Leishmania-induced increases in activation of macrophage SHP-1 tyrosine phosphatase are associated with impaired IFN-gamma-triggered JAK2 activation.

Leishmania-induced macrophage (Mphi) dysfunctions have been correlated with altered signaling events. Recent findings from our laboratory suggest that modulation of host protein tyrosine phosphatase (PTP) following Leishmania infection could lead to these Mphi defects. To address this issue, Mphi PTP activity and IFN-gamma-inducible signaling events were evaluated in Leishmania donovani (Ld)-infected cells. We observed that Ld promastigotes can rapidly trigger host PTP activity simultaneously with dephosphorylation of Mphi protein tyrosyl residues and inhibition of protein tyrosine kinase (PTK). Our results further revealed that Mphi SHP-1 PTP was rapidly activated by the infection. This Ld-evoked signaling alteration was reflected by absence of IFN-gamma-induced intracellular phosphorylation. IFN-gamma-inducible JAK2 PTK phosphorylation was also markedly diminished in Ld-infected cells. We also observed that co-immunoprecipitation of JAK2 with SHP-1 was considerably higher in infected as compared to uninfected cells. Altogether, these results suggest that SHP-1-mediated JAK2 dephosphorylation triggered by Leishmania is partly responsible for abnormal Mphi IFN-gamma signaling and represent an important mechanism supporting persistent parasitic infection.