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* Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, and
Veterinary Resources Program, Office of Research Services, National Institutes of Health, Bethesda, MD 20892;
Laboratory of Mycobacterial Diseases and Cellular Immunity, Division of Bacterial, Allergenic, and Parasitic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, MD 20852; and
Departments of Medicine and Immunology and Center for the Study of Aging and Human Development, and Geriatric Research, Education, and Clinical Center, Veterans Affairs Medical Center, Duke University, Durham, NC 27710
Although IFN-
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--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--dependent manner. LRG-47-/- mice were unable to control bacterial replication, but survived the acute phase, succumbing 11–16 wk postinfection. IFN--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- 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- response to persistent infection, LRG-47 can have downstream regulatory effects on lymphocyte survival.
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