Impaired Expression of Inflammatory Cytokines and Chemokines at Early Stages of Infection withLeishmania amazonensis

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Abstract
Infection of mice withLeishmania majorresults in disease progression or resolution, largely depending on the genetic backgrounds of the mouse strains. Infection withLeishmania amazonensis, on the other hand, causes progressive cutaneous lesions in most inbred strains of mice. We hypothesized that deficient activation of early immune responses contributes to the pathogenesis inL. amazonensis-infected mice. To distinguish early molecular events that determine the outcome ofLeishmaniainfections, we examined cytokine gene expression in C57BL/6 mice infected with eitherL. amazonensisorL. major(a healing model). After 2 to 4 weeks,L. amazonensis-infected mice had significantly delayed and depressed expression of inflammatory cytokines (interleukin-12 [IL-12], gamma interferon, IL-1α, IL-1β), CC chemokines (CC chemokine ligand 3 [CCL3]/macrophage inflammatory protein 1α [MIP-1α], CCL4/MIP-1β, CCL5/RANTES, MIP-2), and chemokine receptors (CCR1, CCR2, CCR5) in foot tissues and draining lymph nodes compared to the expression inL. major-infected controls. These findings correlated with defective T-cell responsiveness to parasite stimulation in vivo and in vitro. Adoptive transfer ofL. amazonensis-specific Th1 cells prior to infection overcame the immune defects of the animals, leading to complete control of the disease. Studies with gene knockout mice suggested that IL-10, but not IL-4, contributed partially to compromised immunity inL. amazonensis-infected hosts. The data suggest that there is impairment in multiple immune functions at early stages of infection withL. amazonensisparasites and provide a compelling rationale to explore immune augmentation as an intervention in American cutaneous leishmaniasis.