Lipophosphoglycan is not required for infection of macrophages or mice by Leishmania mexicana

Abstract

Cell surface lipophosphoglycan (LPG) is commonly regarded as a multifunctional Leishmania virulence factor required for survival and development of these parasites in mammals. In this study, the LPG biosynthesis gene lpg1 was deleted in Leishmania mexicana by targeted gene replacement. The resulting mutants are de®cient in LPG synthesis but still display on their surface and secrete phosphoglycan-modi®ed molecules, most likely in the form of proteophosphoglycans, whose expression appears to be up-regulated. LPG-de®cient L.mexicana promastigotes show no signi®cant differences to LPG-expressing parasites with respect to attachment to, uptake into and multiplication inside macrophages. Moreover, in Balb/c and C57/BL6 mice, LPG-de®cient L.mexicana clones are at least as virulent as the parental wild-type strain and lead to lethal disseminated disease. The results demonstrate that at least L.mexicana does not require LPG for experimental infections of macrophages or mice. Leishmania mexicana LPG is therefore not a virulence factor in the mammalian host.

Cysteine Protease B of Leishmania mexicana Inhibits Host Th1 Responses and Protective Immunity

“…Furthermore, the disease courses in more resistant mouse strains (e.g., C3H and B6) are quite different for L. major infection, in which lesion resolution occurs, and L. mexicana infection, in which chronic lesions persist. Lipophosphoglycan and other phosphoglycan molecules are important L. major virulence factors, but do not play this role for L. mexicana (49,50). Likewise, the protein Leishmania homolog of receptors for activated C kinase is an immunodominant Ag responsible for virulence of L. major in BALB/c mice, but not for L. mexicana (51,52).…”

Regulated Degradation of an Endoplasmic Reticulum Membrane Protein in a Tubular Lysosome inLeishmania mexicana

“…These GPI-anchored macromolecules and free GPIs are most highly expressed in the promastigote (sandfly) stage and are thought to form a protective surface glycocalyx. They also mediate specific hostparasite interactions in the midgut of the sandfly vector and are required for promastigote invasion of macrophages in the mammalian host (Ilg, 2000;Sacks et al, 2000;Spath et al, 2000). Recent studies with the use of L. mexicana promastigotes suggest that the protein anchor and LPG anchor precursors and free GPIs are assembled on distinct phosphatidylinositol molecular species in a subcompartment of the ER (Ralton and McCon-ville, 1998;Ilgoutz et al, 1999b).…”

Manipulación genética y el estudio del parásito protozoario Leishmania.

“…Igualmente, la eliminación de los genes que codifican para las proteínas SHERP/HASP (proteína hidrofílica en membrana del retículo endoplásmico y mitocondria/proteína de superficie hidrofílica acilada) abundantes en estadio metacíclico infectivo (64), y la ausencia de proteínas que intervienen en la síntesis de diferentes glicoconjugados implicados en la virulencia tuvieron un efecto pequeño en la pérdida de virulencia (76,77,80,81,90).…”

“…En L. major, la eliminación de lpg1 (gen que codifica para galactofuranosil transferasa) produjo promastigotes específicamente deficientes en la síntesis del mayor componente del glicocálix denso de la superficie de los promastigotes de Leishmania, lipofosfoglicano (LPG) (77). Los mutantes de L. major fueron incapaces de sobrevivir en el insecto o de establecer de manera eficiente infecciones en macrófagos o ratón, mientras que la eliminación de lpg1 en L. mexicana no produjo ningún cambio de fenotipo en las infecciones a ratón o macrófago (76). Estos hallazgos muestran que las diferentes especies de Leishmania hacen uso de su repertorio de genes y moléculas potenciales de virulencia a diferentes grados en su interacción con el hospedero.…”