Mice deficient in LRG-47 display increased susceptibility to mycobacterial infection associated with the induction of lymphopenia.
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.
Feng
Carl G
CG
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Room 6148, Building 50, 50 South Drive, Bethesda, MD 20892, USA. cfeng@niaid.nih.gov
Collazo-Custodio
Carmen M
CM
Eckhaus
Michael
M
Hieny
Sara
S
Belkaid
Yasmine
Y
Elkins
Karen
K
Jankovic
Dragana
D
Taylor
Gregory A
GA
Sher
Alan
A
D000818:Animals; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006099:Granuloma / Q000235:genetics / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D007371:Interferon-gamma / Q000502:physiology; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008213:Lymphocyte Activation / Q000235:genetics; D008231:Lymphopenia / Q000235:genetics* / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009162:Mycobacterium avium / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014376:Tuberculosis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology
C096000:Ifi1 protein, mouse; D007371:Interferon-gamma; D019204:GTP-Binding Proteins