Mice Deficient in LRG-47 Display Increased Susceptibility to Mycobacterial Infection Associated with the Induction of Lymphopenia

Abstract

Although IFN-γ is essential for host control of mycobacterial infection, the mechanisms by which the cytokine restricts pathogen growth are only partially understood. LRG-47 is an IFN-inducible GTP-binding protein previously shown to be required for IFN-γ-dependent host resistance to acute Listeria monocytogenes and Toxoplasma gondii infections. To examine the role of LRG-47 in control of mycobacterial infection, LRG-47−/− and wild-type mice were infected with Mycobacterium avium, and host responses were analyzed. LRG-47 protein was strongly induced in livers of infected wild-type animals in an IFN-γ-dependent manner. LRG-47−/− mice were unable to control bacterial replication, but survived the acute phase, succumbing 11–16 wk postinfection. IFN-γ-primed, bone marrow-derived macrophages from LRG-47−/− and wild-type animals produced equivalent levels of TNF and NO upon M. avium infection in vitro and developed similar intracellular bacterial loads. In addition, priming for IFN-γ production was observed in T cells isolated from infected LRG-47−/− mice. Importantly, however, mycobacterial granulomas in LRG-47−/− mice showed a marked lymphocyte deficiency. Further examination of these animals revealed a profound systemic lymphopenia and anemia triggered by infection. As LRG47−/− T lymphocytes were found to both survive and confer resistance to M. avium in recipient recombinase-activating gene-2−/− mice, the defect in cellular response and bacterial control in LRG-47−/− mice may also depend on a factor(s) expressed in a nonlymphocyte compartment. These findings establish a role for LRG-47 in host control of mycobacteria and demonstrate that in the context of the IFN-γ response to persistent infection, LRG-47 can have downstream regulatory effects on lymphocyte survival.