Control of New World cutaneous leishmaniasis is IL-12 independent but STAT4 dependent.
Leishmania mexicana, a New World protozoan parasite, induces small, chronic, but non-progressive lesions in C57BL/6 (B6) mice. In this study we investigated the role of IL-12, and subsequent Th1 factors, in controlling cutaneous L. mexicana infection. IL-12 treatment failed to promote disease resolution, suggesting that the inability of mice to heal is not related to a deficiency of endogenous IL-12 production. Surprisingly, L. mexicana-induced cutaneous lesions in wild-type and IL-12p40-deficient mice were indistinguishable, with similar parasite burdens, immune responses, and lesion histopathology. In contrast, iNOS, IFN-gamma, and STAT4-deficient mice developed progressive disease and uncontrolled parasite growth. These results differ dramatically from L. major infection, in which IL-12p40-deficient mice are highly susceptible, with very rapid lesion growth, very large parasite burdens, and the development of a strong Th2 response. These data uncover the existence of an alternate IFN-gamma and iNOS pathway for control of Leishmania lesions, which is IL-12 independent, but which unexpectedly requires STAT4.
Buxbaum
Laurence U
LU
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, USA.
Uzonna
Jude E
JE
Goldschmidt
Michael H
MH
Scott
Phillip
P
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004268:DNA-Binding Proteins / Q000502:physiology*; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000502:physiology*; D053762:Interleukin-12 Subunit p40; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000502:physiology; D052247:Nitric Oxide Synthase Type II; D021122:Protein Subunits / Q000502:physiology*; D050797:STAT4 Transcription Factor; D015534:Trans-Activators / Q000502:physiology*
D004268:DNA-Binding Proteins; D053762:Interleukin-12 Subunit p40; D021122:Protein Subunits; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse