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Nitric oxide increases susceptibility of Toll-like receptor-activated macrophages to spreading Listeria monocytogenes.

ABSTRACT: Toll-like receptor (TLR) stimulation activates macrophages to resist intracellular pathogens. Yet, the intracellular bacterium Listeria monocytogenes (Lm) causes lethal infections in spite of innate immune cell activation. Lm uses direct cell-cell spread to disseminate within its host. Here, we have shown that TLR-activated macrophages killed cell-free Lm but failed to prevent infection by spreading Lm. Instead, TLR signals increased the efficiency of Lm spread from "donor" to "recipient" macrophages. This enhancement required nitric oxide (NO) production by nitric oxide synthase-2 (NOS2). NO increased Lm escape from secondary vacuoles in recipient cells and delayed maturation of phagosomes containing membrane-like particles that mimic Lm-containing pseudopods. NO also promoted Lm spread during systemic in vivo infection, as shown by the fact that inhibition of NOS2 with 1400W reduced spread-dependent Lm burdens in mouse livers. These findings reveal a mechanism by which pathogens capable of cell-cell spread can avoid the consequences of innate immune cell activation by TLR stimuli.

SUBMITTER: Cole C

PROVIDER: S-EPMC3361567 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Nitric oxide increases susceptibility of Toll-like receptor-activated macrophages to spreading Listeria monocytogenes.

Cole Caroline C Thomas Stacey S Filak Holly H Henson Peter M PM Lenz Laurel L LL

Immunity 20120426 5

Toll-like receptor (TLR) stimulation activates macrophages to resist intracellular pathogens. Yet, the intracellular bacterium Listeria monocytogenes (Lm) causes lethal infections in spite of innate immune cell activation. Lm uses direct cell-cell spread to disseminate within its host. Here, we have shown that TLR-activated macrophages killed cell-free Lm but failed to prevent infection by spreading Lm. Instead, TLR signals increased the efficiency of Lm spread from "donor" to "recipient" macrop ...[more]

PMID: 22542147

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Project description:BackgroundA westernized diet comprising a high caloric intake from animal fats is known to influence the development of pathological inflammatory conditions. However, there has been relatively little focus upon the implications of such diets for the progression of infectious disease. Here, we investigated the influence of a high-fat (HF) diet upon parameters that influence Listeria monocytogenes infection in mice.ResultsWe determined that short-term administration of a HF diet increases the number of goblet cells, a known binding site for the pathogen, in the gut and also induces profound changes to the microbiota and promotes a pro-inflammatory gene expression profile in the host. Host physiological changes were concordant with significantly increased susceptibility to oral L. monocytogenes infection in mice fed a HF diet relative to low fat (LF)- or chow-fed animals. Prior to Listeria infection, short-term consumption of HF diet elevated levels of Firmicutes including Coprococcus, Butyricicoccus, Turicibacter and Clostridium XIVa species. During active infection with L. monocytogenes, microbiota changes were further exaggerated but host inflammatory responses were significantly downregulated relative to Listeria-infected LF- or chow-fed groups, suggestive of a profound tempering of the host response influenced by infection in the context of a HF diet. The effects of diet were seen beyond the gut, as a HF diet also increased the sensitivity of mice to systemic infection and altered gene expression profiles in the liver.ConclusionsWe adopted a systems approach to identify the effects of HF diet upon L. monocytogenes infection through analysis of host responses and microbiota changes (both pre- and post-infection). Overall, the results indicate that short-term consumption of a westernized diet has the capacity to significantly alter host susceptibility to L. monocytogenes infection concomitant with changes to the host physiological landscape. The findings suggest that diet should be a consideration when developing models that reflect human infectious disease.

Project description:In Listeria monocytogenes the acid tolerance response (ATR) takes place through a programmed molecular response which ensures cell survival under unfavorable conditions. Much evidence links ATR with virulence, but the molecular determinants involved in the reactivity to low pHs and the behavior of acid-exposed bacteria within host cells are still poorly understood. We have investigated the effect of acid adaptation on the fate of L. monocytogenes in human macrophages. Expression of genes encoding determinants for cell invasion and intracellular survival was tested for acid-exposed bacteria, and invasive behavior in the human myelomonocytic cell line THP-1 activated with gamma interferon was assessed. Functional approaches demonstrated that preexposure to an acidic pH enhances the survival of L. monocytogenes in activated human macrophages and that this effect is associated with an altered pattern of expression of genes involved in acid resistance and cell invasion. Significantly decreased transcription of the plcA gene, encoding a phospholipase C involved in vacuolar escape and cell-to-cell spread, was observed in acid-adapted bacteria. This effect was due to a reduction in the quantity of the bicistronic plcA-prfA transcript, concomitant with an increase in the level(s) of the monocistronic prfA mRNA(s). The transcriptional shift from distal to proximal prfA promoters resulted in equal levels of the prfA transcript (and, as a consequence, of the inlA, hly, and actA transcripts) under neutral and acidic conditions. In contrast, the sodC and gad genes, encoding a cytoplasmic superoxide dismutase and the glutamate-based acid resistance system, respectively, were positively regulated at a low pH. Morphological approaches confirmed the increased intracellular survival and growth of acid-adapted L. monocytogenes cells both in vacuoles and in the cytoplasm of interferon gamma-activated THP-1 macrophages. Our data indicate that preexposure to a low pH has a positive impact on subsequent challenge of L. monocytogenes with macrophagic cells.

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Nitric oxide increases susceptibility of Toll-like receptor-activated macrophages to spreading Listeria monocytogenes.

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Nitric oxide increases susceptibility of Toll-like receptor-activated macrophages to spreading Listeria monocytogenes.

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