TY - JOUR
T1 - The Trypanosoma Brucei KIFC1 Kinesin Ensures the Fast Antibody Clearance Required for Parasite Infectivity
AU - Lecordier, Laurence
AU - Uzureau, Sophie
AU - Vanwalleghem, Gilles
AU - Deleu, Magali
AU - Crowet, Jean Marc
AU - Barry, Paul
AU - Moran, Barry
AU - Voorheis, Paul
AU - Dumitru, Andra Cristina
AU - Yamaryo-Botté, Yoshiki
AU - Dieu, Marc
AU - Tebabi, Patricia
AU - Vanhollebeke, Benoit
AU - Lins, Laurence
AU - Botté, Cyrille Y.
AU - Alsteens, David
AU - Dufrêne, Yves
AU - Pérez-Morga, David
AU - Nolan, Derek P.
AU - Pays, Etienne
N1 - Funding Information:
We thank V. Flamant for the gift of μMT KO mice, S. Dean for the gift of pPOTv7 plasmid, A. Gauquier for help in the BL approach, and D. Monteyne for SEM analysis. This work was supported by the European Research Council (ERC 669007 -APOLs), the “Action de Recherches Concertées” of the University of Brussels (ULB) (ARC ADV), and the Fonds de la Recherche Scientifique (F.R.S.-FNRS) ( PDR T.0159.13 to D.P.-M and PDR T.1003.14 to L.Lins and M.Deleu). The Center for Microscopy and Molecular Imaging is supported by the European Regional Development Fund and Wallonia. C.Y.B. and Y.Y. are supported by the Atip-Avenir and Fondation FINOVI programs (CNRS-INSERM-Finovi Atip-Avenir Apicolipid projects), and the Laboratoire d’Excellence Parafrap , France (grant number ANR-11-LABX-0024 ). Computational resources have been provided by the Consortium des Equipements de Calcul Intensif (CECI), funded by the FNRS (Grant No. 2.5020.11 ). D.P.N. thanks the Wellcome Trust and Science Foundation Ireland (SFI) for financial support. M.D. and L.L. thank the FRS-FNRS for their positions as Senior Research Associates.
Funding Information:
We thank V. Flamant for the gift of ?MT KO mice, S. Dean for the gift of pPOTv7 plasmid, A. Gauquier for help in the BL approach, and D. Monteyne for SEM analysis. This work was supported by the European Research Council (ERC 669007-APOLs), the ?Action de Recherches Concert?es? of the University of Brussels (ULB) (ARC ADV), and the Fonds de la Recherche Scientifique (F.R.S.-FNRS) (PDR T.0159.13 to D.P.-M and PDR T.1003.14 to L.Lins and M.Deleu). The Center for Microscopy and Molecular Imaging is supported by the European Regional Development Fund and Wallonia. C.Y.B. and Y.Y. are supported by the Atip-Avenir and Fondation FINOVI programs (CNRS-INSERM-Finovi Atip-Avenir Apicolipid projects), and the Laboratoire d'Excellence Parafrap, France (grant number ANR-11-LABX-0024). Computational resources have been provided by the Consortium des Equipements de Calcul Intensif (CECI), funded by the FNRS (Grant No. 2.5020.11). D.P.N. thanks the Wellcome Trust and Science Foundation Ireland (SFI) for financial support. M.D. and L.L. thank the FRS-FNRS for their positions as Senior Research Associates. E.P. D.P.N. and L. Lecordier designed the research; L. Lecordier, S.U. G.V. M.Deleu, J.-M.C. P.B. B.M. A-C.D. Y.Y. M.Dieu, P.T. D.P.-M. and D.P.N. performed the research; B.V. L. Lins, C.Y.B. D.A. Y.D. D.P.-M. and D.P.N. supervised some aspects of the work; E.P. and D.P.N. wrote the paper. The authors declare that they have no competing financial interest.
Publisher Copyright:
© 2020 The Author(s)
PY - 2020/9/25
Y1 - 2020/9/25
N2 - Human innate immunity to Trypanosoma brucei involves the trypanosome C-terminal kinesin TbKIFC1, which transports internalized trypanolytic factor apolipoprotein L1 (APOL1) within the parasite. We show that TbKIFC1
preferentially associates with cholesterol-containing membranes and is
indispensable for mammalian infectivity. Knockdown of TbKIFC1 did not affect trypanosome growth in vitro
but rendered the parasites unable to infect mice unless antibody
synthesis was compromised. Surface clearance of Variant Surface
Glycoprotein (VSG)-antibody complexes was far slower in these cells,
which were more susceptible to capture by macrophages. This phenotype
was not due to defects in VSG expression or trafficking but to decreased
VSG mobility in a less fluid, stiffer surface membrane. This change can
be attributed to increased cholesterol level in the surface membrane in
TbKIFC1 knockdown cells. Clearance of surface-bound antibodies by T. brucei
is therefore essential for infectivity and depends on high membrane
fluidity maintained by the cholesterol-trafficking activity of TbKIFC1.
AB - Human innate immunity to Trypanosoma brucei involves the trypanosome C-terminal kinesin TbKIFC1, which transports internalized trypanolytic factor apolipoprotein L1 (APOL1) within the parasite. We show that TbKIFC1
preferentially associates with cholesterol-containing membranes and is
indispensable for mammalian infectivity. Knockdown of TbKIFC1 did not affect trypanosome growth in vitro
but rendered the parasites unable to infect mice unless antibody
synthesis was compromised. Surface clearance of Variant Surface
Glycoprotein (VSG)-antibody complexes was far slower in these cells,
which were more susceptible to capture by macrophages. This phenotype
was not due to defects in VSG expression or trafficking but to decreased
VSG mobility in a less fluid, stiffer surface membrane. This change can
be attributed to increased cholesterol level in the surface membrane in
TbKIFC1 knockdown cells. Clearance of surface-bound antibodies by T. brucei
is therefore essential for infectivity and depends on high membrane
fluidity maintained by the cholesterol-trafficking activity of TbKIFC1.
KW - Cell Biology
KW - Immunology
KW - Microbiology Parasite
UR - http://www.scopus.com/inward/record.url?scp=85089998027&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2020.101476
DO - 10.1016/j.isci.2020.101476
M3 - Article
C2 - 32889430
AN - SCOPUS:85089998027
SN - 2589-0042
VL - 23
JO - iScience
JF - iScience
IS - 9
M1 - 101476
ER -