Trypanosome Lytic Factor, an Antimicrobial High-Density Lipoprotein, Ameliorates Leishmania Infection

PLoS Pathogens

Barbara A. Burleigh¹  Anne-Danielle C. Chessler¹  Maria Pilar Molina-Portela²  Jayne Raper²  Marie Samanovic² 

[1]Immunology and Infectious Disease, Harvard School of Public Health, Boston, Massachusetts, United States of America

[2]Medical Parasitology, New York University Langone Medical Center, New York, New York, United States of America

关键词: Macrophages;    Trypanosoma;    Parasitic diseases;    Leishmania;    Promastigotes;    Trypanosoma cruzi;    Amastigotes;    Lysosomes;   

DOI  :  10.1371/journal.ppat.1000276

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Innate immunity is the first line of defense against invading microorganisms. Trypanosome Lytic Factor (TLF) is a minor sub-fraction of human high-density lipoprotein that provides innate immunity by completely protecting humans from infection by most species of African trypanosomes, which belong to the Kinetoplastida order. Herein, we demonstrate the broader protective effects of human TLF, which inhibits intracellular infection by Leishmania, a kinetoplastid that replicates in phagolysosomes of macrophages. We show that TLF accumulates within the parasitophorous vacuole of macrophages in vitro and reduces the number of Leishmania metacyclic promastigotes, but not amastigotes. We do not detect any activation of the macrophages by TLF in the presence or absence of Leishmania, and therefore propose that TLF directly damages the parasite in the acidic parasitophorous vacuole. To investigate the physiological relevance of this observation, we have reconstituted lytic activity in vivo by generating mice that express the two main protein components of TLFs: human apolipoprotein L-I and haptoglobin-related protein. Both proteins are expressed in mice at levels equivalent to those found in humans and circulate within high-density lipoproteins. We find that TLF mice can ameliorate an infection with Leishmania by significantly reducing the pathogen burden. In contrast, TLF mice were not protected against infection by the kinetoplastid Trypanosoma cruzi, which infects many cell types and transiently passes through a phagolysosome. We conclude that TLF not only determines species specificity for African trypanosomes, but can also ameliorate an infection with Leishmania, while having no effect on T. cruzi. We propose that TLFs are a component of the innate immune system that can limit infections by their ability to selectively damage pathogens in phagolysosomes within the reticuloendothelial system.

【 授权许可】

CC BY