The Phosphatidylserine Receptor TIM-1 Enhances Authentic Chikungunya Virus Cell Entry
Jared Kirui,
Yara Abidine,
Annasara Lenman,
Koushikul Islam,
Yong-Dae Gwon,
Lisa Lasswitz,
Magnus Evander,
Marta Bally,
Gisa Gerold
Affiliations
Jared Kirui
Centre for Experimental and Clinical Infection Research, TWINCORE, Institute for Experimental Virology, a Joint Venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, 30625 Hannover, Germany
Yara Abidine
Department of Clinical Microbiology, Umeå University, 90185 Umeå, Sweden
Annasara Lenman
Centre for Experimental and Clinical Infection Research, TWINCORE, Institute for Experimental Virology, a Joint Venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, 30625 Hannover, Germany
Koushikul Islam
Department of Clinical Microbiology, Umeå University, 90185 Umeå, Sweden
Yong-Dae Gwon
Department of Clinical Microbiology, Umeå University, 90185 Umeå, Sweden
Lisa Lasswitz
Centre for Experimental and Clinical Infection Research, TWINCORE, Institute for Experimental Virology, a Joint Venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, 30625 Hannover, Germany
Magnus Evander
Department of Clinical Microbiology, Umeå University, 90185 Umeå, Sweden
Marta Bally
Department of Clinical Microbiology, Umeå University, 90185 Umeå, Sweden
Gisa Gerold
Centre for Experimental and Clinical Infection Research, TWINCORE, Institute for Experimental Virology, a Joint Venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, 30625 Hannover, Germany
Chikungunya virus (CHIKV) is a re-emerging, mosquito-transmitted, enveloped positive stranded RNA virus. Chikungunya fever is characterized by acute and chronic debilitating arthritis. Although multiple host factors have been shown to enhance CHIKV infection, the molecular mechanisms of cell entry and entry factors remain poorly understood. The phosphatidylserine-dependent receptors, T-cell immunoglobulin and mucin domain 1 (TIM-1) and Axl receptor tyrosine kinase (Axl), are transmembrane proteins that can serve as entry factors for enveloped viruses. Previous studies used pseudoviruses to delineate the role of TIM-1 and Axl in CHIKV entry. Conversely, here, we use the authentic CHIKV and cells ectopically expressing TIM-1 or Axl and demonstrate a role for TIM-1 in CHIKV infection. To further characterize TIM-1-dependent CHIKV infection, we generated cells expressing domain mutants of TIM-1. We show that point mutations in the phosphatidylserine binding site of TIM-1 lead to reduced cell binding, entry, and infection of CHIKV. Ectopic expression of TIM-1 renders immortalized keratinocytes permissive to CHIKV, whereas silencing of endogenously expressed TIM-1 in human hepatoma cells reduces CHIKV infection. Altogether, our findings indicate that, unlike Axl, TIM-1 readily promotes the productive entry of authentic CHIKV into target cells.
