The wound repair response controls outcome to cutaneous leishmaniasis

Abstract

Chronic microbial infections are associated with fibrotic and inflammatory reactions known as granulomas showing similarities to wound-healing and tissue repair processes. We have previously mapped three leishmaniasis susceptibility loci, designated lmr1, -2, and -3, which exert their effect independently of T cell immune responses. Here, we show that the wound repair response is critically important for the rapid cure in murine cutaneous leishmaniasis caused by Leishmania major. Mice congenic for leishmaniasis resistance loci, which cured their lesions more rapidly than their susceptible parents, also expressed differentially genes involved in tissue repair, laid down more ordered collagen fibers, and healed punch biopsy wounds more rapidly. Fibroblast monolayers from these mice repaired in vitro wounds faster, and this process was accelerated by supernatants from infected macrophages. Because these effects are independent of T cell-mediated immunity, we conclude that the rate of wound healing is likely to be an important component of innate immunity involved in resistance to cutaneous leishmaniasis.

Fig. 1.

Histological sections of punch biopsies and L. major lesions stained with Masson's trichrome showing strain-dependent deposition of collagen fibrils. (A–D) Punch biopsy lesions. (E–H) L. major lesions. (A and E) -C57BL/6. (B and F) -B6.lmr1/2. (C and G) -BALB/c. (D and H) –C.lmr1/2.

Fig. 2.

Closure kinetics of skin punch biopsy lesions and of scratches in fibroblast monolayers showing strain dependent closure times. (A) Closure kinetics of surgically induced skin lesions from C57BL/6, B6.lmr1/2, C.lmr1/2, and BALB/c. (B and C) Kinetics of closure of scratches in fibroblast monolayer.

Fig. 3.

Giemsa-stained skin fibroblast monolayer showing the differences in scratch closure between BALB/c(A) and C.lmr1/2 fibroblasts (B) 32 and 48 h after wounding (0).

Fig. 4.

Kinetics of scratch closure in fibroblasts from C57BL/6, BALB/c, C.lmr1/2, and B6.lmr1/2 grown in medium conditioned by infected (filled circles), uninfected (open circles and dashed line) C57BL/6 macrophages, or control medium (gray circles) expressed as a percentage of the original scratch width.