The Phosphatidylserine Receptor TIM-1 Enhances Authentic Chikungunya Virus Cell Entry

Abstract

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 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.

Enveloped RNA virus utilization of phosphatidylserine receptors: Advantages of exploiting a conserved, widely available mechanism of entry

“…Interestingly, viruses seem to preferentially use one PS receptor over others. TIM-1 is preferentially used by EBOV, CHIKV, and DENV, whereas SARS-CoV-2 or ZIKV entry is preferentially enhanced by AXL [ 7 , 25 , 39 , 40 ]. The mechanism driving this distinction is unknown.…”

A Review on Chikungunya Virus Epidemiology, Pathogenesis and Current Vaccine Development

“…Additionally, other phosphatidylserine binding proteins, such as Axl and TIM-4, have also been demonstrated to facilitate CHIKV infection [ 51 ]. However, a recent independent study showed that only TIM-1, unlike Axl, is functional as an entry factor for CHIKV infection [ 52 ].…”

Scrambled or flipped: 5 facts about how cellular phosphatidylserine localization can mediate viral replication

“…Numerous enveloped viruses including dengue virus [11,12], Ebola virus (EBOV) [11,[13][14][15][16][17][18], chikungunya virus [11,13,19], vaccinia virus [20][21][22], and others [11,13,19,[23][24][25][26][27][28][29][30][31][32][33] utilize PtdSer receptors for initial host cell attachment, a mechanism termed apoptotic mimicry (Fig 2A). PtdSer within the outer leaflet of the viral envelope mediates binding to PtdSer receptors on phagocytic cells that typically recognize PtdSer-coated apoptotic bodies.…”