Serum resistance-associated protein blocks lysosomal targeting of trypanosome lytic factor in Trypanosoma brucei.
Trypanosoma brucei brucei is the causative agent of nagana in cattle and can infect a wide range of mammals but is unable to infect humans because it is susceptible to the innate cytotoxic activity of normal human serum. A minor subfraction of human high-density lipoprotein (HDL) containing apolipoprotein A-I (apoA-I), apolipoprotein L-I (apoL-I), and haptoglobin-related protein (Hpr) provides this innate protection against T. b. brucei infection. This HDL subfraction, called trypanosome lytic factor (TLF), kills T. b. brucei following receptor binding, endocytosis, and lysosomal localization. Trypanosoma brucei rhodesiense, which is morphologically and physiologically indistinguishable from T. b. brucei, is resistant to TLF-mediated killing and causes human African sleeping sickness. Human infectivity by T. b. rhodesiense correlates with the evolution of a resistance-associated protein (SRA) that is able to ablate TLF killing. To examine the mechanism of TLF resistance, we transfected T. b. brucei with an epitope-tagged SRA gene. Transfected T. b. brucei expressed SRA mRNA at levels comparable to those in T. b. rhodesiense and was highly resistant to TLF. In the SRA-transfected cells, intracellular trafficking of TLF was altered, with TLF being mainly localized to a subset of SRA-containing cytoplasmic vesicles but not to the lysosome. These results indicate that the cellular distribution of TLF is influenced by SRA expression and may directly determine the organism's susceptibility to TLF.
Oli
Monika W
MW
Global Infectious Disease Program, Josephine Bay Paul Center, Marine Biological Laboratory, 7 MBL Street, Woods Hole, Massachusetts 02543, USA.
Cotlin
Laura F
LF
Shiflett
April M
AM
Hajduk
Stephen L
SL
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D005838:Genotype; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D021381:Protein Transport; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014346:Trypanosoma brucei brucei / Q000166:cytology* / Q000378:metabolism*
D008075:Lipoproteins, HDL; D008562:Membrane Glycoproteins; D015800:Protozoan Proteins; D012333:RNA, Messenger; C434063:TLF1 protein, human; C403774:serum resistance associated protein, Trypanosoma brucei