Inhibition of Interferon‐γ Signaling byLeishmania donovani

Abstract

Leishmania infection causes marked down-regulation of interferon (IFN)-gamma-induced gene activity in macrophages, but the mechanism of the blockade has not been fully defined. The IFN-gamma signal transduction pathway was analyzed in Leishmania donovani-infected phorbol-differentiated U937 human promonocytic cells. IFN-gamma stimulation induced marked phosphorylation of its own receptor (IFN-gammaR)-alpha chain. Phosphorylation of the receptor subunit was significantly inhibited after 24 h of infection with the parasite, apparently because of decreased amounts of the receptor subunit. Formation of the IFN-gammaR complex, as assessed by tyrosine phosphorylation and association of Jak2, was strongly inhibited in cells infected for 24 h. Inhibition of the IFN-gammaR complex formation correlated with inhibition of STAT1alpha binding to the IFN-gamma response region. Pretreatment with purified parasite lipophosphoglycan before IFN-gamma stimulation had no effect on tyrosine phosphorylation. Thus, inhibition of tyrosine phosphorylation of the IFN-gammaR-alpha chain and subsequent signal transduction are most likely due to the decreased amount of IFN-gammaR-alpha protein after infection.

Camptothecin induced mitochondrial dysfunction leading to programmed cell death in unicellular hemoflagellate Leishmania donovani

“…After incubation at 371C for the 18 h, noningested parasites were removed by vigorous washing with RPMI three times. The infected macrophages were treated with 2.5 mM CPT and 0.2% DMSO separately for 12 h. 49 …”

The amastigote forms of Leishmania are experts at exploiting host cell processes to establish infection and persist

“…A few reports have shown that infection results in expression of fewer IFNγ receptors on the infected cell surface and reduced phosphorylation of the remaining receptors ( Fig. 1) (Nandan and Reiner, 1995;Ray et al, 2000). Using mice genetically altered to lack SHP-1, Olivier and colleagues have shown that activation of this phosphatase during infection blocks Jak2 signaling (Blanchette et al, 1999;Forget et al, 2001).…”

Analysis of the expression of toll-like receptors 2 and 4 and cytokine production during experimental Leishmania chagasi infection

“…IL-12 induces the differentiation and proliferation of CD4 + Th1 cells populations, which produce more IFN-γ (Cunningham 2002). IFN-γ is responsible for activating macrophages to produce TNF-α, which, in synergism with IFN-γ, increases phagocytosis and induces macrophage leishmanicidal activity through the production of nitrogen and oxygen metabolites (Belosevic et al 1989, Bodgan et al 1990, Liew et al 1990, Theodos et al 1991, Ray et al 2000, Wilhelm et al 2001, Cunningham 2002. On the other hand, susceptibility to leishmaniasis is associated with a Th2 type immune response, characterised by the predominance of the humoral response and the production of cytokines, such as IL-4 and IL-10 ( Agnello et al 2003, Sharma & Singh 2009.…”