Manipulations of metallothionein gene dose accelerate the response to Listeria monocytogenes

Metallothioneins (MTs) are cysteine-rich proteins that assist in cellular homeostasis and protect against oxidant injury. MTs can be induced by heavy metals and inflammatory mediators and function as free radical scavengers, reservoirs for essential heavy metals, and immunomodulators. In light of MTs’ roles in responses to stress, we evaluated the in vivo effects of MT gene dose on the course of Listeria monocytogenes (LM) infection. LM burden was measured in livers and spleens, and flow cytometric assays were used to analyze splenocyte surface sulfhydryls, oxidative burst and apoptosis. Our results suggest that deviations from the normal complement of MT genes alter the course of LM infection. Compared to the wild-type C57BL/6J (B6-WT) strain, a congenic partner that carries a larger number of Mt1 genes (B6-MTTGN) and a congenic strain in which both Mt1 and Mt2 are disrupted (B6-MTKO) both showed lower bacterial burdens three days post-inoculation. This difference was prominent in the first 48 h of infection, after which LM clearance occurred at comparable rates in all three strains. Lymphocytes from B6-MTKO mice exhibited increased cell death and increased levels of surface sulfhydryls compared to B6-WT and B6-MTTGN mice. Lymphocytes from B6-MTTGN mice had increased levels of intracellular oxidants compared to B6-WT and B6-MTKO mice. The oxidative burst by macrophages from infected B6-MTTGN and B6-MTKO mice was increased, suggesting one mechanism by which these strains might reduce the LM burden. These results indicate that MT gene dose dramatically influences host-defenses against LM infection.