Genetic background influences immune responses and disease outcome of cutaneous L. mexicana infection in mice
The experimental model of high-dose Leishmania mexicana infection is used frequently to study molecular mechanisms regulating T h 2 response since most inbred mice regardless of their genetic background display T h 2 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
... ins 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 T h 2-associated cytokines and developed non-healing lesions full of parasites, whereas CBA/J mice preferentially produced T h 1-associated IFN-c but low levels of IL-4, and developed small self-resolving lesions. Both BALB/c and C57BL/6 mice produced comparable amounts of IFN-c following L. mexicana infection, but later produced less T h 2-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, CD41 T cells and CD81 T cells into their lesions. Finally, we analyzed the course of low-dose L. mexicana infection in signal transducers and activators of transcription (STAT) 6ÿ/ÿ and STAT61/1 BALB/c mice. We found that STAT6ÿ/ÿ mice mount a T h 1 response, produce high levels of IL-12 and IFN-c and develop smaller lesions containing fewer parasites as compared with STAT61/1 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.