For their survival, many intracellular pathogens build and retain pathogen-containing vacuoles (PVs) to hide from the cytosolic host defense systems. Among the several PV-resident human pathogens are the obligate intracellular protozoa parasites Leishmania donovani and Toxoplasma gondii. The proinflammatory cytokine IFN?, a key player in cellular immunity, can orchestrate a variety of defensive functions that destroy or prevent these intravacuolar pathogens from replicating inside host. While recent studies have shown that activating host cells with IFN? causes the recruitment and accumulation of IFN?-inducible GTPases, Immunity Related GTPases (IRGs), and Guanylate Binding Proteins (GBPs) around Toxoplasma PVs in order to destroy them, little is known about their function in destroying Leishmania containing vacuoles (LCVs). We recently reported that, in non-phagocytic mammalian cells without efficient targeting to LCVs, mouse and human GBPs play an important role as host protective factors against L. donovani infection, even in the absence of IFN? stimulation. Despite the fact that IFN?-inducible IRGs are required for GBP-mediated T. gondii PV destruction in murine cells, our findings showed that murine GBPs promote host defense against L. donovani from a distance, suggesting that the molecular machinery of this defense pathway is distinct from the IRG-dependent defense pathway active against T. gondii.

Leishmania, Nonphagocytic cells, GTPases, Guanylate binding proteins (GBPs), immunity related GTPases (IRGs), LAMP, LC3