title: Differential microbicidal effects of human histone proteins H2A and H2B on Leishmania promastigotes and amastigotes.
abstract: Recent studies have shown that histone proteins can act as antimicrobial peptides in host defense against extracellular bacteria, fungi, and Leishmania promastigotes. In this study, we used human recombinant histone proteins to further study their leishmaniacidal effects and the underlying mechanisms. We found that the histones H2A and H2B (but not H1(0)) could directly and efficiently kill promastigotes of Leishmania amazonensis, L. major, L. braziliensis, and L. mexicana in a treatment dose-dependent manner. Scanning electron microscopy revealed surface disruption of histone-treated promastigotes. More importantly, the preexposure of promastigotes to histone proteins markedly decreased the infectivity of promastigotes to murine macrophages (Mφs) in vitro. However, axenic and lesion-derived amastigotes of L. amazonensis and L. mexicana were relatively resistant to histone treatment, which correlated with the low levels of intracellular H2A in treated amastigotes. To understand the mechanisms underlying these differential responses, we investigated the role of promastigote surface molecules in histone-mediated killing. Compared with the corresponding controls, transgenic L. amazonensis promastigotes expressing lower levels of surface gp63 proteins were more susceptible to histone H2A, while L. major and L. mexicana promastigotes with targeted deletion of the lipophosphoglycan 2 (lpg2) gene (but not the lpg1 gene) were more resistant to histone H2A. We discuss the influence of promastigote major surface molecules in the leishmaniacidal effect of histone proteins. This study provides new information on host innate immunity to different developmental stages of Leishmania parasites.
authors.affiliation: College of Veterinary Medicine, China Agricultural University, Beijing, China 100193.
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
authors.forename: Lijun
authors.initials: L
authors.lastname: Xin
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Beverley
authors.forename: Eric D
authors.initials: ED
authors.lastname: Carlsen
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Popov
authors.forename: Kwang-Poo
authors.initials: KP
authors.lastname: Chang
authors.forename: Ming
authors.initials: M
authors.lastname: Wang
authors.forename: Lynn
authors.initials: L
authors.lastname: Soong
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D005700:Galactosyltransferases / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006028:Glycosphingolipids / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007891:Leishmania / Q000187:drug effects* / Q000472:pathogenicity / Q000648:ultrastructure; D008018:Life Cycle Stages / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008855:Microscopy, Electron, Scanning; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000981:Antiprotozoal Agents; D006028:Glycosphingolipids; D006657:Histones; C095909:LPG2 protein, Leishmania; D008565:Membrane Proteins; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D005700:Galactosyltransferases; C083281:LPG1 protein, Leishmania; D008666:Metalloendopeptidases; C055146:glycoprotein gp63, Leishmania