INTRACELLULAR INFECTION BY LEISHMANIA-DONOVANI INHIBITS MACROPHAGE APOPTOSIS

The phagocytic macrophage plays a critical role in host immune respons es to microbial infection, and represents a major source of inflammato ry and growth cytokines. Intramacrophage infection by the protozoan pa rasite Leishmania donovani results in increased viability of the host cell in the absence of exogenous growth factor. We demonstrate that in fection of bone marrow-derived macrophages (BMMs) by L. donovani proma stigotes or treatment of BMMs with lipophosphoglycan LPG, the major su rface molecule of the promastigote, inhibits apoptosis in the macropha ge induced by the removal of macrophage (M)-CSF. This effect was also achieved by supernatants collected from L. donovani-infected macrophag es, implicating the elaboration of a soluble factor by infected cells as the mediator of this inhibition. To identify candidate factors, rev erse transcription PCR was employed to characterize the mRNA cytokine profile of infected macrophages. L. donovani infection of BMMs was fou nd to induce gene expression for granulocyte-macrophage CSF, TNF-alpha , TGF-beta, and IL-6, but not M-CSF or IL-1 beta. Of the cytokines ind uced by L. donovani, rTNF-alpha and recombinant granulocyte-macrophage CSF were shown to inhibit apoptosis of BMMs induced by the removal of M-CSF. The amount of these cytokines in L. donovani-infected cell sup ernatants was quantified by ELISA. The mechanism by which L. donovani may inhibit apoptosis is discussed.