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Apolipoprotein L1 Variant Associated with Increased Susceptibility to Trypanosome Infection
Cuypers, B. Lecordier, L. Meehan, Conor J. Van den Broeck, F. Imamura, H. Büscher, P. Dujardin, J.-C. Laukens, K. Schnaufer, A. Dewar, C.
Cuypers, B.
Lecordier, L.
Meehan, Conor J.
Van den Broeck, F.
Imamura, H.
Büscher, P.
Dujardin, J.-C.
Laukens, K.
Schnaufer, A.
Dewar, C.
Publication Date
12/04/2016
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© 2016 Cuypers et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.
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12/04/2016
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Abstract
African trypanosomes, except Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, which cause
human African trypanosomiasis, are lysed by the human serum protein apolipoprotein L1 (ApoL1). These two subspecies can
resist human ApoL1 because they express the serum resistance proteins T. b. gambiense glycoprotein (TgsGP) and serum
resistance-associated protein (SRA), respectively. Whereas in T. b. rhodesiense, SRA is necessary and sufficient to inhibit ApoL1,
in T. b. gambiense, TgsGP cannot protect against high ApoL1 uptake, so different additional mechanisms contribute to limit this
uptake. Here we report a complex interplay between trypanosomes and an ApoL1 variant, revealing important insights into innate human immunity against these parasites. Using whole-genome sequencing, we characterized an atypical T. b. gambiense
infection in a patient in Ghana. We show that the infecting trypanosome has diverged from the classical T. b. gambiense strains
and lacks the TgsGP defense mechanism against human serum. By sequencing the ApoL1 gene of the patient and subsequent in
vitro mutagenesis experiments, we demonstrate that a homozygous missense substitution (N264K) in the membrane-addressing
domain of this ApoL1 variant knocks down the trypanolytic activity, allowing the trypanosome to avoid ApoL1-mediated immunity.
IMPORTANCE. Most African trypanosomes are lysed by the ApoL1 protein in human serum. Only the subspecies Trypanosoma
b. gambiense and T. b. rhodesiense can resist lysis by ApoL1 because they express specific serum resistance proteins. We here
report a complex interplay between trypanosomes and an ApoL1 variant characterized by a homozygous missense substitution
(N264K) in the domain that we hypothesize interacts with the endolysosomal membranes of trypanosomes. The N264K substitution knocks down the lytic activity of ApoL1 against T. b. gambiense strains lacking the TgsGP defense mechanism and against
T. b. rhodesiense if N264K is accompanied by additional substitutions in the SRA-interacting domain. Our data suggest that
populations with high frequencies of the homozygous N264K ApoL1 variant may be at increased risk of contracting human African trypanosomiasis.
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Cuypers B, Lecordier L, Meehan CJ et al (2016) Apolipoprotein L1 Variant Associated with Increased Susceptibility to Trypanosome Infection. mBio. 7 (2): e02198-15.
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