Apolipoprotein A-I truncations in Chagas disease are caused by cruzipain, the major cysteine protease of Trypanosoma cruzi.
Trypanosoma cruzi is the etiologic agent of Chagas disease. Approximately 10 million people are infected worldwide. We have previously reported that in individuals infected with T. cruzi, apolipoprotein A-I (Apo A-I), the major structural component of host high-density lipoprotein, was truncated into fragments that are specific to Chagas disease and have the potential to be used as diagnostic biomarkers. We investigated the possibility that cruzipain, the major cysteine protease of T. cruzi, is responsible for truncating host Apo A-I. We found that due to Apo A-I truncation, the high-density lipoprotein subspecies profile is altered in individuals with Chagas disease compared with healthy controls. Western blot analysis revealed that both purified Apo A-I protein and Apo A-I in the high-density lipoprotein complex were susceptible to cruzipain cleavage, and the sizes of the truncation product in the latter matched the sizes of Apo A-I biomarkers. We also found that in vitro feeding T. cruzi-infected differentiated human adipocytes with purified human high-density lipoprotein led to the appearance of the biomarker fragments of Apo A-I. Cruzipain is found both on the cytoplasmic membrane and in the internal lysosomal structure of T. cruzi. We demonstrate that cruzipain from both sources contributes to the production of Apo A-I truncation in the biomarker set.
National Reference Centre for Parasitology, Research Institute of McGill University Health Centre, Montreal, Quebec, Canada; Department of Microbiology and Immunology, McGill University, Montreal General Hospital, Montreal, Quebec, Canada.
Qianqian
Q
Miao
National Reference Centre for Parasitology, Research Institute of McGill University Health Centre, Montreal, Quebec, Canada.
Cynthia
C
Santamaria
National Reference Centre for Parasitology, Research Institute of McGill University Health Centre, Montreal, Quebec, Canada.
Dana
D
Bailey
Division of Cardiology, Research Institute of McGill University Health Centre, Montreal, Quebec, Canada.
Jacques
J
Genest
National Reference Centre for Parasitology, Research Institute of McGill University Health Centre, Montreal, Quebec, Canada; Department of Microbiology and Immunology, McGill University, Montreal General Hospital, Montreal, Quebec, Canada.
Brian J
BJ
Ward
National Reference Centre for Parasitology, Research Institute of McGill University Health Centre, Montreal, Quebec, Canada; Department of Microbiology and Immunology, McGill University, Montreal General Hospital, Montreal, Quebec, Canada. Electronic address: momar.ndao@mcgill.ca.
Momar
M
Ndao
D000595:Amino Acid Sequence; D016632:Apolipoprotein A-I / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D014355:Chagas Disease / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015180:Electrophoresis, Gel, Two-Dimensional; D006790:Host-Parasite Interactions; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism; D015800:Protozoan Proteins; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014349:Trypanosoma cruzi / Q000201:enzymology*
D016632:Apolipoprotein A-I; D015415:Biomarkers; D010446:Peptide Fragments; D015800:Protozoan Proteins; D003546:Cysteine Endopeptidases; C063214:cruzipain