The mechanism of human ApoL 1 killing of African trypanosomes
Greene, Amy Styer
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Trypanosoma brucei brucei parasites are rapidly lysed by human serum due to innate immune factors called trypanosome lytic factors (TLFs). Related parasites T. b. rhodesiense and T. b. gambiense evolved resistance to the TLFs and cause the deadly disease human African trypanosomiasis. My work focused on TLF-1, a high density lipoprotein particle (HDL) containing the pore-forming toxin Apolipoprotein L1 (ApoL1) and hemoglobin-binding protein haptoglobin related protein (Hpr). I found that TLF-1 and ApoL1 cause rapid changes at the plasma membrane, including dissipating the plasma membrane potential and inducing sensitivity to hypotonic lysis. ApoL1-induced osmotic stress at the plasma membrane leads to water influx and eventual lysis. Moreover, osmotic lysis is exacerbated by oxidizing agents and molecules which bind to free thiols in proteins. My work suggests that ApoL1 in TLF-1 traffics to the plasma membrane of T. b. brucei, facilitating sodium influx, ionic imbalance, oxidation of osmoregulatory proteins, cell swelling, and trypanosome lysis.