|
Title
|
|
|
|
Apolipoprotein L1 variant associated with increased susceptibility to trypanosome infection
| |
|
Author
|
|
|
|
| |
|
Abstract
|
|
|
|
| African trypanosomes, except Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, which cause human African trypanosomiasis, are lysed by the human serum protein apolipoprotein Li (ApoL I). These two subspecies can resist human ApoLl 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 ApoLl, in T. b. gambiense, TgsGP cannot protect against high ApoLl uptake, so different additional mechanisms contribute to limit this uptake. Here we report a complex interplay between trypanosomes and an ApoLl 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 ApoLl 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 ApoLl variant knocks down the trypanolytic activity, allowing the trypanosome to avoid ApoLl-mediated immunity. IMPORTANCE Most African trypanosomes are lysed by the ApoLl protein in human serum. Only the subspecies Trypanosoma b. gambiense and T. b. rhodesiense can resist lysis by ApoLl because they express specific serum resistance proteins. We here report a complex interplay between trypanosomes and an ApoLl 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 ApoLl 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 ApoLl variant may be at increased risk of contracting human African trypanosomiasis. |
| |
|
Language
|
|
|
|
English
| |
|
Source (journal)
|
|
|
|
mBio / American Society for Microbiology. - Washington, D.C., 2010, currens
| |
|
Publication
|
|
|
|
Washington, D.C.
:
American Society for Microbiology
,
2016
| |
|
ISSN
|
|
|
|
2150-7511
| |
|
DOI
|
|
|
|
10.1128/MBIO.02198-15
| |
|
Volume/pages
|
|
|
|
7
:2
(2016)
, 8 p.
| |
|
Article Reference
|
|
|
|
e02198-15
| |
|
ISI
|
|
|
|
000377768700026
| |
|
Medium
|
|
|
|
E-only publicatie
| |
|
Full text (Publisher's DOI)
|
|
|
|
| |
|
Full text (open access)
|
|
|
|
| |
|