title: TIM-family proteins promote infection of multiple enveloped viruses through virion-associated phosphatidylserine.
abstract: Human T-cell Immunoglobulin and Mucin-domain containing proteins (TIM1, 3, and 4) specifically bind phosphatidylserine (PS). TIM1 has been proposed to serve as a cellular receptor for hepatitis A virus and Ebola virus and as an entry factor for dengue virus. Here we show that TIM1 promotes infection of retroviruses and virus-like particles (VLPs) pseudotyped with a range of viral entry proteins, in particular those from the filovirus, flavivirus, New World arenavirus and alphavirus families. TIM1 also robustly enhanced the infection of replication-competent viruses from the same families, including dengue, Tacaribe, Sindbis and Ross River viruses. All interactions between TIM1 and pseudoviruses or VLPs were PS-mediated, as demonstrated with liposome blocking and TIM1 mutagenesis experiments. In addition, other PS-binding proteins, such as Axl and TIM4, promoted infection similarly to TIM1. Finally, the blocking of PS receptors on macrophages inhibited the entry of Ebola VLPs, suggesting that PS receptors can contribute to infection in physiologically relevant cells. Notably, infection mediated by the entry proteins of Lassa fever virus, influenza A virus and SARS coronavirus was largely unaffected by TIM1 expression. Taken together our data show that TIM1 and related PS-binding proteins promote infection of diverse families of enveloped viruses, and may therefore be useful targets for broad-spectrum antiviral therapies.
authors.affiliation: Division of Respiratory Diseases Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Jemielity
authors.forename: Jinyize J
authors.initials: JJ
authors.lastname: Wang
authors.forename: Ying Kai
authors.initials: YK
authors.lastname: Chan
authors.forename: Asim A
authors.initials: AA
authors.lastname: Ahmed
authors.forename: Wenhui
authors.initials: W
authors.lastname: Li
authors.forename: Sheena
authors.initials: S
authors.lastname: Monahan
authors.forename: Xia
authors.initials: X
authors.lastname: Bu
authors.forename: Michael
authors.initials: M
authors.lastname: Farzan
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Dale T
authors.initials: DT
authors.lastname: Umetsu
authors.forename: Rosemarie H
authors.initials: RH
authors.lastname: Dekruyff
authors.forename: Hyeryun
authors.initials: H
authors.lastname: Choe
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002213:Capsid; D002460:Cell Line; D004285:Dogs; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000821:virology; D051379:Mice; D010718:Phosphatidylserines / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors; D014759:Viral Envelope Proteins; D014771:Virion / Q000378:metabolism; D014777:Virus Diseases / Q000378:metabolism* / Q000821:virology; D053586:Virus Internalization; D014780:Viruses / Q000472:pathogenicity*
chemical_list: C577228:ARHGEF5 protein, human; D000998:Antiviral Agents; D020662:Guanine Nucleotide Exchange Factors; D010718:Phosphatidylserines; D011518:Proto-Oncogene Proteins; D011991:Receptors, Virus; D064067:Rho Guanine Nucleotide Exchange Factors; D014759:Viral Envelope Proteins
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