Nature︱On bacterial self-cultivation: a new mechanism to promote neuroinvasion and survival persistence

By | Sister Xian Central nervous system infections are among the most serious infections, yet little is known about the mechanisms by which pathogens enter the brain
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Listeria monocytogenes (Lm) is one such gram-positive, facultative anaerobic, intracellular food-borne pathogen with a special affinity for the central nervous system, which can cause neurological listeriosis, It is manifested as meningitis, encephalitis or brainstem encephalitis, and very few patients may be accompanied by intracranial hemorrhage and brain abscess.
The disease progresses rapidly, is critically ill, and has a high mortality rate.
It is one of the most deadly infections of the central nervous system
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Although immunosuppression is currently recognized as a major host risk factor for neurological listeriosis, the bacterial factors that promote Lm neuroinvasion and their mechanisms of action remain unknown [1,2]
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Recently, the team of Marc Lecuit from the University of Paris, France, published an article online in Nature entitled Bacterial inhibition of Fas-mediated killing promotes neuroinvasion and persistence.
Using the inoculation of a highly virulent neuroinvasion strain in a humanized infection mouse model, the first constructed A clinically relevant experimental model of neurological listeriosis has been developed
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At the same time, the model revealed a specific mechanism by which bacterial pathogens can make their infected cells resistant to cell-mediated immunity, thereby prolonging the lifespan of their infected cells, which in turn promotes Lm in the host.
Persistence and spread to the central nervous system
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The researchers first orally inoculated Lm into humanized KIE16P mice (the mice were receptive to oral-acquired Listeria).
After 3 days of inoculation, compared with the control strains, they belonged to the highly virulent clonal complexes CC1 and CC4.
and CC6 clinical isolates can systemically induce high levels of neuroinvasion, and the bacterial load in the brain is the same whether or not gentamicin (which kills extracellular but not intracellular Lm) is administered, suggesting that cellular The inner Lm was involved in neural invasion, and infected monocytes were shown to be a necessary and sufficient condition for Lm neural invasion
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Further experiments showed that Lm enters the brain parenchyma from adherent blood-borne infected inflammatory monocytes primarily through actin assembly-inducing protein (ActA)-mediated intercellular diffusion (Figure 1)
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Figure 1 Schematic representation of the neuroinvasion process of Lm After establishing that infected mononuclear cells are closely related to the pathogenesis of neurological listeriosis, researchers set out to search for factors that mediate neuroinvasion in Lm
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The findings suggest that overexpression of InlB (part of the Lm core genome) is critical for the neuroinvasiveness of Lm, whereas InlB significantly increases the number of Lm-infected inflammatory monocytes in the blood and spleen, but InlB did not increase the number of bacteria per infected monocyte, nor did it affect the ability of monocytes to adhere to cerebral blood vessels
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Further experiments showed that the contribution of InlB to neural invasion required the presence of functional lymphocytes and was dependent on T lymphocytes rather than B lymphocytes
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Although neuroinvasion of Lm is increased in the absence of functional CD8+ T cells, it becomes InlB-independent, as InlB protects specifically infected monocytes from anti-Lm-specific killing by CD8+ T cells
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The cytotoxicity of CD8+ T cells is dependent on the perforin-granzyme and Fas ligand (FasL)-Fas pathways
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We found that the protective effect of InlB-mediated CD8+ T cell killing of infected monocytes was fully preserved in perforin-deficient mice, but the inhibitory effect of InlB on infected monocyte death was less pronounced in Fas-deficient mice.
was completely eliminated, thus indicating that InlB blocks Fas-mediated killing, but has no effect on the perforin pathway
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In-depth experiments showed that InlB blocked Fas-mediated killing of infected monocytes by CD8+ T cells, extending their lifespan and giving them the necessary time to adhere to brain blood vessels and put their cells inside the cells.
Lm metastases to the brain parenchyma
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In contrast, blockade of the InlB-mediated Fas cell death pathway in infected monocytes was caused by InlB, c-Met, and PI3Kα-dependent cell-autonomous upregulation of the caspase-8 inhibitor FLIP, resulting in prolonged infection in infected monocytes.
The half-life of Lm promotes neuroinvasion, and this mechanism also promotes Lm persistence in the host and release in excreta (Fig.
2)
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Figure 2.
In1B-mediated blockade of CD8+ T cell-mediated cell death results in neuroinvasion and intestinal persistence Killing is resistant, and selective blocking of the Fas-FasL death pathway in infected monocytes allows these cells to survive longer in the blood and transfer more Lm to the brain
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Notably, this unexpected mechanism of creating an intracellular protected niche for Lm also involves its persistence in gut tissue and its release in feces and ultimately in the environment, which undoubtedly increases neuroinvasion.
The opportunity for sexual Lm to be passed back into the environment and to colonize a new host
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Original link: https://doi.
org/10.
1038/s41586-022-04505-7 Publisher: Eleven References 1.
Arslan F, Meynet E, Sunbul M, et a.
The clinical features, diagnosis, treatment, and prognosis of neuroinvasive listeriosis: A multinational study[J] Eur J Clin Micmbiol Infect Dis,2015,34(6):1213—1221.
2.
Charlier, C.
et al.
Clinical features and prognostic factors of listeriosis: the MONALISA national prospective cohort study .
Lancet Infect.
Dis.
17, 510–519 (2017).
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