Journal article
TIM1 (HAVCR1) Is Not Essential for Cellular Entry of Either Quasi-enveloped or Naked Hepatitis A Virions
mBio, Vol.8(5), p.e00969-17
09/05/2017
DOI: 10.1128/mBio.00969-17
PMCID: PMC5587907
PMID: 28874468
Abstract
Receptor molecules play key roles in the cellular entry of picornaviruses, and TIM1 (HAVCR1) is widely accepted to be the receptor for hepatitis A virus (HAV), an unusual, hepatotropic human picornavirus. However, its identification as the hepatovirus receptor predated the discovery that hepatoviruses undergo nonlytic release from infected cells as membrane-cloaked, quasi-enveloped HAV (eHAV) virions that enter cells via a pathway distinct from naked, nonenveloped virions. We thus revisited the role of TIM1 in hepatovirus entry, examining both adherence and infection/replication in cells with clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-engineered TIM1 knockout. Cell culture-derived, gradient-purified eHAV bound Huh-7.5 human hepatoma cells less efficiently than naked HAV at 4°C, but eliminating TIM1 expression caused no difference in adherence of either form of HAV, nor any impact on infection and replication in these cells. In contrast, TIM1-deficient Vero cells showed a modest reduction in quasi-enveloped eHAV (but not naked HAV) attachment and replication. Thus, TIM1 facilitates quasi-enveloped eHAV entry in Vero cells, most likely by binding phosphatidylserine (PtdSer) residues on the eHAV membrane. Both
and
double-knockout mice were susceptible to infection upon intravenous challenge with infected liver homogenate, with fecal HAV shedding and serum alanine aminotransferase (ALT) elevations similar to those in
mice. However, intrahepatic HAV RNA and ALT elevations were modestly reduced in
mice compared to
mice challenged with a lower titer of gradient-purified HAV or eHAV. We conclude that TIM1 is not an essential hepatovirus entry factor, although its PtdSer-binding activity may contribute to the spread of quasi-enveloped virus and liver injury in mice.
T cell immunoglobulin and mucin-containing domain protein 1 (TIM1) was reported more than 2 decades ago to be an essential cellular receptor for hepatitis A virus (HAV), a picornavirus in the
genus, resulting in its designation as "hepatitis A virus cellular receptor 1" (HAVCR1) by the Human Genome Organization Gene Nomenclature Committee. However, recent studies have shown that HAV exists in nature as both naked, nonenveloped (HAV) virions and membrane-cloaked, quasi-enveloped infectious virus (eHAV), prompting us to revisit the role of TIM1 in viral entry. We show here that TIM1 (HAVCR1) is not an essential cellular receptor for HAV entry into cultured cells or required for viral replication and pathogenesis in permissive strains of mice, although it may facilitate early stages of infection by binding phosphatidylserine on the eHAV surface. This work thus corrects the published record and sets the stage for future efforts to identify specific hepatovirus entry factors.
Details
- Title: Subtitle
- TIM1 (HAVCR1) Is Not Essential for Cellular Entry of Either Quasi-enveloped or Naked Hepatitis A Virions
- Creators
- Anshuman Das - Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USAAsuka Hirai-Yuki - Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USAOlga González-López - Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USABethany Rhein - Department of Microbiology, University of Iowa, Iowa City, Iowa, USASven Moller-Tank - Department of Microbiology, University of Iowa, Iowa City, Iowa, USARachel Brouillette - Department of Microbiology, University of Iowa, Iowa City, Iowa, USALucinda Hensley - Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USAIchiro Misumi - Department of Microbiology & Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USAWilliam Lovell - Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USAJohn M Cullen - Department of Population Health & Pathobiology, North Carolina State University College of Veterinary Medicine, Raleigh, North Carolina, USAJason K Whitmire - Department of Microbiology & Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USAWendy Maury - Department of Microbiology, University of Iowa, Iowa City, Iowa, USAStanley M Lemon - Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Resource Type
- Journal article
- Publication Details
- mBio, Vol.8(5), p.e00969-17
- DOI
- 10.1128/mBio.00969-17
- PMID
- 28874468
- PMCID
- PMC5587907
- NLM abbreviation
- mBio
- ISSN
- 2161-2129
- eISSN
- 2150-7511
- Grant note
- U19 AI109965 / NIAID NIH HHS R01 AI103083 / NIAID NIH HHS R01 AI077519 / NIAID NIH HHS R01 AI131685 / NIAID NIH HHS R21 AI117575 / NIAID NIH HHS U54 AI057160 / NIAID NIH HHS T32 AI007533 / NIAID NIH HHS
- Language
- English
- Date published
- 09/05/2017
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984083274602771
Metrics
41 Record Views