Metallothionein differentially affects the host response to Listeria infection both with and without an additional stress from cold-restraint

Abstract

Acute stress alters anti-bacterial defenses, but the neuroimmunological mechanisms underlying this association are not yet well understood. Metallothionein (MT), a cysteinerich protein, is a stress response protein that is induced by a variety of chemical, biological, and psychological stressors, and MT has been shown to influence immune activities. We investigated MT's role in the management of anti-bacterial responses that occur during stress, using a C57BL/6 (B6) strain that has targeted disruptions of the Mt1 and Mt2 genes (B6-MTKO), and a B6 strain that has additional copies of Mt (B6-MTTGN). The well-characterized listeriosis model was used to examine immune mechanisms that are altered by a 1-h stress treatment (cold-restraint, CR) administered just prior to bacterial infection. Intriguingly, MT gene doses both greater and lower than that of wild-type (WT) B6 mice were associated with improved host defenses against Listeria monocytogenes (LM). This augmented protection was diminished by CR stress in the MTKO mice, but transgenic mice with additional MT copies had no CR stress-induced increase in their listerial burden. During the transition from innate to adaptive immunity, on day 3 after infection, oxidative burst and apoptosis were assessed by flow cytometric methods, and cytokine transcription was measured by real-time quantitative PCR. MT gene expression and CR-stress affected the expression of IL-6 and TNFα. Additionally, these genetic and environmental modulations altered the generation of ROS responses as well as the number of apoptotic cells in livers and spleens. Although the level of MT altered the listerial response, MT expression was equally elevated by listerial infection with or without CR stress. These results indicate the ability of MT to regulate immune response mechanisms and demonstrate that increased amounts of MT can eliminate the immunosuppression induced by CR.

Dual Transcriptome Profiling ofLeishmania-Infected Human Macrophages Reveals Distinct Reprogramming Signatures

“…Metallothioneins are known to have an immunomodulatory role ( 47 ) and to be induced by a wide range of conditions, including exposure to reactive oxygen species ( 48 ), and were recently shown to affect the host response to Listeria spp. infection ( 49 ). Although metallothioneins have previously been shown to be highly upregulated in macrophages infected with Leishmania ( 31 , 32 ), their potential role in the establishment of infection is poorly understood.…”

In Search of Biomarkers for Pathogenesis and Control of Leishmaniasis by Global Analyses of Leishmania-Infected Macrophages

“…These potential biomarkers are proteins that have previously been associated with an immunomodulatory response (Lynes et al, 1993 ) and are known to be activated by certain stimuli, such as exposure to reactive oxygen species (Ghoshal and Jacob, 2001 ), which has been confirmed to influence the host response to Listeria spp. (Emeny et al, 2015 ). Metallothioneins have also been found to be highly upregulated in macrophages infected with Leishmania (Chaussabel et al, 2003 ; Ettinger and Wilson, 2008 ) and have also been associated with resistance to treatment with antimonial drugs (Gómez et al, 2014 ).…”

Metallothionein 1: A New Spotlight on Inflammatory Diseases

“…Coordination of both innate and adaptive immune responses is required for effective host clearance (84). MTs have been shown to influence immune activities (115). The MT1 doses dramatically influence host defenses against LM infection (Figure 3H).…”