The Trypanosoma Brucei KIFC1 Kinesin Ensures the Fast Antibody Clearance Required for Parasite Infectivity

Laurence Lecordier; Sophie Uzureau; Gilles Vanwalleghem; Magali Deleu; Jean Marc Crowet; Paul Barry; Barry Moran; Paul Voorheis; Andra Cristina Dumitru; Yoshiki Yamaryo-Botté; Marc Dieu; Patricia Tebabi; Benoit Vanhollebeke; Laurence Lins; Cyrille Y. Botté; David Alsteens; Yves Dufrêne; David Pérez-Morga; Derek P. Nolan; Etienne Pays

doi:10.1016/j.isci.2020.101476

The Trypanosoma Brucei KIFC1 Kinesin Ensures the Fast Antibody Clearance Required for Parasite Infectivity

Laurence Lecordier, Sophie Uzureau, Gilles Vanwalleghem, Magali Deleu, Jean Marc Crowet, Paul Barry, Barry Moran, Paul Voorheis, Andra Cristina Dumitru, Yoshiki Yamaryo-Botté, Marc Dieu, Patricia Tebabi, Benoit Vanhollebeke, Laurence Lins, Cyrille Y. Botté, David Alsteens, Yves Dufrêne, David Pérez-Morga, Derek P. Nolan, Etienne Pays

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Article number	101476
Journal	iScience
Volume	23
Issue number	9
Early online date	2020
DOIs	https://doi.org/10.1016/j.isci.2020.101476
Publication status	Published - 25 Sept 2020

Keywords

Cell Biology
Immunology
Microbiology Parasite

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10.1016/j.isci.2020.101476

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Lecordier, L., Uzureau, S., Vanwalleghem, G., Deleu, M., Crowet, J. M., Barry, P., Moran, B., Voorheis, P., Dumitru, A. C., Yamaryo-Botté, Y., Dieu, M., Tebabi, P., Vanhollebeke, B., Lins, L., Botté, C. Y., Alsteens, D., Dufrêne, Y., Pérez-Morga, D., Nolan, D. P., & Pays, E. (2020). The Trypanosoma Brucei KIFC1 Kinesin Ensures the Fast Antibody Clearance Required for Parasite Infectivity. iScience, 23(9), Article 101476. https://doi.org/10.1016/j.isci.2020.101476

@article{11134031c3ca49a8bf594317118e539f,

title = "The Trypanosoma Brucei KIFC1 Kinesin Ensures the Fast Antibody Clearance Required for Parasite Infectivity",

abstract = "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.",

keywords = "Cell Biology, Immunology, Microbiology Parasite",

author = "Laurence Lecordier and Sophie Uzureau and Gilles Vanwalleghem and Magali Deleu and Crowet, {Jean Marc} and Paul Barry and Barry Moran and Paul Voorheis and Dumitru, {Andra Cristina} and Yoshiki Yamaryo-Bott{\'e} and Marc Dieu and Patricia Tebabi and Benoit Vanhollebeke and Laurence Lins and Bott{\'e}, {Cyrille Y.} and David Alsteens and Yves Dufr{\^e}ne and David P{\'e}rez-Morga and Nolan, {Derek P.} and Etienne Pays",

note = "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 Concert{\'e}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{\textquoteright}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: {\textcopyright} 2020 The Author(s)",

year = "2020",

month = sep,

day = "25",

doi = "10.1016/j.isci.2020.101476",

language = "English",

volume = "23",

journal = "iScience",

issn = "2589-0042",

publisher = "Cell Press",

number = "9",

}

Lecordier, L, Uzureau, S, Vanwalleghem, G, Deleu, M, Crowet, JM, Barry, P, Moran, B, Voorheis, P, Dumitru, AC, Yamaryo-Botté, Y, Dieu, M, Tebabi, P, Vanhollebeke, B, Lins, L, Botté, CY, Alsteens, D, Dufrêne, Y, Pérez-Morga, D, Nolan, DP & Pays, E 2020, 'The Trypanosoma Brucei KIFC1 Kinesin Ensures the Fast Antibody Clearance Required for Parasite Infectivity', iScience, vol. 23, no. 9, 101476. https://doi.org/10.1016/j.isci.2020.101476

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 -

The Trypanosoma Brucei KIFC1 Kinesin Ensures the Fast Antibody Clearance Required for Parasite Infectivity

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