TLR Signaling Is Required for Salmonella typhimurium Virulence

Arpaia, Nicholas; Godec, Jernej; Lau, Laura; Sivick, Kelsey E.; McLaughlin, Laura M.; Jones, Marcus B.; Dracheva, Tatiana; Peterson, Scott N.; Monack, Denise M.; Barton, Gregory M.

doi:10.1016/j.cell.2011.01.031

Cited by 222 publications

(230 citation statements)

References 77 publications

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“…4E and F). These data are consistent with observed increases in expression of TLRs in IFN-␥-pretreated, compared to resting, macrophages (32,39). Thus, macrophages may be more likely to hemophagocytose as acute infection develops and proinflammatory cytokines stimulate increased TLR expression.…”

Section: Figsupporting

confidence: 80%

Bacterial Stimulation of Toll-Like Receptor 4 Drives Macrophages To Hemophagocytose

et al. 2016

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During acute infection with bacteria, viruses or parasites, a fraction of macrophages engulf large numbers of red and white blood cells, a process called hemophagocytosis. Hemophagocytes persist into the chronic stage of infection and have an anti-inflammatory phenotype. Salmonella enterica serovar Typhimurium infection of immunocompetent mice results in acute followed by chronic infection, with the accumulation of hemophagocytes. The mechanism(s) that triggers a macrophage to become hemophagocytic is unknown, but it has been reported that the proinflammatory cytokine gamma interferon (IFN-␥) is responsible. We show that primary macrophages become hemophagocytic in the absence or presence of IFN-␥ upon infection with Gram-negative bacterial pathogens or prolonged exposure to heat-killed Salmonella enterica, the Gram-positive bacterium Bacillus subtilis, or Mycobacterium marinum. Moreover, conserved microbe-associated molecular patterns are sufficient to stimulate macrophages to hemophagocytose. Purified bacterial lipopolysaccharide (LPS) induced hemophagocytosis in resting and IFN-␥-pretreated macrophages, whereas lipoteichoic acid and synthetic unmethylated deoxycytidine-deoxyguanosine dinucleotides, which mimic bacterial DNA, induced hemophagocytosis only in IFN-␥-pretreated macrophages. Chemical inhibition or genetic deletion of Toll-like receptor 4, a pattern recognition receptor responsive to LPS, prevented both Salmonella-and LPS-stimulated hemophagocytosis. Inhibition of NF-B also prevented hemophagocytosis. These results indicate that recognition of microbial products by Toll-like receptors stimulates hemophagocytosis, a novel outcome of prolonged Toll-like receptor signaling, suggesting hemophagocytosis is a highly conserved innate immune response.

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Section: Figsupporting

confidence: 80%

Bacterial Stimulation of Toll-Like Receptor 4 Drives Macrophages To Hemophagocytose

et al. 2016

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“…Several host factors, such as reactive oxygen species (ROS), reactive nitrogen species (RNS), and phagosomal acidification and maturation, have been implicated in the regulation of microbial virulence genes within host macrophages. Using pharmacological inhibitors to block each of these signals, we analyzed the effects on intracellular T4519 expression (24). Cycloheximide (CHX) failed to prevent T4519 induction, indicating that the host signals to which S. Typhi responded were generated independently of new protein synthesis.…”

Section: Resultsmentioning

confidence: 99%

An Inducible and Secreted Eukaryote-Like Serine/Threonine Kinase of Salmonella enterica Serovar Typhi Promotes Intracellular Survival and Pathogenesis

Theeya

Das

et al. 2015

Infect Immun

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e Eukaryote-like serine/threonine kinases (eSTKs) constitute an important family of bacterial virulence factors. Genome analysis had predicted putative eSTKs in Salmonella enterica serovar Typhi, although their functional characterization and the elucidation of their role in pathogenesis are still awaited. We show here that the primary sequence and secondary structure of the t4519 locus of Salmonella Typhi Ty2 have all the signatures of eukaryotic superfamily kinases. t4519 encodes a ϳ39-kDa protein (T4519), which shows serine/threonine kinase activities in vitro. Recombinant T4519 (rT4519) is autophosphorylated and phosphorylates the universal substrate myelin basic protein. Infection of macrophages results in decreased viability of the mutant (Ty2⌬t4519) strain, which is reversed by gene complementation. Moreover, reactive oxygen species produced by the macrophages signal to the bacteria to induce T4519, which is translocated to the host cell cytoplasm. That T4519 may target a host substrate(s) is further supported by the activation of host cellular signaling pathways and the induction of cytokines/chemokines. Finally, the role of T4519 in the pathogenesis of Salmonella Typhi is underscored by the significantly decreased mortality of mice infected with the Ty2⌬t4519 strain and the fact that the competitive index of this strain for causing systemic infection is 0.25% that of the wild-type strain. This study characterizes the first eSTK of Salmonella Typhi and demonstrates its role in promoting phagosomal survival of the bacteria within macrophages, which is a key determinant of pathogenesis. This, to the best of our knowledge, is the first study to describe the essential role of eSTKs in the in vivo pathogenesis of Salmonella spp.

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“…It is known that macrophage SCVs are more acidic in nature than epithelial SCVs (Hautefort et al, 2008). For instance, TLR2-, 4-and 9-mediated acidification of phagosomes is required for SPI-2 induction in S. Typhimurium (Arpaia et al, 2011). Interestingly, epithelial cells transfected with both human TLR2 and 4 partially rescued the intracellular proliferation of the mutant (Fig.…”

Section: Discussionmentioning

confidence: 97%

“…Recently, Denise Monack's group has revealed the importance of TLR signalling in recognition of intracellular S. Typhimurium (Arpaia et al, 2011). They have shown that the presence of TLR2, 4 and 9 in mouse BMDMs is necessary for the establishment of an acidic phagosomal compartment and induction of SPI-2 genes in Salmonella.…”

Section: Ipmentioning

confidence: 99%

Salmonella methylglyoxal detoxification by STM3117-encoded lactoylglutathione lyase affects virulence in coordination with Salmonella pathogenicity island 2 and phagosomal acidification

et al. 2014

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Intracellular pathogens such as Salmonella enterica serovar Typhimurium (S. Typhimurium) manipulate their host cells through the interplay of various virulence factors. A multitude of such virulence factors are encoded on the genome of S. Typhimurium and are usually organized in pathogenicity islands. The virulence-associated genomic stretch of STM3117–3120 has structural features of pathogenicity islands and is present exclusively in non-typhoidal serovars of Salmonella. It encodes metabolic enzymes predicted to be involved in methylglyoxal metabolism. STM3117-encoded lactoylglutathione lyase significantly impacts the proliferation of intracellular Salmonella. The deletion mutant of STM3117 (Δlgl) fails to grow in epithelial cells but hyper-replicates in macrophages. This difference in proliferation outcome was the consequence of failure to detoxify methylglyoxal by Δlgl, which was also reflected in the form of oxidative DNA damage and upregulation of kefB in the mutant. Within macrophages, the toxicity of methylglyoxal adducts elicits the potassium efflux channel (KefB) in the mutant which subsequently modulates the acidification of mutant-containing vacuoles (MCVs). The perturbation in the pH of the MCV milieu and bacterial cytosol enhances the Salmonella pathogenicity island 2 translocation in Δlgl, increasing its net growth within macrophages. In epithelial cells, however, the maturation of Δlgl-containing vacuoles were affected as these non-phagocytic cells maintain less acidic vacuoles compared to those in macrophages. Remarkably, ectopic expression of Toll-like receptors 2 and 4 on epithelial cells partially restored the survival of Δlgl. This study identified a novel metabolic enzyme in S. Typhimurium whose activity during intracellular infection within a given host cell type differentially affected the virulence of the bacteria.

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TLR Signaling Is Required for Salmonella typhimurium Virulence

Cited by 222 publications

References 77 publications

Bacterial Stimulation of Toll-Like Receptor 4 Drives Macrophages To Hemophagocytose

Bacterial Stimulation of Toll-Like Receptor 4 Drives Macrophages To Hemophagocytose

An Inducible and Secreted Eukaryote-Like Serine/Threonine Kinase of Salmonella enterica Serovar Typhi Promotes Intracellular Survival and Pathogenesis

Salmonella methylglyoxal detoxification by STM3117-encoded lactoylglutathione lyase affects virulence in coordination with Salmonella pathogenicity island 2 and phagosomal acidification

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