Apolipoprotein L1 Variant Associated with Increased Susceptibility to Trypanosome Infection

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 prot...

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Autores principales:	Bart Cuypers, Laurence Lecordier, Conor J. Meehan, Frederik Van den Broeck, Hideo Imamura, Philippe Büscher, Jean-Claude Dujardin, Kris Laukens, Achim Schnaufer, Caroline Dewar, Michael Lewis, Oliver Balmer, Thomas Azurago, Sardick Kyei-Faried, Sally-Ann Ohene, Boateng Duah, Prince Homiah, Ebenezer Kofi Mensah, Francis Anleah, Jose Ramon Franco, Etienne Pays, Stijn Deborggraeve
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/16ed32b2f6534b7296f6ac0683f6f5da
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spelling	oai:doaj.org-article:16ed32b2f6534b7296f6ac0683f6f5da2021-11-15T15:41:41ZApolipoprotein L1 Variant Associated with Increased Susceptibility to Trypanosome Infection10.1128/mBio.02198-152150-7511https://doaj.org/article/16ed32b2f6534b7296f6ac0683f6f5da2016-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02198-15https://doaj.org/toc/2150-7511ABSTRACT 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.Bart CuypersLaurence LecordierConor J. MeehanFrederik Van den BroeckHideo ImamuraPhilippe BüscherJean-Claude DujardinKris LaukensAchim SchnauferCaroline DewarMichael LewisOliver BalmerThomas AzuragoSardick Kyei-FariedSally-Ann OheneBoateng DuahPrince HomiahEbenezer Kofi MensahFrancis AnleahJose Ramon FrancoEtienne PaysStijn DeborggraeveAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 2 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Bart Cuypers Laurence Lecordier Conor J. Meehan Frederik Van den Broeck Hideo Imamura Philippe Büscher Jean-Claude Dujardin Kris Laukens Achim Schnaufer Caroline Dewar Michael Lewis Oliver Balmer Thomas Azurago Sardick Kyei-Faried Sally-Ann Ohene Boateng Duah Prince Homiah Ebenezer Kofi Mensah Francis Anleah Jose Ramon Franco Etienne Pays Stijn Deborggraeve Apolipoprotein L1 Variant Associated with Increased Susceptibility to Trypanosome Infection
description	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.
format	article
author	Bart Cuypers Laurence Lecordier Conor J. Meehan Frederik Van den Broeck Hideo Imamura Philippe Büscher Jean-Claude Dujardin Kris Laukens Achim Schnaufer Caroline Dewar Michael Lewis Oliver Balmer Thomas Azurago Sardick Kyei-Faried Sally-Ann Ohene Boateng Duah Prince Homiah Ebenezer Kofi Mensah Francis Anleah Jose Ramon Franco Etienne Pays Stijn Deborggraeve
author_facet	Bart Cuypers Laurence Lecordier Conor J. Meehan Frederik Van den Broeck Hideo Imamura Philippe Büscher Jean-Claude Dujardin Kris Laukens Achim Schnaufer Caroline Dewar Michael Lewis Oliver Balmer Thomas Azurago Sardick Kyei-Faried Sally-Ann Ohene Boateng Duah Prince Homiah Ebenezer Kofi Mensah Francis Anleah Jose Ramon Franco Etienne Pays Stijn Deborggraeve
author_sort	Bart Cuypers
title	Apolipoprotein L1 Variant Associated with Increased Susceptibility to Trypanosome Infection
title_short	Apolipoprotein L1 Variant Associated with Increased Susceptibility to Trypanosome Infection
title_full	Apolipoprotein L1 Variant Associated with Increased Susceptibility to Trypanosome Infection
title_fullStr	Apolipoprotein L1 Variant Associated with Increased Susceptibility to Trypanosome Infection
title_full_unstemmed	Apolipoprotein L1 Variant Associated with Increased Susceptibility to Trypanosome Infection
title_sort	apolipoprotein l1 variant associated with increased susceptibility to trypanosome infection
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/16ed32b2f6534b7296f6ac0683f6f5da
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Apolipoprotein L1 Variant Associated with Increased Susceptibility to Trypanosome Infection

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