SECRETED PROTEOPHOSPHOGLYCAN OF LEISHMANIA-MEXICANA AMASTIGOTES ACTIVATES COMPLEMENT BY TRIGGERING THE MANNAN-BINDING LECTIN PATHWAY

Cutaneous lesions induced by infection of mice with the protozoan para site, Leishmania mexicana contain abundant amounts of a high molecular mass proteophosphoglycan (PPG), which is secreted by the amastigote s tage residing in phagolysosomes of macrophages and can then be release d into the tissue upon rupture of the infected cells. Amastigote PPG f orms sausage-shaped but soluble particles and belongs to a novel class of serine-rich proteins that are extensively O-glycosylated by phosph ooligosaccharides capped by mannooligosaccharides. The purified molecu le is shown here to efficiently activate complement (C) and deplete he molytic activity of normal serum and may prevent the opsonization of L . mexicana amastigotes. Complement activation is Ca2+ dependent but do es not depend on antibodies or the complement component C1. PPG binds to serum mannan binding protein (MBP), thus activating the MBP-associa ted serine protease, P100. Subsequently, the C cascade is triggered th rough C3 leading to covalent modification probably of carbohydrate hyd roxyls of PPG by C3 fragments. Thus, PPG is able to activate C via the mannan binding lectin pathway which is unusual for secreted, soluble products of microbial origin. The proteophosphoglycan-induced compleme nt activation is postulated to contribute to the lesion development an d pathology caused by the parasite.