Evolution of lesion formation, parasitic load, immune response, and reservoir potential in C57BL/6 mice following high- and low-dose challenge with Leishmania major

A model of cutaneous leishmaniasis using 10(2) Leishmania major metacyclic promastigotes inoculated into the footpads of genetically resistant C57BL/6 mice was studied in order to more accurately reproduce the evolution of le sion formation and the kinetics of parasite growth and immune response as t hey might occur in naturally exposed reservoirs and in human hosts. In cont rast to the more conventional experimental model employing 10(6) metacyclic promastigotes, in which the rapid development of footpad lesions was assoc iated with an increasing number of amastigotes in the site, the low-dose mo del revealed a remarkably "silent" phase of parasite growth, lasting approx imately 6 weeks, during which peak parasitic loads were established in the absence of any overt pathology. Footpad swelling was observed after 6 weeks , coincident with the onset of parasite clearance and with production of hi gh levels of interleukin-12 (IL-12) and gamma interferon (IFN-gamma) in dra ining lymph nodes. Low-dose challenge of IL-12- and IFN-gamma-depleted or - deficient mice provided strong evidence that the induction or expression of cellular immunity is essentially absent during the first 6 to 8 weeks of i ntracellular growth, since the concentration of amastigotes in the site nas not enhanced compared to that for wild-type animals during this time. By m onitoring the ability of infected mice to transmit parasites to vector sand flies, it was observed that following low-dose challenge, footpads without apparent lesions provided an efficient source of parasites for exposed fli es and that the low-dose challenge actually extended the duration of parasi te transmissibility during the course of infection.