Axonal transport ofListeria monocytogenes and nerve-cell-induced bacterial killing (original) (raw)
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Targeting of the central nervous system by Listeria monocytogenes
Virulence
Among bacteria that reach the central nervous system (CNS), Listeria monocytogenes (Lm) is one of deadliest, in human and ruminant. This facultative intracellular bacterium has the particularity to induce meningitis, meningoencephalitis and rhombencephalitis. Mechanisms by which Lm accesses the CNS remain poorly understood, but two major routes of infection have been proposed, based on clinical, in vitro and in vivo observations. A retrograde neural route is likely to occur in ruminants upon crossing of the oral epithelium, and this probably accounts for the observation that Lm induces almost exclusively rhombencephalitis in these animals. In contrast, the hematogenous route is likely the most frequent in human, in whom bacteria circulating in the blood, either free or associated with leukocytes are thought to breach the blood-brain barrier. New animal models that faithfully reproduce the hallmarks of human neurolisterisosis will allow addressing the molecular mechanisms underlying ...
Bacteremia is required for invasion of the murine central nervous system by Listeria monocytogenes
Microbial Pathogenesis, 1995
Bacteremia is required for invasion of the murine central nervous system by Listeria monocytogenes. Microbial Pathogenesis 1995; 18: 323-336. The ability of the facultative intracellular pathogen Listeria monocytogenes to penetrate the central nervous system (CNS) was studied by following the kinetics of brain invasion and histological lesions during an acute intravenous (i.v.) infection in the mouse. CNS invasion occurred during the early phase of infection and produced severe meningoencephalitis characterized by multiple granulomatous foci predominantly located in the brainstem and associated with diffuse meningitis and an intense inflammatory reaction involving the choroid plexuses. Bacterial counts in the brain could reach 10 4.5-10 5.8 by day 5 of infection with 1-2×10 6 bacteria i.v., depending upon the bacterial strain used. It was found that CNS invasion was highly dependent upon the level and the duration of bacteremia, thus indicating that persistent bacteremia is essential to induce meningoencephalitis to L. monocytogenes.
Infection and Immunity, 2001
The pathologic features of cerebral Listeria monocytogenes infection strongly suggest that besides hematogenous spread, bacteria might also spread via a neural route. We propose that after snout infection of recombination activating gene 1 (RAG-1)-deficient mice, L. monocytogenesspreads to the brain via a neural route. The neural route of invasion is suggested by (i) the immunostaining of L. monocytogenesin the trigeminal ganglia (TG) and brain stem but not in other areas of the brain; (ii) the kinetics of bacterial loads in snout, TG, and brain; and (iii) the increased resistance of mice infected with aplcB bacterial mutant (unable to spread from cell to cell). Gamma interferon (IFN-γ) plays a protective role in neuroinvasion; inducible nitric oxide synthase (iNOS) accounts only partially for the protection, as shown by a comparison of the susceptibilities of IFN-γ receptor (IFN-γR)-deficient, iNOS-deficient, and wild-type mice to snout infection with L. monocytogenes. The dramatic...
Rat dorsal root ganglia neurons as a model for Listeria monocytogenes infections in culture
Medical Microbiology and Immunology, 1999
Neurotropism of Listeria monocytogenes was studied in rat dorsal root ganglia (DRG) and hippocampal neurons in culture. Using a system in which the DRG neurons can grow relatively free from other cells, it was observed that such DRG neurons, in contrast to hippocampal neurons, can be eectively infected by L. monocytogenes. The bacteria aligned along DRG axons, but not along hippocampal neurites. A mutant de®cient in internalin, a protein required for entry into E-cadherin-expressing cells, did not interact with DRG neurons. Axonal migration of bacteria was studied in the DRG neurons grown in a double-chamber system, where either the neurites or the nerve cell bodies were exposed to the bacteria. The data suggest that L. monocytogenes can infect both axons and DRG nerve cell bodies, and that the bacteria can migrate in a retrograde as well as anterograde direction. These results support the notion that L. monocytogenes can spread via primary sensory neurons to the central nervous system. Infection of DRG primary sensory neurons, as employed in the present study, provides a model for analysis of bacterial and neuronal factors of importance for neurovirulence of L. monocytogenes.
The Journal of Immunology, 2004
Mononuclear phagocytes can be used by intracellular pathogens to disseminate throughout the host. In the bloodstream these cells are generically referred to as monocytes. However, blood monocytes are a heterogeneous population, and the exact identity of the leukocyte(s) relevant for microbial spreading is not known. Experiments reported in this study used Listeria monocytogenesinfected mice to establish the phenotype of parasitized blood leukocytes and to test their role in systemic dissemination of intracellular bacteria. More than 90% of the blood leukocytes that were associated with bacteria were CD11b ؉ mononuclear cells. Analysis of newly described monocyte subsets showed that most infected cells belonged to the Ly-6C high monocyte subset and that Ly-6C high and Ly-6C neg-low monocytes harbored similar numbers of bacteria per cell. Interestingly, systemic infection with wildtype or ⌬actA mutants of L. monocytogenes, both of which escape from phagosomes and replicate intracellularly, caused expansion of the Ly-6C high subset. In contrast, this was not evident after infection with ⌬hly mutants, which neither escape phagosomes nor replicate intracellularly. Importantly, when CD11b ؉ leukocytes were isolated from the brains of lethally infected mice, 88% of these cells were identified as Ly-6C high monocytes. Kinetic analysis showed a significant influx of Ly-6C high monocytes into the brain 2 days after systemic infection. This coincided with both bacterial invasion and up-regulation of brain macrophage chemoattractant protein-1 gene expression. These data indicate that the Ly-6C high monocyte subset transports L. monocytogenes into the brain and establish their role as Trojan horses in vivo.
mSphere, 2020
Progress in understanding the two naturally occurring central nervous system (CNS) manifestations of listeriosis (meningitis/meningoencephalitis and rhombencephalitis) has been limited by the lack of small animal models that can readily distinguish between these distinct infections. We report here that certain neurotropic strains of Listeria monocytogenes can spread to the brains of young otherwise healthy mice and cause neurological deficits without causing a fatal bacteremia. The novel strains described here fall within phylogenetic lineage III, a small collection of L. monocytogenes isolates that have not been well characterized to date. The animal model reported here mimics many features of human rhombencephalitis and will be useful for studying the mechanisms that allow L. monocytogenes to disseminate to the brain stem following natural foodborne transmission.
Neuropathogenesis of Naturally Occurring Encephalitis Caused by Listeria monocytogenes in Ruminants
Brain Pathology, 2010
Listeriosis is a serious food-borne disease with increasing frequency in humans and ruminants. Despite the facts that in both hosts, listeriosis can occur as rhombencephalitis and ruminants are a reservoir of Listeria monocytogenes (LM) strains pathogenic for humans, little work has been done on the pathogenesis in ruminants. This study investigates the neuropathogenesis of listeric encephalitis in over 200 natural cases in cattle, sheep and goats by analyzing anatomical distribution, severity, bacterial load and temporal evolution of the lesions. Our results suggest that LM gains access to the brainstem of all three species via axonal migration not only along the trigeminal nerve, but also along other nerves. The ensuing encephalitis does not remain restricted to the brainstem. Rather, LM spreads further from the brainstem into rostral brain regions likely by intracerebral axonal migration. Significant differences in severity of the lesions and bacterial load were found between cattle and small ruminants, which may be caused by species-specific properties of antibacterial immune responses. As histopathological lesions of human rhombencephalitis caused by LM strongly resemble those of ruminants, the disease likely has a similar pathogenesis in both hosts.
Infection and Immunity
Invasion of endothelial tissues may be crucial in a Listeria monocytogenes infection leading to meningitis and/or encephalitis. Internalization of L. monocytogenes into endothelial cells has been previously demonstrated by using human umbilical vein endothelial cells as a model system. However, during the crossing of the blood-brain barrier, L. monocytogenes most likely encounters brain microvascular endothelial cells which are strikingly different from macrovascular or umbilical vein endothelial cells. In the present study human brain microvascular endothelial cells (HBMEC) were used to study the interaction of L. monocytogenes with endothelial cells, which closely resemble native microvascular endothelial cells of the brain. We show that L. monocytogenes invades HBMEC in an InlB-dependent and wortmannin-insensitive manner. Once within the HBMEC, L. monocytogenes replicates efficiently over a period of at least 18 h, moves intracellularly by inducing actin tail formation, and sprea...
Infection and Immunity, 2000
Invasion of endothelial tissues may be crucial in a Listeria monocytogenes infection leading to meningitis and/or encephalitis. Internalization of L. monocytogenes into endothelial cells has been previously demonstrated by using human umbilical vein endothelial cells as a model system. However, during the crossing of the blood-brain barrier, L. monocytogenes most likely encounters brain microvascular endothelial cells which are strikingly different from macrovascular or umbilical vein endothelial cells. In the present study human brain microvascular endothelial cells (HBMEC) were used to study the interaction of L. monocytogenes with endothelial cells, which closely resemble native microvascular endothelial cells of the brain. We show that L. monocytogenes invades HBMEC in an InlB-dependent and wortmannin-insensitive manner. Once within the HBMEC, L. monocytogenes replicates efficiently over a period of at least 18 h, moves intracellularly by inducing actin tail formation, and spreads from cell to cell. Using a green fluorescent protein-expressing L. monocytogenes strain, we present direct evidence that HBMEC are highly resistant to damage by intracellularly growing L. monocytogenes. Infection of HBMEC with L. monocytogenes results in foci of heavily infected, but largely undamaged endothelial cells. Heterologous plaque assays with L. monocytogenes-infected P388D 1 macrophages as vectors demonstrate efficient spreading of L. monocytogenes into HBMEC, fibroblasts, hepatocytes, and epithelial cells, and this phenomenon is independent of the inlC gene product.