Leishmania virulence: it's a knock out!

Abstract

Leishmania spp. are obligatory intracellular parasites of mammalian host macrophages. After inoculation into the dermis by the bite of infected sandflies, the flagellated promastigotes infect macrophages or dendritic cells, in which they transform into non-flagellated amastigotes. Multiple macrophage receptors have been implicated in the invasion process, including complement receptors 1 and 3, the mannose (Man) receptor and the fibronectin receptor. Many studies in Leishmania have demonstrated the involvement of two major cell surface glycoconjugates, the gp63 protease (Mr 65 000) and a complex glycolipid, lipophosphoglycan (LPG). LPG belongs to the phosphoglycans, a family of unique Leishmania glycoconjuates characterized by linear or branched arrays of disaccharide repeats of [Galβ1-4Manα1-PO4]n with or without glycan side chains. LPG contains the unusual sugar galactofuranose. In addition to LPG, this family includes proteophosphoglycans (PPG), which exist as secreted or membrane-bound forms. Earlier studies on LPG-deficient mutants generated by chemical mutagenesis or by ablation of a galactofuranosyl transferase-encoding gene (lpg1), indicated that LPG is essential for virulence, as defined by infection of macrophages and mice 1.xLipophosphoglycan is a virulence factor distinct from related glycoconjugates in the protozoan parasite Leishmania major. Spath, G.F et al. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 9258–9263Crossref | PubMed | Scopus (193)See all References, 2.xLipophosphoglycan is not required for infection of macrophages or mice by Leishmania mexicana. Ilg, T. EMBO J. 2000; 19: 1953–1962Crossref | PubMedSee all References.However, doubts were raised earlier this year about the importance of LPG for virulence in Leishmania mexicana, a parasite causing cutaneous disease in Central and South America. Mutants that lacked lpg1, were indistinguishable from wild-type organisms when tested for virulence 3xSee all References3. Careful examination of previous work carried out in Leishmania major and Leishmania donovani, which cause cutaneous and visceral disease in the Old World, showed that the parasites were severely attenuated, but not totally avirulent. Although LPG was absent in all mutants including L. mexicana, the PPGs carrying the same glycans as LPG were synthesized normally, and they might have substituted for LPG in the interaction with the host. Recent work by Ilg 2xLipophosphoglycan is not required for infection of macrophages or mice by Leishmania mexicana. Ilg, T. EMBO J. 2000; 19: 1953–1962Crossref | PubMedSee all References2 provides what seems to be definitive proof that neither LPG nor PPG is essential for virulence. Ablation of the gene encoding the guanidine diphosphate–Man transporter (lpg2) leading to the loss of phosphoglycan synthesis on protein or polysaccharide backbones generated L. mexicana parasites that were as virulent as wild type.What are we to make of this? The easy way out is to invoke differences between Leishmania spp. Another possibility is that there is a high degree of redundancy built into the parasite surface molecules able to interact with host macrophages. Molecules such as gp63 or other glycoproteins, normally less accessible than LPG and PPG, which extend far out of the glycocalyx, might play an important role in the ‘denuded’ mutants. This hypothesis is supported by the observation that there was increased exposure of mannose residues on the virulent lpg2 null L. mexicana, presumably on N-linked glycans. Although the wild-type organisms might use LPG and the complement receptors, the mutants might use gp63 and the mannose receptor to gain entry into the macrophage. A successful parasite relies on multiple ligands tackling multiple host receptors, but much work remains to be done to elucidate the various partners in this host–parasite relationship.