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International Immunology Advance Access originally published online on September 2, 2005
International Immunology 2005 17(10):1347-1357; doi:10.1093/intimm/dxh313
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© The Japanese Society for Immunology. 2005. All rights reserved. For permissions, please e-mail: journals.permissions@oupjournals.org

Genetic background influences immune responses and disease outcome of cutaneous L. mexicana infection in mice

Lucia E. Rosas1, Tracy Keiser1, Joseph Barbi1, Anjali A. Satoskar2, Alecia Septer1, Jennifer Kaczmarek1, Claudio M. Lezama-Davila1 and Abhay R. Satoskar1,3

1 Department of Microbiology, 2 Department of Pathology and 3 Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, 484 West 12th Avenue, Columbus, OH 43210, USA

Correspondence to: A. R. Satoskar; E-mail: satoskar.2{at}osu.edu

The experimental model of high-dose Leishmania mexicana infection is used frequently to study molecular mechanisms regulating Th2 response since most inbred mice regardless of their genetic background display Th2 cytokine-dependent susceptibility to L. mexicana unlike Leishmania major. Here, we analyzed the course of L. mexicana infection in BALB/c, C57BL/6 and CBA/J mouse strains using low-dose ear infection model that mimics natural transmission. Although all three strains were equally susceptible to high-dose back rump L. mexicana infection, they displayed marked differences in their ability to control parasite growth after low-dose ear infection. Leishmania mexicana-infected BALB/c mice produced high levels of Th2-associated cytokines and developed non-healing lesions full of parasites, whereas CBA/J mice preferentially produced Th1-associated IFN-{gamma} but low levels of IL-4, and developed small self-resolving lesions. Both BALB/c and C57BL/6 mice produced comparable amounts of IFN-{gamma} following L. mexicana infection, but later produced less Th2-associated cytokines, and exhibited an ‘intermediate’ susceptibility phenotype characterized by lesion sizes that were significantly smaller than BALB/c mice but larger than CBA/J mice. Interestingly, all three strains also showed marked differences in trafficking of macrophages, CD4+ T cells and CD8+ T cells into their lesions. Finally, we analyzed the course of low-dose L. mexicana infection in signal transducers and activators of transcription (STAT) 6–/– and STAT6+/+ BALB/c mice. We found that STAT6–/– mice mount a Th1 response, produce high levels of IL-12 and IFN-{gamma} and develop smaller lesions containing fewer parasites as compared with STAT6+/+ mice. Our findings demonstrate that genetic background plays a critical role in determining susceptibility of inbred mice to low-dose L. mexicana infection. Furthermore, together with our previous findings, they show that STAT6-mediated signaling is involved in mediating susceptibility to L. mexicana following both high-dose back rump and low-dose ear dermis infection.

Keywords: cutaneous leishmaniasis, Leishmania mexicana, Th1/Th2

Transmitting editor: C. Terhorst


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