehydrogenase release In the human vascular endothelial cell line EaHy, plasmin bound to the pneumococcal cell surface cleaved vascular endothelial cadherin from adherens junctions and increased bacterial translocation across endothelial barriers Taken together, group B streptococcus, S.

Plasminogen has also been shown to bind to N. In HBMECs, these hemolysins are cytotoxic and promote lactate dehydrogenase release, the loss of cytoplasmic density, discontinuity of cytoplasmic membranes, clumping of nuclear chromatin, dilation of the endoplasmic reticulum, cell rounding, and detachment 97 , , These morphological changes most likely result in the formation of paracellular gaps.

The effects of pneumolysin have also been investigated in rat astrocytes; the addition of pneumolysin to monolayers of primary astrocytes resulted in cell shrinkage and the subsequent separation of cells from each other In rat brain slices, exposure to pneumolysin led to astrocytic process retraction and reorganization of astrocytes within the glia limitans.

These pneumolysin-induced changes were associated with increased interstitial fluid retention and BBB permeability, which facilitated the penetration of macromolecules and bacteria into brain slices These data suggest that in addition to mediating cytotoxic effects in brain microvascular endothelial cells, bacterial hemolysins may also induce morphological changes in other components of the neurovascular unit.

Bacteria that are capable of surviving within host peripheral immune cells have the ability to invade the CNS via the Trojan horse route.

This route of entry has been suggested for L. Furthermore, CNS infection was not reduced following the elimination of extracellular L. In a hematogenous model of melioidosis meningitis, B.

In contrast, bacterial burdens within the brain were attenuated following the adoptive transfer of B. These data suggest that B. Further experiments demonstrated that the expression of selectin on B.

The olfactory system Fig. Within the nasal cavity, the olfactory epithelium lines the more dorsal and caudal regions of the cavity. Olfactory sensory neurons reside within the olfactory epithelium and project a dendritic knob-like swelling with 20 to 30 cilia into the mucous layer lining the nasal cavity.

The olfactory sensory neuron cilia possess odorant receptors , which bind a large spectrum of ligands Binding of an inhaled odorant to its receptor results in signal amplification and the activation of a signal transduction pathway, leading to the generation of an action potential The olfactory epithelium also comprises sustentacular cells, which are glia-like cells whose apical surfaces form the epithelial surface lining the nasal cavity.

These supporting cells form tight junctions with each other and with the dendrites of the olfactory sensory neurons, forming the primary barrier from the environment The olfactory epithelium also contains basal cells, which are stem and multipotent progenitors from which new olfactory sensory neurons are generated, and developing neurons, which are newly generated from the basal cells , The axons of olfactory sensory neurons penetrate the basement membrane beneath the epithelium entering the lamina propria, where they are met by specialized glial cells, the olfactory ensheathing cells.

Olfactory ensheathing cells surround multiple axons and bundle them together in larger fascicles that comprise the olfactory nerve , The olfactory system is a direct portal for bacterial pathogens to the brain.

A The cilia of olfactory sensory neurons penetrate the nasal mucosa and provide a direct pathway from the external environment to the CNS.

Olfactory sensory neurons in the olfactory epithelium are supported by sustentacular cells and replaced by proliferation and differentiation of basal stem cells, and their axons pass through the lamina propria and cribriform plate of the skull to synapse with mitral cells in the glomeruli of the olfactory bulb.

Microbial pathogens can potentially access the brain through the olfactory epithelium via axonal transport, by travel within olfactory ensheathing cells that surround the axons, or external to these cells, within the perineural space and by passage through holes in the cribriform plate to access the subarachnoid space.

Also see references and B Primary olfactory neurons green reside in the olfactory epithelium, which lines the nasal cavity NC. The boxed region is shown in panel C.

C Bundles of olfactory axons project from the olfactory epithelium OE through the cribriform plate CP; chondrocytes are bright red and enter the nerve fiber layer NFL , which forms the outer layer of the olfactory bulb.

Olfactory ensheathing cells dull red, arrows surround the axon bundles. D Sagittal section through the olfactory bulb and nasal cavity of a mouse that was intranasally inoculated with B.

E A higher-power view of the ventral nerve fiber layer shows bacterial infestation within the nasal cavity NC and the olfactory epithelium OE and invasion of the NFL by bacteria.

Inset Higher-power view of B. The axons of the olfactory nerve course through the lamina propria toward the brain, penetrating the skull through the cribriform plate and entering the brain at the olfactory bulb Fig.

Within the olfactory bulb, the sensory axons form specialized structures, the glomeruli, where they synapse with mitral cells, which carry the sensory signal to higher brain structures , Olfactory sensory neurons are directly exposed to the external environment via the nasal cavity; therefore, microbes within the nasal cavity may potentially exploit the olfactory pathway and access the subarachnoid space and the olfactory bulb.

From the olfactory bulb, viruses have been shown to migrate to higher brain regions, including the basal nuclei, thalamus, hypothalamus, cerebrum, and cerebellum, in animal models of infection , — The trigeminal nerve is the largest cranial nerve, whose afferent branches carry touch, pain, and noxious stimuli from the face, the corneas of the eyes, and the oral and nasal cavities.

The trigeminal nerve innervates the olfactory and respiratory epithelia of the nasal cavity via branches of the ophthalmic V1 and maxillary V2 nerves Fig.

The trigeminal nerve endings are separated from the lumen of the nasal cavity via an apical tight junction complex at the epithelial surface , The same trigeminal nerves that innervate the olfactory epithelium also branch to innervate the olfactory bulb, providing an alternative route for entry of pathogens Lipid-soluble trigeminal irritants within the nasal cavity may reach their receptors on trigeminal nerve endings by diffusing across tight junctions, potentially by using paracellular mechanisms , or by interacting with specialized solitary chemosensory cells within the nasal and respiratory epithelia which form synaptic contacts with trigeminal nerve fibers Solitary chemosensory cells isolated from mice were shown to detect bacterial signals, such as acyl-homoserine lactones, and to trigger downstream signaling pathways associated with bitter irritant transduction Trigeminal nerve route of entry.

A Schematic showing the three branches of the trigeminal nerve: V1, V2, and V3. Branches V1 and V2 innervate the nasal cavity and project to the brain stem BS.

B to D In coronal sections of the mouse nasal cavity, B. The boxed area in panel B is shown in panel C. Bacteria arrows are contained within the trigeminal nerve, while adjacent olfactory nerve bundles arrows with tails do not contain bacteria.

D Higher-magnification view of the trigeminal nerve in a nearby section. The trigeminal nerve fibers course to the brain, forming the trigeminal ganglion outside the brain stem but beneath the dura mater From the trigeminal ganglion, the sensory axons innervate the trigeminal nucleus in the brain stem.

Therefore, the trigeminal nerve, like the olfactory nerve, may provide a direct pathway by which bacteria within the nasal mucosa may access the brain independently of the blood.

It should be noted that bacterial entry to the brain via the trigeminal nerve might not be limited to intranasal infection. For example, viruses such as herpes simplex virus type 1 access the trigeminal nerve through infection of the cornea , and potentially any epithelial infection of the facial skin or oral cavity could allow access to the trigeminal nerve.

The nasal cavity is constantly exposed to inhaled microbes, allergens, and particulate material. The epithelium lining the nasal nares , and the nasal cavity harbor normal bacterial flora, and CNS pathogens, such as S.

Therefore, the nasal cavity features innate defense mechanisms to filter inhaled air and prevent microbes from invading deeper tissues.

Through a mucociliary clearance process, inhaled bacteria and particulate matter become trapped in the mucous layer and are swept toward the pharynx by the coordinated beating of cilia located on the surfaces of epithelial cells.

A recent study demonstrated that MUC5B, but not MUC5AC, is essential for mucociliary clearance activity and the prevention of bacterial spread from the nasal cavity to the lower respiratory tract Mucus secretion and mucociliary clearance are enhanced in the presence of inflammatory mediators and microbial pathogens , — and following exposure to cigarette smoke Finally, tight junctions and adherens junctions between the epithelial cells lining the nasal cavity and airway create a cellular barrier that prevents microbial spread.

Dendritic cells localized beyond the epithelium extend processes through these tight junctions to interact with ligands and collaborate with resident macrophages to remove foreign antigens Despite the host defenses that exist within the nasal cavity and upper airways, bacteria colonizing the epithelium may invade deeper tissues and cause disease.

In the case of asymptomatic colonizers, the transition from a commensal to a pathogenic phenotype may be due to within-host evolution that results in genetic changes to the regulation of virulence factors , Alterations in susceptibility to disease in immunocompromised individuals may also promote the spread of bacteria from the nasal cavity Respiratory pathogens, such as Pseudomonas aeruginosa and Burkholderia cenocepacia , have been demonstrated to trigger the disassembly of tight junctions between epithelial cells to migrate to the lower respiratory tract , , whereas N.

Indeed, damage to the olfactory epithelium within the nasal cavity appears to be an important and common event in bacterial spread to the CNS via the olfactory nerve , — Bacterial signaling molecules, such as acyl-homoserine lactones, are detected by solitary chemosensory cells within the nasal mucosa that synapse with the trigeminal nerve, triggering trigeminally mediated reflex reactions Mouse solitary chemosensory cells exposed to P.

Furthermore, in vivo studies demonstrated that mice exposed to acyl-homoserine lactones via the retronasal stream experienced significant reductions in respiratory rate, suggesting that interactions between bacterial acyl-homoserine lactones and chemosensory cells are capable of inducing responses indicative of nasal trigeminal irritants The activation of nasal solitary chemosensory cells by acyl-homoserine lactones triggers a proinflammatory response ; this response may damage the integrity of the epithelium and enable bacteria to access the trigeminal nerve endings.

Meningeal pathogens, such as S. Animal models of infection have also highlighted an alternative route of CNS entry, by which these bacteria may directly invade the olfactory bulb within the brain from the nasal mucosa.

The following section reviews the evidence for CNS invasion from the nasal cavity for these pathogens.

Early studies by Rake demonstrated that S. Remarkably, pneumococci were isolated from the olfactory bulbs of the brain at 1 min postinfection.

At this time point, bacteria were not isolated from the blood, effectively excluding a hematogenous route of CNS invasion.

At 2 min postinfection, pneumococci were observed between the sustentacular cells of the olfactory epithelium, within the perineural space of the olfactory nerve, and within the subarachnoid space Similar findings were reported by van Ginkel et al.

These sites remained colonized throughout the duration of the experiment, until day 39 postinfection; however, this did not lead to extensive brain infection.

In contrast, nonencapsulated pneumococci were unable to persist within the nasal cavity and olfactory epithelium and did not invade the olfactory bulb within the brain.

In these studies, intranasally delivered S. These mice also fail to respond to capsular polysaccharide; therefore, pneumococcal infection in this mouse strain is unlikely to accurately model human disease.

Phosphorylcholine residues on the pneumococcal cell wall have been shown to bind to gangliosides , suggesting that gangliosides may be an important target for S.

In vitro studies have also demonstrated that S. In a mouse model of intranasal N. At 3 days postinfection, lesions and polymorphonuclear cells were observed within the olfactory epithelium.

Immunofluorescence studies demonstrated N. Meningococci were also isolated from the CSF. Due to the absence of bacteremia, it was suggested that N.

In rhesus macaques, commensal neisseria bacteria RM Neisseria were shown to be transmitted between animals and naturally colonized the epithelium covering the cribriform plate , suggesting that migration of neisseria bacteria along the olfactory pathway is not a phenomenon that is observed only in animals experimentally inoculated with pathogenic N.

It has been hypothesized that these harsh environmental conditions may irritate the mucus membranes such as the olfactory mucosa and enable N.

These data suggest that N. The mechanisms by which N. The meninges and the subarachnoid space extend over the cribriform plate and further into the olfactory foramen, where the olfactory nerves pass through the cribriform plate , Bacteria traveling along the olfactory pathway may potentially invade the meninges after traversing the cribriform plate, and subsequently enter the CSF.

However, there is a positive pressure from the brain to the nasal lymphatics due to the drainage of CSF through the cribriform plate, and it is unknown how N.

The olfactory pathway has been identified as a route of CNS invasion by B. It was also shown that when colonization occurred in only one side of the nasal cavity, wild-type B.

Combined, these data suggest that B. However, it might be the case that an absence of capsule does diminish translocation via the olfactory or trigeminal nerves, since it is not possible to definitively compare with the presence of capsule, due to hematogenous spread in the latter case.

It may be noted that mice, like most mammals, are naturally susceptible to melioidosis. The mechanisms by which B. This neuronal loss led to the degeneration of olfactory axons within 24 to 48 h, and the axon-devoid, hollow olfactory nerve fascicles, surrounded by olfactory ensheathing cells, provided an open conduit for bacterial passage from the nasal cavity through the cribriform plate and into the nerve fiber layer of the olfactory bulb.

By migrating within the nerve sheath, B. This may also explain why B. During our initial studies in mice, we also demonstrated that B.

We have now confirmed that B. Although there is currently no direct evidence of B. Our unpublished data also demonstrate that following the inhalation of aerosolized B.

Second, for human cases of primary neurological melioidosis, Currie et al. In addition to our animal studies, these data provide evidence that B.

Furthermore, the trigeminal route of CNS invasion may explain the brain stem-related neurological presentations of melioidosis patients, without requiring frank encephalitis.

In ruminants naturally infected with L. Similar findings are observed in human cases of L. Of the cranial nerves, the trigeminal nerve pathway is thought to represent a primary route by which L.

It has been proposed that L. However, binding of L. In animals spontaneously infected and experimentally infected with L. In a mouse model of brain stem encephalitis, L.

Following this, bacteria were then observed within the brain stem but not in other regions of the brain. In vivo and in vitro studies have demonstrated that colony-stimulating factor 1-dependent cells including macrophages and dendritic cells facilitate the neuronal spread of L.

Following replication and escape from the phagosome in colony-stimulating factor 1-dependent cells, L.

Indeed, the presence of L. In vivo , herpesviruses demonstrate a tropism for the olfactory epithelium but not the respiratory epithelium , — Expression of the herpesvirus receptors heparan sulfate and nectin-1 on the apical side of the olfactory epithelium may facilitate binding to the neuroepithelium , In the respiratory epithelium, these receptors are either expressed on the basal side of the epithelium and are thus inaccessible or not highly expressed , Herpes simplex virus type 1 , bovine herpesvirus 5 , and equine herpesvirus 9 , spread from the nasal mucosa to the CNS via the olfactory nerves in animal models of infection.

In bovine herpesvirus 5 CNS invasion, the viral protein Us9 and the glycine-rich epitope region of glycoprotein E are required for transport from the olfactory sensory neurons to the olfactory bulb , In suckling hamsters, equine herpesvirus 9 antigen was detected within olfactory sensory neurons 12 h after intranasal infection At 48 h postinfection, viral antigen was detected within the olfactory nerve and olfactory bulb, and at 60 h postinfection, virus was observed within the frontal and temporal lobes of the cerebral cortex.

Some positive staining occurred within the trigeminal nerve, the trigeminal ganglia, and the region where the trigeminal sensory nerve root connects to the brain stem, although this was observed at the later time points, suggesting that the olfactory nerve is likely to be the primary route of infection Interestingly, Shivkumar et al.

In this model, the virus rarely reached the olfactory bulbs within the brain. However, in another study, herpes simplex virus type 1 was isolated from the olfactory bulbs and higher brain regions of mice 3 days after intranasal inoculation In a study of human autopsy material, Harberts et al.

In the same study, the prevalence of herpesvirus 6 within the nasal mucosa was determined in 3 cohorts of patients: Overall, herpesvirus 6 DNA was detected in These findings suggest that the nasal cavity may be a reservoir for herpesvirus 6 and that virus within the nasal cavity may travel to the olfactory bulbs and tract via the olfactory pathway Immunohistological evidence from fatal cases of herpes simplex encephalitis demonstrated that herpes simplex virus type 1 antigen was detected within the olfactory tract, the olfactory cortex, and regions of the limbic system that are connected by the olfactory pathway.

In contrast, viral antigen was not detected within the trigeminal pathway Combined, these studies suggest that the olfactory route of CNS entry is highly relevant in human cases of symptomatic and asymptomatic herpesvirus infections.

The role of the trigeminal nerve as a portal of entry for herpesviruses in humans is less clear, although the sensory neurons of the trigeminal ganglia are the principal site of herpes simplex virus type 1 latent infection in humans , In ferrets intranasally infected with different H5N1 strains, three-dimensional 3D imaging demonstrated that brain lesions were distributed i along the olfactory pathway, ii along the olfactory pathway and within the brain stem, or iii surrounding the brain vasculature These data suggest that there may be different routes of entry used by H5N1 strains; however, the olfactory pathway was identified as the most common route used by the small number of strains that were investigated The neurovirulence of influenza A virus subtypes may be influenced by the ability of the virus to disseminate from the olfactory bulb into other regions of the brain , which in turn may be controlled by the host immune response.

The infection was therefore restricted to the neuroepithelium and did not spread to the olfactory bulb. This suggested that apoptosis of olfactory sensory neurons might be a mechanism by which the host is protected from microbial invasion from the nasal cavity Influenza A virus also stimulates a host proinflammatory cytokine response within the olfactory bulb , which may also act to protect the host from further CNS invasion Autopsy of a severely immunocompromised month-old infant revealed influenza A virus antigen within the olfactory bulb, olfactory tract, and gyrus rectus, which is located inferolaterally to the olfactory bulb Viral antigen was not detected within any other regions of the CNS, the respiratory tract, or any other organs.

Viral RNA was also not detected within plasma, suggesting that viremia was not present. These findings provide evidence for influenza A virus entry into the CNS via the olfactory route in a severely immunocompromised infant Paramyxoviruses, including Nipah virus, Hendra virus, and parainfluenza virus, may enter the CNS directly from the nasal mucosa.

In vivo , the Sendai strain of parainfluenza virus infected mouse olfactory sensory neurons, but not sustentacular cells, and traveled to the glomeruli of the olfactory bulb , Infection of second-order neurons and virus spread to the rest of the brain did not occur , — The Sendai virus nucleoprotein gene was consistently detected within the olfactory bulb for up to days postinfection, indicating that persistence may occur within the olfactory bulb In hamsters, Nipah virus was detected in olfactory sensory neurons as they passed through the cribriform plate into the olfactory bulb, providing evidence of direct brain infection following intranasal infection Similar results were reported for a porcine model of Nipah virus infection, in which Nipah virus antigen was detected within a cross section of the olfactory nerve Temporal analysis demonstrated that Nipah virus entered the olfactory bulb within 4 days in mice , whereas the virus spread from the olfactory nerve to the granular cells of the olfactory bulb within 7 days in pigs The related Hendra virus was also shown to target the olfactory pathway and to invade the brain directly from the nasal cavity in the absence of viremia in a mouse model of encephalitis Thus, it is likely that Nipah virus exploits both the hematogenous and olfactory routes of invasion.

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Wholesales high quality with competive price pvc flooring malaysia. Remarkably, pneumococci were isolated from the olfactory bulbs of the brain at 1 min postinfection.

At this time point, bacteria were not isolated from the blood, effectively excluding a hematogenous route of CNS invasion. At 2 min postinfection, pneumococci were observed between the sustentacular cells of the olfactory epithelium, within the perineural space of the olfactory nerve, and within the subarachnoid space Similar findings were reported by van Ginkel et al.

These sites remained colonized throughout the duration of the experiment, until day 39 postinfection; however, this did not lead to extensive brain infection.

In contrast, nonencapsulated pneumococci were unable to persist within the nasal cavity and olfactory epithelium and did not invade the olfactory bulb within the brain.

In these studies, intranasally delivered S. These mice also fail to respond to capsular polysaccharide; therefore, pneumococcal infection in this mouse strain is unlikely to accurately model human disease.

Phosphorylcholine residues on the pneumococcal cell wall have been shown to bind to gangliosides , suggesting that gangliosides may be an important target for S.

In vitro studies have also demonstrated that S. In a mouse model of intranasal N. At 3 days postinfection, lesions and polymorphonuclear cells were observed within the olfactory epithelium.

Immunofluorescence studies demonstrated N. Meningococci were also isolated from the CSF. Due to the absence of bacteremia, it was suggested that N.

In rhesus macaques, commensal neisseria bacteria RM Neisseria were shown to be transmitted between animals and naturally colonized the epithelium covering the cribriform plate , suggesting that migration of neisseria bacteria along the olfactory pathway is not a phenomenon that is observed only in animals experimentally inoculated with pathogenic N.

It has been hypothesized that these harsh environmental conditions may irritate the mucus membranes such as the olfactory mucosa and enable N.

These data suggest that N. The mechanisms by which N. The meninges and the subarachnoid space extend over the cribriform plate and further into the olfactory foramen, where the olfactory nerves pass through the cribriform plate , Bacteria traveling along the olfactory pathway may potentially invade the meninges after traversing the cribriform plate, and subsequently enter the CSF.

However, there is a positive pressure from the brain to the nasal lymphatics due to the drainage of CSF through the cribriform plate, and it is unknown how N.

The olfactory pathway has been identified as a route of CNS invasion by B. It was also shown that when colonization occurred in only one side of the nasal cavity, wild-type B.

Combined, these data suggest that B. However, it might be the case that an absence of capsule does diminish translocation via the olfactory or trigeminal nerves, since it is not possible to definitively compare with the presence of capsule, due to hematogenous spread in the latter case.

It may be noted that mice, like most mammals, are naturally susceptible to melioidosis. The mechanisms by which B. This neuronal loss led to the degeneration of olfactory axons within 24 to 48 h, and the axon-devoid, hollow olfactory nerve fascicles, surrounded by olfactory ensheathing cells, provided an open conduit for bacterial passage from the nasal cavity through the cribriform plate and into the nerve fiber layer of the olfactory bulb.

By migrating within the nerve sheath, B. This may also explain why B. During our initial studies in mice, we also demonstrated that B.

We have now confirmed that B. Although there is currently no direct evidence of B. Our unpublished data also demonstrate that following the inhalation of aerosolized B.

Second, for human cases of primary neurological melioidosis, Currie et al. In addition to our animal studies, these data provide evidence that B.

Furthermore, the trigeminal route of CNS invasion may explain the brain stem-related neurological presentations of melioidosis patients, without requiring frank encephalitis.

In ruminants naturally infected with L. Similar findings are observed in human cases of L. Of the cranial nerves, the trigeminal nerve pathway is thought to represent a primary route by which L.

It has been proposed that L. However, binding of L. In animals spontaneously infected and experimentally infected with L. In a mouse model of brain stem encephalitis, L.

Following this, bacteria were then observed within the brain stem but not in other regions of the brain. In vivo and in vitro studies have demonstrated that colony-stimulating factor 1-dependent cells including macrophages and dendritic cells facilitate the neuronal spread of L.

Following replication and escape from the phagosome in colony-stimulating factor 1-dependent cells, L. Indeed, the presence of L. In vivo , herpesviruses demonstrate a tropism for the olfactory epithelium but not the respiratory epithelium , — Expression of the herpesvirus receptors heparan sulfate and nectin-1 on the apical side of the olfactory epithelium may facilitate binding to the neuroepithelium , In the respiratory epithelium, these receptors are either expressed on the basal side of the epithelium and are thus inaccessible or not highly expressed , Herpes simplex virus type 1 , bovine herpesvirus 5 , and equine herpesvirus 9 , spread from the nasal mucosa to the CNS via the olfactory nerves in animal models of infection.

In bovine herpesvirus 5 CNS invasion, the viral protein Us9 and the glycine-rich epitope region of glycoprotein E are required for transport from the olfactory sensory neurons to the olfactory bulb , In suckling hamsters, equine herpesvirus 9 antigen was detected within olfactory sensory neurons 12 h after intranasal infection At 48 h postinfection, viral antigen was detected within the olfactory nerve and olfactory bulb, and at 60 h postinfection, virus was observed within the frontal and temporal lobes of the cerebral cortex.

Some positive staining occurred within the trigeminal nerve, the trigeminal ganglia, and the region where the trigeminal sensory nerve root connects to the brain stem, although this was observed at the later time points, suggesting that the olfactory nerve is likely to be the primary route of infection Interestingly, Shivkumar et al.

In this model, the virus rarely reached the olfactory bulbs within the brain. However, in another study, herpes simplex virus type 1 was isolated from the olfactory bulbs and higher brain regions of mice 3 days after intranasal inoculation In a study of human autopsy material, Harberts et al.

In the same study, the prevalence of herpesvirus 6 within the nasal mucosa was determined in 3 cohorts of patients: Overall, herpesvirus 6 DNA was detected in These findings suggest that the nasal cavity may be a reservoir for herpesvirus 6 and that virus within the nasal cavity may travel to the olfactory bulbs and tract via the olfactory pathway Immunohistological evidence from fatal cases of herpes simplex encephalitis demonstrated that herpes simplex virus type 1 antigen was detected within the olfactory tract, the olfactory cortex, and regions of the limbic system that are connected by the olfactory pathway.

In contrast, viral antigen was not detected within the trigeminal pathway Combined, these studies suggest that the olfactory route of CNS entry is highly relevant in human cases of symptomatic and asymptomatic herpesvirus infections.

The role of the trigeminal nerve as a portal of entry for herpesviruses in humans is less clear, although the sensory neurons of the trigeminal ganglia are the principal site of herpes simplex virus type 1 latent infection in humans , In ferrets intranasally infected with different H5N1 strains, three-dimensional 3D imaging demonstrated that brain lesions were distributed i along the olfactory pathway, ii along the olfactory pathway and within the brain stem, or iii surrounding the brain vasculature These data suggest that there may be different routes of entry used by H5N1 strains; however, the olfactory pathway was identified as the most common route used by the small number of strains that were investigated The neurovirulence of influenza A virus subtypes may be influenced by the ability of the virus to disseminate from the olfactory bulb into other regions of the brain , which in turn may be controlled by the host immune response.

The infection was therefore restricted to the neuroepithelium and did not spread to the olfactory bulb. This suggested that apoptosis of olfactory sensory neurons might be a mechanism by which the host is protected from microbial invasion from the nasal cavity Influenza A virus also stimulates a host proinflammatory cytokine response within the olfactory bulb , which may also act to protect the host from further CNS invasion Autopsy of a severely immunocompromised month-old infant revealed influenza A virus antigen within the olfactory bulb, olfactory tract, and gyrus rectus, which is located inferolaterally to the olfactory bulb Viral antigen was not detected within any other regions of the CNS, the respiratory tract, or any other organs.

Viral RNA was also not detected within plasma, suggesting that viremia was not present. These findings provide evidence for influenza A virus entry into the CNS via the olfactory route in a severely immunocompromised infant Paramyxoviruses, including Nipah virus, Hendra virus, and parainfluenza virus, may enter the CNS directly from the nasal mucosa.

In vivo , the Sendai strain of parainfluenza virus infected mouse olfactory sensory neurons, but not sustentacular cells, and traveled to the glomeruli of the olfactory bulb , Infection of second-order neurons and virus spread to the rest of the brain did not occur , — The Sendai virus nucleoprotein gene was consistently detected within the olfactory bulb for up to days postinfection, indicating that persistence may occur within the olfactory bulb In hamsters, Nipah virus was detected in olfactory sensory neurons as they passed through the cribriform plate into the olfactory bulb, providing evidence of direct brain infection following intranasal infection Similar results were reported for a porcine model of Nipah virus infection, in which Nipah virus antigen was detected within a cross section of the olfactory nerve Temporal analysis demonstrated that Nipah virus entered the olfactory bulb within 4 days in mice , whereas the virus spread from the olfactory nerve to the granular cells of the olfactory bulb within 7 days in pigs The related Hendra virus was also shown to target the olfactory pathway and to invade the brain directly from the nasal cavity in the absence of viremia in a mouse model of encephalitis Thus, it is likely that Nipah virus exploits both the hematogenous and olfactory routes of invasion.

Eastern, western, and Venezuelan equine encephalitis viruses can cause encephalitis in horses and humans and are transmitted by mosquitoes or following aerosol exposure.

Using a bioluminescent western equine encephalitis virus, Phillips et al. The bioluminescent signal was initially detected in the nasal turbinates and olfactory bulb and was amplified in the basal nuclei, thalamus, and hypothalamus.

The distribution of lesions within the brain and the detection of viral antigen by immunohistochemistry supported the olfactory pathway as the route of infection and suggested that the trigeminal nerve may provide a secondary conduit to the brain Venezuelan equine encephalitis virus also targeted both the olfactory primary route and trigeminal secondary route nerve pathways for CNS entry , whereas eastern equine encephalitis virus appeared to infect only the olfactory nerve In CD-1 mice, ablation of the olfactory epithelium and the main olfactory bulb prevented invasion of Venezuelan equine encephalitis virus into the brain via the olfactory nerve; however, the virus was still able to spread to the CNS along the trigeminal nerve Interestingly, replication of Venezuelan equine encephalitis virus within the nasal mucosa induced the expression of proinflammatory cytokines, matrix metalloproteinase-9, and intracellular adhesion molecule 1 within the olfactory bulb, which led to subsequent breakdown of the BBB These events enabled circulating virus to penetrate the brain, suggesting that in addition to the olfactory and trigeminal routes of entry, Venezuelan equine encephalitis virus may also enter the CNS by a hematogenous route.

Among the members of the Rhabdoviridae family, rabies virus and vesicular stomatitis virus within the nasal cavity directly invade the olfactory bulbs within the brain.

In a fatal human case of airborne rabies encephalitis, rabies virions were observed only within the nerve fibers of the olfactory bulb, not in any other regions of the brain Data from animal studies have also demonstrated that intranasally delivered rabies virus selectively targets the olfactory epithelium and migrates to the olfactory bulb, including the glomeruli, mitral cells, and tufted cells Rabies virus antigen was also detected in the mouse trigeminal nerve.

The tropism of rabies virus to the olfactory epithelium may be due to the expression by olfactory sensory neurons of neural cell adhesion molecule , which was identified as a receptor for rabies virus in vitro Similar to rabies virus, intranasal vesicular stomatitis virus infected the olfactory epithelium, but not the respiratory epithelium, in a mouse model By 6 h postinfection, viral antigen was observed within the olfactory sensory neurons.

In contrast to the case with rabies virus, the trigeminal nerve was not implicated as a portal of CNS entry for vesicular stomatitis virus Naegleria fowleri is a free-living amoeba that causes primary amoebic meningoencephalitis, a rare but almost always fatal disease in humans.

Contaminated tap water used to reconstitute saline for nasal irrigation or for ablution of the nasal cavity has also been implicated as a source of infection , Pathological investigations of fatal human cases revealed hemolytic, necrotic encephalitis of the olfactory area, the contiguous forebrain, and the cerebellum , The suspected route of CNS entry was the olfactory route, due to the presence of amoebae and acute inflammation within the nasal mucosa and the olfactory nerve bundles , In murine models of the early stages of primary amoebic meningoencephalitis, intranasal N.

In vivo studies have shown that N. Despite this host response, by 12 h, N. In vitro , it was shown that both live trophozoites and crude total N.

A kDa cysteine protease of N. Penetration of the olfactory epithelium in mice occurred without cellular disruption or damage , and microscopy studies have shown that N.

A recent study demonstrated that N. Balamuthia mandrillaris , an opportunistic free-living amoeba that can cause granulomatous amoebic encephalitis, was also shown to enter the CNS directly from the nasal cavity after penetrating the olfactory epithelium and cribriform plate in immunodeficient mice following intranasal infection However, the implications of these findings in humans are unclear, as B.

The encapsulated yeast Cryptococcus neoformans is an important cause of fungal meningoencephalitis worldwide and can enter the CNS by penetrating the BBB by use of transcellular, paracellular, and Trojan horse mechanisms following blood-borne dissemination from the lungs as reviewed elsewhere [ ].

Although the hematogenous route of CNS entry is well accepted for cryptococcal meningoencephalitis, some strains of C. These findings prompted investigations into the possibility of an alternative direct route of CNS entry from the nose.

No cryptococci were located within the lamina propria or the olfactory epithelium, and thus the authors suggested that C. Using a guinea pig model, Lima and Vital provided further evidence that the olfactory route is unlikely to represent a portal of C.

In contrast, the fungal infection rhinocerebral mucormycosis has been demonstrated to spread to the brain via the trigeminal nerve.

Rhinocerebral mucormycosis refers to infections caused by fungi within the order Mucorales and usually affects individuals with poorly controlled diabetes mellitus or the immunocompromised.

These organisms display a predilection for the nasal cavity and paranasal sinuses; from these sites, the organisms typically invade blood vessel walls and then spread to the cavernous sinus, internal carotid artery, and brain , — However, fungal hyphae and lesions have been demonstrated within the trigeminal nerve and the pons within the brain stem in the absence of leptomeningitis, suggesting that direct invasion occurred from the sinuses to the brain along the trigeminal nerve , The perineural route of CNS entry was thought to be atypical; however, a study of the histologic features of patients with mucormycosis demonstrated that perineural invasion, characterized by fungal hyphae within the perineurium that surrounds the nerves, was a common feature that occurred concurrently with angioinvasion The mechanisms of rhinocerebral mucormycosis CNS infection have not been investigated.

A wide range of microbes can invade the CNS, and any organisms that can enter the CSF have the potential to cause meningitis. These nerves are well recognized as portals of entry for many viruses, as well as protozoa and fungi, and there is now evidence from animal models that some bacteria can infect the brain via the olfactory and trigeminal nerves.

The purpose of this review is to highlight these alternative routes of entry that have thus far received little attention and may explain some of the pathological features observed in human disease.

These routes of bacterial invasion require investigation in humans, especially in cases where the etiological agent is known to colonize the nasal mucosa.

In such cases, clinical assessment of olfactory function and the nasal mucosa should be considered. Furthermore, several questions remain unanswered.

We have demonstrated that B. It is unknown if similar mechanisms of transport are used by other bacterial pathogens, such as S. Second, which bacterial virulence factors are required for penetration of the olfactory epithelium and invasion of the brain via the olfactory and trigeminal nerves?

This review has highlighted the requirement for additional research to characterize the roles of the olfactory and trigeminal nerves in bacterial penetration of the brain and to determine the molecular and cellular mechanisms by which bacterial pathogens may exploit these pathways.

Dando received her Ph. She was subsequently appointed a Postdoctoral Research Fellow at the Institute for Glycomics, Griffith University, and undertook research to investigate the virulence of Burkholderia pseudomallei in a murine model of acute melioidosis.

She recently accepted a postdoctoral research position at Monash University, to research dendritic cell biology in the central nervous system during autoimmune disease.

Alan Mackay-Sim obtained his Ph. He is currently Professor of Neuroscience, Griffith University. With over 30 years of research in the field, Professor Mackay-Sim is a leading expert on the human sense of smell and the biology and development of the olfactory mucosa.

In the last 16 years, he has concentrated on the clinical applications of olfactory cells and their use for neural regeneration therapies, as well as the involvement of the olfactory nerve pathway in the development of disease.

Robert Norton graduated with a degree in medicine in and has worked in a variety of clinical positions, including 5 years in Australian indigenous communities.

He trained in microbiology at the Institute of Medical and Veterinary Science in Adelaide between and He gained an M. In his current capacity as Director of Microbiology at Townsville Hospital, Queensland, Australia, he has collaborated with researchers locally and nationally on projects relating to melioidosis, rheumatic fever, invasive group A streptococcal disease, and Q fever.

Norton is part of the Infectious Diseases and Immunopathogenesis Research Group, which includes clinicians and academic staff of James Cook University.

He has published over peer-reviewed publications and has been successful in obtaining local and national collaborative grants.

His areas of interest include clinical and epidemiological aspects of tropical and emerging infections, development of treatment guidelines, and clinical toxinology.

He initiated the Darwin Prospective Melioidosis Study in , and this remains the basis for ongoing multidisciplinary collaborations on melioidosis.

John obtained his Ph. He then held full-time research fellowships at the University of Melbourne and The University of Queensland.

Since obtaining his Ph. He performs detailed microscopic anatomical studies of the olfactory system and has identified subpopulations of olfactory glia by using live-cell imaging of in vitro cultures.

He is particularly interested in the role of olfactory glia in protecting the brain from bacterial infections.

Together with Jenny Ekberg, he recently performed the majority of the work which identified the intranasal route of infection via the olfactory nerve by Burkholderia pseudomallei.

Ekberg obtained her Ph. In , she moved to Griffith University as a Research Fellow and is now focusing on neuron-glia interactions and neural regeneration in the olfactory nervous system.

She continues her work on neural repair and has expanded into the field of bacterial infections of the central nervous system. Together with James St.

John and Ifor Beacham, she recently investigated how B. The focus of Dr. Michael Batzloff obtained his Ph. He has been the recipient of two fellowships from the National Heart Foundation of Australia for his research into vaccine development for Streptococcus pyogenes.

He was subsequently appointed the inaugural Head of the Bacterial Vaccines Laboratory at the Queensland Institute of Medical Research and recently accepted a position at the Institute for Glycomics at Griffith University.

His research interests include neglected tropical diseases, focusing on pathogenesis and vaccine development for the bacterial pathogens Streptococcus pyogenes and Burkholderia pseudomallei.

Ulett is an Associate Professor who received his Ph. He is currently an Australian Research Council ARC Future Fellow in Microbiology at Griffith University, where he leads a research team studying bacterial pathogenesis and the mechanisms of host defense against infection.

His laboratory focuses on infections related to the urogenital tract, programmed cell death, and mechanisms of virulence and disease associated with Escherichia coli , Streptococcus agalactiae , and Burkholderia pseudomallei.

He has been a microbiology researcher in the field of bacterial pathogenesis for 17 years and is a two-time recipient of the George McCracken Infectious Disease Fellow Award from the American Society for Microbiology.

His research program in microbiology and infectious diseases is supported by funding from the National Health and Medical Research Council of Australia.

Beacham undertook undergraduate studies in biochemistry at the University of Otago, New Zealand, and obtained his Ph. He worked in the general area of molecular microbiology on a variety of bacteria before undertaking work with Burkholderia pseudomallei 16 years ago.

The latter studies were motivated by the endemicity of melioidosis in northern Australia, difficulties with genetic manipulation, and the enigmatic status of B.

He hopes his continuing work will contribute to a greater understanding of the molecular nature of the virulence of B.

National Center for Biotechnology Information , U. Journal List Clin Microbiol Rev v. Author information Copyright and License information Disclaimer.

Address correspondence to Glen C. This article has been cited by other articles in PMC. Meningitis Meningitis, or inflammation of the meninges, is usually acute but can also be subacute and most frequently presents with headache, fever, and neck stiffness Encephalitis 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 Focal Infections The range of focal CNS infections includes brain abscesses, subdural empyema, and epidural abscesses.

Open in a separate window. Immunosurveillance of the CNS 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 , — TABLE 1 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 Transcellular penetration of brain microvascular endothelial cells, mainly via receptor-mediated mechanisms Fig.

Trojan Horse Penetration of Brain Microvascular Endothelial Cells Bacteria that are capable of surviving within host peripheral immune cells have the ability to invade the CNS via the Trojan horse route.

Protozoa Naegleria fowleri is a free-living amoeba that causes primary amoebic meningoencephalitis, a rare but almost always fatal disease in humans.

Yeasts and Fungi The encapsulated yeast Cryptococcus neoformans is an important cause of fungal meningoencephalitis worldwide and can enter the CNS by penetrating the BBB by use of transcellular, paracellular, and Trojan horse mechanisms following blood-borne dissemination from the lungs as reviewed elsewhere [ ].

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