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 and cause nagana in cattle. The present study demonstrates the potentially broad protective effects of human TLF, which can reduce an intracellular infection of Leishmania, a kinetoplastid that replicates in the phagolysosomes of macrophages.
We first showed that TLF accumulates within the phagolysosome of macrophages in vitro and reduces the number of parasites at an early stage of the infection, without activating the macrophages. We found that TLF forms pores directly in the plasma membrane of the parasite, when in acidic conditions that mimic the pH of the phagolysosome. Lastly, to investigate the physiological relevance of this observation we 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 were expressed in mice at levels equivalent to those found in humans and circulate within high-density lipoproteins. We found that TLF mice can ameliorate an infection with Leishmania by significantly reducing the pathogen burden.
In conclusion we propose that TLF is a recently evolved component of the primate innate immune system, which can limit infections by its ability to selectively damage pathogens in acidified phagolysosomes within the reticuloendothelial system. Furthermore, depending on their exposure to TLF, a primate specific factor, certain pathogens will have evolved mechanisms of resistance to prevent TLF pore formation.
|Commitee:||Adesnik, Milton B., Belkaid, Yasmine, Fisher, Edward A., Rodriguez, Ana|
|School:||New York University|
|Department:||Basic Medical Science|
|School Location:||United States -- New York|
|Source:||DAI-B 70/12, Dissertation Abstracts International|
|Keywords:||African trypanosomes, Apolipoprotein, Innate immunity, Leishmania, Pore formation, Trypanosome lytic factor|
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