Scientific Publications by FDA Staff

J Immunol 2004 Jan 15;172(2):1163-8

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

Feng CG, Collazo-Custodio CM, Eckhaus M, Hieny S, Belkaid Y, Elkins K, Jankovic D, Taylor GA, Sher A

Feng CG, NIAID, Immunol Sect, Parasit Dis Lab, NIH, Room 6148,Bldg 50,50 S Dr, Bethesda, MD 20892 USA NIAID, Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA NIH, Vet Resources Program, Off Res Serv, Bethesda, MD 20892 USA US FDA, Ctr Biol Evaluat & Res, Div Bacterial Allergen & Parasit Prod, Lab Mycobacterial Dis & Cellular Immun, Rockville, MD 20852 USA Duke Univ, Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Durham, NC 27710 USA Duke Univ, Vet Affairs Med Ctr, Ctr Study Aging & Human Dev, Durham, NC 27710 USA Duke Univ, Vet Affairs Med Ctr, Dept Med, Durham, NC 27710 USA Duke Univ, Vet Affairs Med Ctr, Dept Immunol, Durham, NC 27710 USA

Although IFN-gamma 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-gamma-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-gamma-dependent manner. LRG-47(-/-) mice were unable to control bacterial replication, but survived the acute phase, succumbing 11-16 wk postinfection. IFN-gamma-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-gamma 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-gamma response to persistent infection, LRG-47 can have downstream regulatory effects on lymphocyte survival.