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C-terminal mutants of apolipoprotein L-I efficiently kill both Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense.

ABSTRACT: Apolipoprotein L-I (apoL1) is a human-specific serum protein that kills Trypanosoma brucei through ionic pore formation in endosomal membranes of the parasite. The T. brucei subspecies rhodesiense and gambiense resist this lytic activity and can infect humans, causing sleeping sickness. In the case of T. b. rhodesiense, resistance to lysis involves interaction of the Serum Resistance-Associated (SRA) protein with the C-terminal helix of apoL1. We undertook a mutational and deletional analysis of the C-terminal helix of apoL1 to investigate the linkage between interaction with SRA and lytic potential for different T. brucei subspecies. We confirm that the C-terminal helix is the SRA-interacting domain. Although in E. coli this domain was dispensable for ionic pore-forming activity, its interaction with SRA resulted in inhibition of this activity. Different mutations affecting the C-terminal helix reduced the interaction of apoL1 with SRA. However, mutants in the L370-L392 leucine zipper also lost in vitro trypanolytic activity. Truncating and/or mutating the C-terminal sequence of human apoL1 like that of apoL1-like sequences of Papio anubis resulted in both loss of interaction with SRA and acquired ability to efficiently kill human serum-resistant T. b. rhodesiense parasites, in vitro as well as in transgenic mice. These findings demonstrate that SRA interaction with the C-terminal helix of apoL1 inhibits its pore-forming activity and determines resistance of T. b. rhodesiense to human serum. In addition, they provide a possible explanation for the ability of Papio serum to kill T. b. rhodesiense, and offer a perspective to generate transgenic cattle resistant to both T. b. brucei and T. b. rhodesiense.

SUBMITTER: Lecordier L

PROVIDER: S-EPMC2778949 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Trypanosoma brucei rhodesiense is the causative agent for Rhodesian human African trypanosomiasis. The disease is considered acute, but varying clinical outcomes including chronic infections have been observed. The basis for these different clinical manifestations is thought to be associated with a combination of parasite and host factors. In the current study, Trypanosoma brucei rhodesiense strains responsible for varying infection outcomes were sought using mouse model. Clinical rHAT parasite isolates were subjected to PCR tests to confirm presence of the serum resistance associated (SRA) gene. Thereafter, four T. b. rhodesiense isolates were subjected to a comparative pathogenicity study using female Swiss white mice; the parasite strains were compared on the basis of parasitaemia, host survival time, clinical and postmortem biomarkers of infection severity. Isolates identified to cause acute and chronic disease were compared for establishment in insect vector, tsetse fly. The mouse survival time was significantly different (Log-rankp = 0.0001). With mice infected with strain KETRI 3801 exhibiting the shortest survival time (20 days) as compared to those infected with KETRI 3928 that, as controls, survived past the 60 days study period. In addition, development of anaemia was rapid in KETRI 3801 and least in KETRI 3928 infections, and followed the magnitude of survival time. Notably, hepatosplenomegaly was pronounced with longer survival. Mouse weight and feed intake reduced (KETRI 3801 > KETRI 2636 > EATRO 1762) except in KETRI 3928 infections which remained similar to controls. Comparatively, acute to chronic infection outcomes is in the order of KETRI 3801 > KETRI 2636 > EATRO 1762 > KETRI 3928, indicative of predominant role of strain dependent factors. Further, KETRI 3928 strain established better in tsetse as compared to KETRI 3801, suggesting that transmission of strains causing chronic infections could be common. In sum, we have identified Trypanosoma brucei rhodesiense strains that cause acute and chronic infections in mice, that will be valuable in investigating pathogen - host interactions responsible for varying disease outcomes and transmission in African trypanosomiasis.

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C-terminal mutants of apolipoprotein L-I efficiently kill both Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense.

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