Several species of African trypanosomes cause fatal disease in livestock but most cannot infect humans due to innate trypanosome lytic factors (TLFs). Human TLF is a pore-forming high-density lipoprotein (HDL) particle that contains apolipoprotein L-I (apoL-I), the trypanolytic component, and haptoglobin-related protein (Hpr), which binds free hemoglobin (Hb) in blood and facilitates the uptake of TLF via a trypanosome haptoglobin-hemoglobin receptor. TLF is activated in the acidic lysosome and forms pores in trypanosome membranes. TLF can also kill the intracellular Leishmania parasite within the acidic parasitophorous vacuole of macrophages. Therefore, we evaluated the potential antimicrobial activity of TLF against the facultative intracellular pathogen Salmonella typhimurium. In support of a general antimicrobial role TLF inhibited growth of S. typhimurium at acidic pH in vitro, however, TLF had no detectable effect on S. typhimurium infection of macrophages or mice.
The human-infective Trypanosoma brucei rhodesiense escapes lysis by TLF due to the expression of serum resistance-associated (SRA) protein, which binds and neutralizes apoL-I. Unlike humans, baboons are not susceptible to infection by T. b. rhodesiense due to previously unidentified serum factors. Here we show that baboons have a TLF complex that contains orthologs of Hpr and apoL-I, and that baboon apoL-I confers trypanolytic activity to mice and when expressed together with baboon Hpr and human apoA-I, provides protection against both animal-infective trypanosomes and the human-infective T. b. rhodesiense in vivo. We further define two lysines near the C-terminus of baboon apoL-1 that are sufficient to prevent binding to SRA, and thereby confer resistance to human serum-resistant trypanosomes. These findings form the basis for the creation of TLF transgenic livestock with resistance to animal and human-infective trypanosomes, which would reduce disease in animals and would reduce the zoonotic transmission of human-infective trypanosomes.
|Advisor:||Raper, Jayne, Darwin, Heran|
|Commitee:||Cross, George AM, Ernst, Joel, Rodriguez, Ana|
|School:||New York University|
|Department:||Basic Medical Science|
|School Location:||United States -- New York|
|Source:||DAI-B 70/12, Dissertation Abstracts International|
|Subjects:||Biochemistry, Biomedical engineering, Parasitology|
|Keywords:||Apolipoprotein L-I, Haptoglobin related protein, Serum resistance associated, Trypanosoma, Trypanosome lytic factor, Trypanosomiasis|
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