The site of Leishmania major infection determines disease severity and immune responses

Abstract

Inbred strains of mice infected with Leishmania major have been classified as genetically resistant or susceptible on the basis of their ability to cure their lesions, the parasite burden in the draining lymph nodes, and their type of T helper cell immune responses to the parasite. Using the intradermal infection at the base of the tail and the ear pinna, we compared for the first time the above-mentioned parameters in six strains of mice infected with metacyclic promastigotes, and we show that the severity of disease depends greatly on the site of infection. Although the well-documented pattern of disease susceptibility of BALB/c and C57BL/6 mice described for the footpad and base-of-the-tail models of leishmaniasis were confirmed, C3H/HeN and DBA/2 mice, which are intermediate and susceptible, respectively, in the tail and other models, were resistant to ear infection. Moreover, in the CBA/H, C3H/HeN, C57BL/6J, and DBA/2 mouse strains, there was little correlation between the pattern of cytokines produced and the disease phenotype observed at the ear and tail sites. We conclude that the definition of susceptibility and the immune mechanisms leading to susceptibility or resistance to infection may differ substantially depending on the route of infection.

FIG. 1.

(A and D) Disease patterns in BALB/c (triangles), C3H/HeN (circles), and C57BL/6J (squares) mice infected intradermally in the ear (A) or tail (D) with 10⁴ L. major Friedlin metacyclic promastigotes. The means and standard deviations of the lesion scores are shown as a function of time. (B and E) Parasite burden per 10⁶ lymph node cells in individual mice tested at 5, 10, and 15 weeks after infection with 10⁴ L. major Friedlin metacyclic promastigotes in the ear (B) or tail (E). (C and F) Ratios of IFN-γ to IL-4 in individual mice tested at 0, 5, 10, and 15 weeks post infection with 10⁴ L. major Friedlin metacyclic promastigotes in the ear (C) or tail (F).

FIG. 2.

(A and D) Disease pattern in CBA/H (circles), DBA/2 (squares), and (C57BL/6J × BALB/c)F₁ (triangles) mice infected intradermally in the ear (A) or tail (D) with 10⁴ L. major Friedlin metacyclic promastigotes. The mean lesion scores and standard deviations are shown as a function of time. (B and E) Parasite burden at 5, 10, and 15 weeks after infection with 10⁴ L. major Friedlin metacyclic promastigotes in the ear (B) or tail (E) are shown as in Fig. 1. (C and F) Ratio of IFN-γ to IL-4 at 0, 5, 10, and 15 weeks postinfection with 10⁴ L. major Friedlin metacyclic promastigotes in the ear (C) or tail (F) is shown as in Fig. 1.