title: Genetic background influences immune responses and disease outcome of cutaneous L. mexicana infection in mice.
abstract: 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.
authors.affiliation: Department of Microbiology, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Lucia E
authors.initials: LE
authors.lastname: Rosas
authors.forename: Tracy
authors.initials: T
authors.lastname: Keiser
authors.forename: Joseph
authors.initials: J
authors.lastname: Barbi
authors.forename: Anjali A
authors.initials: AA
authors.lastname: Satoskar
authors.forename: Alecia
authors.initials: A
authors.lastname: Septer
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kaczmarek
authors.forename: Claudio M
authors.initials: CM
authors.lastname: Lezama-Davila
authors.forename: Abhay R
authors.initials: AR
authors.lastname: Satoskar
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D007700:Kinetics; D007894:Leishmania mexicana / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000235:genetics* / Q000276:immunology*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D050800:STAT6 Transcription Factor / Q000172:deficiency / Q000235:genetics
chemical_list: D000953:Antigens, Protozoan; D016207:Cytokines; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse