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Tim-3 inhibits macrophage control of Listeria monocytogenes by inhibiting Nrf2.

ABSTRACT: T cell immunoglobulin mucin-3 (Tim-3) is an immune checkpoint inhibitor and its dysregulation has been related to T cell tolerance and many immune disorders, such as tumors and infection tolerance. However, the physiopathology roles of Tim-3 in innate immunity remain elusive. Here, we demonstrate that Tim-3 inhibits macrophage phagocytosis of L. monocytogenes by inhibiting the nuclear erythroid 2-related factor 2 (Nrf2) signaling pathway and increases bacterial burden. Tim-3 signaling promotes Nrf2 degradation by increasing its ubiquitination and, as a result, decreasing its nuclear translocation. CD36 and heme oxygenase-1 (HO-1), two downstream molecules in the Tim-3-Nrf2 signaling axis, are involved in the Tim-3- mediated immune evasion of L. monocytogenes both in vitro and in vivo. We here identified new mechanisms by which Tim-3 induces infection tolerance. By modulating the Tim-3 pathway, we demonstrate the feasibility of manipulating macrophage function as a potent tool for treating infectious diseases, such as Listeria infection.

SUBMITTER: Wang Z

PROVIDER: S-EPMC5311873 | biostudies-other | 2017 Feb

REPOSITORIES: biostudies-other

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Tim-3 inhibits macrophage control of Listeria monocytogenes by inhibiting Nrf2.

Wang Zhiding Z Sun Dejun D Chen Guojiang G Li Ge G Dou Shuaijie S Wang Renxi R Xiao He H Hou Chunmei C Li Yan Y Feng Jiannan J Shen Beifen B Han Gencheng G

Scientific reports 20170216

T cell immunoglobulin mucin-3 (Tim-3) is an immune checkpoint inhibitor and its dysregulation has been related to T cell tolerance and many immune disorders, such as tumors and infection tolerance. However, the physiopathology roles of Tim-3 in innate immunity remain elusive. Here, we demonstrate that Tim-3 inhibits macrophage phagocytosis of L. monocytogenes by inhibiting the nuclear erythroid 2-related factor 2 (Nrf2) signaling pathway and increases bacterial burden. Tim-3 signaling promotes N ...[more]

PMID: 28205579

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Project description:Listeria monocytogenes is a foodborne pathogen that causes high rates of hospitalization and mortality in people infected. Contamination of fresh, ready to eat produce by this pathogen is especially troubling because of the ability of this bacterium to grow on produce under refrigeration temperatures. In this study, we created a library of over 8,000 plant phyllosphere-associated bacteria and screened them for the ability to inhibit the growth of L. monocytogenes in an in vitro fluorescence-based assay. One isolate, later identified as Bacillus amyloliquefaciens ALB65, was able to inhibit the fluorescence of L. monocytogenes by >30-fold in vitro. B. amyloliquefaciens ALB65 was also able to grow, persist, and reduce the growth of L. monocytogenes by >1.5 log CFU on cantaloupe melon rinds inoculated with 5 × 103 CFU at 30°C and was able to completely inhibit its growth at temperatures below 8°C. DNA sequence analysis of the B. amyloliquefaciens ALB65 genome revealed six gene clusters that are predicted to encode genes for antibiotic production; however, no plant or human virulence factors were identified. These data suggest that B. amyloliquefaciens ALB65 is an effective and safe biological control agent for the reduction of L. monocytogenes growth on intact cantaloupe melons and possibly other types of produce.IMPORTANCEListeria monocytogenes is estimated by the Centers for Disease Control and Prevention and the U.S. Food and Drug Administration to cause disease in approximately 1,600 to 2,500 people in the United States every year. The largest known outbreak of listeriosis in the United States was associated with intact cantaloupe melons in 2011, resulting in 147 hospitalizations and 33 deaths. In this study, we demonstrated that Bacillus amyloliquefaciens ALB65 is an effective biological control agent for the reduction of L. monocytogenes growth on intact cantaloupe melons under both pre- and postharvest conditions. Furthermore, we demonstrated that B. amyloliquefaciens ALB65 can completely inhibit the growth of L. monocytogenes during cold storage (<8°C).

Dataset Information

Tim-3 inhibits macrophage control of Listeria monocytogenes by inhibiting Nrf2.

Publications

Tim-3 inhibits macrophage control of Listeria monocytogenes by inhibiting Nrf2.

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