Role of host phosphotyrosine phosphatase SHP-1 in the development of murine leishmaniasis

Activation of host phosphotyrosine phosphatase SHP-1 by Leishmania and its subsequent impact on tyrosine phosphyorylation-based signaling cascades wer e shown to represent an important mechanism whereby this pathogen may alter host cell functions. Herein, we report that Leishmania-induced macrophage SHP-1 activity is necessary for its survival within phagocytes through the attenuation of nitric oxide-dependent and -independent microbicidal mechani sms. In vivo, Leishmania major infection, which footpad inflammation is mos tly undetectable in SHP-1-deficient viable motheaten mice, was accompanied by increased inducible nitric oxide synthase and activation of neutrophils. These enhanced cellular activities were paralleled by a marked activation of signaling events usually negatively regulated by SHP-1. Overall, this st udy firmly establishes that modulation of the signaling terminator SHP-1 by Leishmania is essential for its installment and propagation.