Development of protective immunity against cutaneous leishmaniasis is dependent on STAT1-mediated IFN signaling pathway.
Although STAT1-dependent signaling mediates biological functions of IFN-alpha/beta and IFN-gamma, recent reports indicate that STAT1-independent IFN signaling also regulates expression of several genes. To determine the roles of STAT1-dependent and -independent IFN signaling in the regulation of immunity during cutaneous leishmaniasis, we studied the course of Leishmania major infection in resistant C57BL/6 mice lacking the STAT1 gene. While L. major-infected STAT1(+/+) mice resolved their lesions, STAT1(-/-) mice developed large lesions containing significantly more parasites. Moreover, the inability of STAT1(-/-) mice to control L. major infection was due to the lack of Th1 development associated with reduced production of IL-12, IFN-gamma and nitric oxide. Although STAT1(-/-) mice produced more IL-4 and total IgE than STAT1(+/+) mice later during infection, these differences were not significant. Nevertheless, at these time points lymph node cells from STAT1(-/-) mice produced significantly more IL-10. Finally, STAT1(-/-) mice were also susceptible to low dose L. major infection. Thesefindings demonstrate that STAT1-mediated IFN signaling is indispensable for the development of protective immunity against cutaneous L. major infection. Moreover, they also suggest that the protective role of STAT1-mediated signaling is due to its ability to induce Th1 development during infection with this parasite.
Rosas
Lucia E
LE
Department of Microbiology, The Ohio State University, 484 West 12th Avenue, Columbus, OH 43210, USA.
Keiser
Tracy
T
Pyles
Ryan
R
Durbin
Joan
J
Satoskar
Abhay R
AR
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007109:Immunity / Q000235:genetics; D007372:Interferons / Q000276:immunology / Q000378:metabolism*; D018320:Leishmania major / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D004268:DNA-Binding Proteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D009569:Nitric Oxide; D007372:Interferons