title: 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 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Biomedical Sciences Department, Institute of Tropical Medicine Antwerp, Antwerp, Belgium Advanced Database Research and Modelling (ADReM), Department of Mathematics and Computer Science, University of Antwerp, Antwerp, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Cuypers
authors.affiliation: Laboratory of Molecular Parasitology, Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: Laurence
authors.initials: L
authors.lastname: Lecordier
authors.affiliation: Biomedical Sciences Department, Institute of Tropical Medicine Antwerp, Antwerp, Belgium.
authors.forename: Conor J
authors.initials: CJ
authors.lastname: Meehan
authors.affiliation: Biomedical Sciences Department, Institute of Tropical Medicine Antwerp, Antwerp, Belgium.
authors.forename: Frederik
authors.initials: F
authors.lastname: Van den Broeck
authors.affiliation: Biomedical Sciences Department, Institute of Tropical Medicine Antwerp, Antwerp, Belgium.
authors.forename: Hideo
authors.initials: H
authors.lastname: Imamura
authors.affiliation: Biomedical Sciences Department, Institute of Tropical Medicine Antwerp, Antwerp, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Büscher
authors.affiliation: Biomedical Sciences Department, Institute of Tropical Medicine Antwerp, Antwerp, Belgium.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Dujardin
authors.affiliation: Advanced Database Research and Modelling (ADReM), Department of Mathematics and Computer Science, University of Antwerp, Antwerp, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Laukens
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Achim
authors.initials: A
authors.lastname: Schnaufer
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dewar
authors.affiliation: Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Lewis
authors.affiliation: Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Balmer
authors.affiliation: Disease Control and Prevention Department, Ghana Health Service, Accra, Ghana.
authors.forename: Thomas
authors.initials: T
authors.lastname: Azurago
authors.affiliation: Disease Control and Prevention Department, Ghana Health Service, Accra, Ghana.
authors.forename: Sardick
authors.initials: S
authors.lastname: Kyei-Faried
authors.affiliation: World Health Organization Country Office in Ghana, Accra, Ghana.
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Ohene
authors.affiliation: Ghana Ports and Harbours Authority Hospital, Takoradi, Ghana.
authors.forename: Boateng
authors.initials: B
authors.lastname: Duah
authors.affiliation: Ghana Ports and Harbours Authority Hospital, Takoradi, Ghana.
authors.forename: Prince
authors.initials: P
authors.lastname: Homiah
authors.affiliation: Public Health Reference Laboratory, Takoradi, Ghana.
authors.forename: Ebenezer Kofi
authors.initials: EK
authors.lastname: Mensah
authors.affiliation: Ghana Health Service, Takoradi, Ghana.
authors.forename: Francis
authors.initials: F
authors.lastname: Anleah
authors.affiliation: Department of Control of Neglected Diseases, World Health Organization, Geneva, Switzerland.
authors.forename: Jose Ramon
authors.initials: JR
authors.lastname: Franco
authors.affiliation: Laboratory of Molecular Parasitology, Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: Etienne
authors.initials: E
authors.lastname: Pays
authors.affiliation: Biomedical Sciences Department, Institute of Tropical Medicine Antwerp, Antwerp, Belgium sdeborggraeve@itg.be.
authors.forename: Stijn
authors.initials: S
authors.lastname: Deborggraeve
mesh_terms: D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics* / Q000276:immunology; D004198:Disease Susceptibility; D014644:Genetic Variation; D006801:Humans; D007113:Immunity, Innate; D008075:Lipoproteins, HDL / Q000235:genetics* / Q000276:immunology; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D014347:Trypanosoma brucei gambiense / Q000502:physiology*; D016833:Trypanosoma brucei rhodesiense / Q000502:physiology*; D014353:Trypanosomiasis, African / Q000235:genetics* / Q000276:immunology / Q000469:parasitology
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D008075:Lipoproteins, HDL; D015800:Protozoan Proteins