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Human innate immunity to Trypanosoma brucei involves the trypanosome C-terminal kinesin Tb KIFC1, which transports internalized trypanolytic factor apolipoprotein L1 (APOL1) within the parasite. We show that Tb KIFC1 preferentially associates with cholesterol-containing membranes and is indispensable for mammalian infectivity. Knockdown of Tb KIFC1 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 Tb KIFC1 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 Tb KIFC1., Competing Interests: The authors declare that they have no competing financial interest., (© 2020 The Author(s).)