Leishmania donovani lacking the Golgi GDP-Man transporter LPG2 exhibit attenuated virulence in mammalian hosts

Surface phosophoglycans such as lipophosphoglycan (LPG) or proteophosphoglycan (PPG) and glycosylinositol phospholipids (GIPLs) modulate essential interactions between Leishmania and mammalian macrophages. Phosphoglycan synthesis depends on the Golgi GDP-mannose transporter encoded by LPG2. LPG2-null (lpg2^-) Leishmania major cannot establish macrophage infections or induce acute pathology, whereas lpg2^- Leishmania mexicana retain virulence. lpg2^- Leishmania donovani has been reported to survive poorly in cultured macrophages but in vivo survival has not been explored. Herein we discovered that, similar to lpg2^- L. major, lpg2^- L. donovani promastigotes exhibited diminished virulence in mice, but persisted at consistently low levels. lpg2^- L. donovani promastigotes could not establish infection in macrophages and could not transiently inhibit phagolysosomal fusion. Furthermore, lpg2^- promastigotes of L. major, L. donovani and L. mexicana were highly susceptible to complement-mediated lysis. We conclude that phosphoglycan assembly and expression mediated by L. donovani LPG2 are important for promastigote and amastigote virulence, unlike L. mexicana but similar to L. major.