A polymorphism in TIM1 is associated with susceptibility to severe hepatitis A virus infection in humans

Hye Young Kim; María Belén Eyheramonho; Muriel Pichavant; Carlos Gonzalez Cambaceres; Ponpan Matangkasombut; Guillermo Cervio; Silvina Kuperman; Rita Moreiro; Krishnamurthy Konduru; Mohanraj Manangeeswaran; Gordon J Freeman; Gerardo G Kaplan; Rosemarie H DeKruyff; Dale T Umetsu; Sergio D Rosenzweig

doi:10.1172/JCI44182

Back

A polymorphism in TIM1 is associated with susceptibility to severe hepatitis A virus infection in humans

Journal article

Open access

Peer reviewed

A polymorphism in TIM1 is associated with susceptibility to severe hepatitis A virus infection in humans

Hye Young Kim, María Belén Eyheramonho, Muriel Pichavant, Carlos Gonzalez Cambaceres, Ponpan Matangkasombut, Guillermo Cervio, Silvina Kuperman, Rita Moreiro, Krishnamurthy Konduru, Mohanraj Manangeeswaran, …

The Journal of clinical investigation, Vol.121(3), pp.1111-1118

03/01/2011

DOI: 10.1172/JCI44182

PMCID: PMC3049365

PMID: 21339644

Files and links (1)

url

https://doi.org/10.1172/JCI44182View

Published (Version of record) Open Access

Abstract

During infection with the hepatitis A virus (HAV), most patients develop mild or asymptomatic disease. However, a small number of patients develop serious, life-threatening hepatitis. We investigated this variability in disease severity by examining 30 Argentinean patients with HAV-induced acute liver failure in a case-control, cross-sectional, observational study. We found that HAV-induced severe liver disease was associated with a 6-amino-acid insertion in TIM1/HAVCR1 (157insMTTTVP), the gene encoding the HAV receptor. This polymorphism was previously shown to be associated with protection against asthma and allergic diseases and with HIV progression. In binding assays, the TIM-1 protein containing the 157insMTTTVP insertion polymorphism bound HAV more efficiently. When expressed by human natural killer T (NKT) cells, this long form resulted in greater NKT cell cytolytic activity against HAV-infected liver cells, compared with the shorter TIM-1 protein without the polymorphism. To our knowledge, the 157insMTTTVP polymorphism in TIM1 is the first genetic susceptibility factor shown to predispose to HAV-induced acute liver failure. Furthermore, these results suggest that HAV infection has driven the natural selection of shorter forms of the TIM-1 protein, which binds HAV less efficiently, thereby protecting against severe HAV-induced disease, but which may predispose toward inflammation associated with asthma and allergy.

Details

Title: Subtitle: A polymorphism in TIM1 is associated with susceptibility to severe hepatitis A virus infection in humans
Creators: Hye Young Kim - Infectious Diseases Susceptibility Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA
María Belén Eyheramonho - Infectious Diseases Susceptibility Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA
Muriel Pichavant - Infectious Diseases Susceptibility Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA
Carlos Gonzalez Cambaceres - Infectious Diseases Susceptibility Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA
Ponpan Matangkasombut - Infectious Diseases Susceptibility Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA
Guillermo Cervio - Infectious Diseases Susceptibility Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA
Silvina Kuperman - Infectious Diseases Susceptibility Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA
Rita Moreiro - Infectious Diseases Susceptibility Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA
Krishnamurthy Konduru - Infectious Diseases Susceptibility Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA
Mohanraj Manangeeswaran - Infectious Diseases Susceptibility Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA
Gordon J Freeman - Infectious Diseases Susceptibility Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA
Gerardo G Kaplan - Infectious Diseases Susceptibility Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA
Rosemarie H DeKruyff - Infectious Diseases Susceptibility Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA
Dale T Umetsu - Infectious Diseases Susceptibility Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA
Sergio D Rosenzweig - Infectious Diseases Susceptibility Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.121(3), pp.1111-1118
Publisher: American Society for Clinical Investigation
DOI: 10.1172/JCI44182
PMID: 21339644
PMCID: PMC3049365
ISSN: 0021-9738
eISSN: 1558-8238
Language: English
Date published: 03/01/2011
Academic Unit: Psychiatry; Stead Family Department of Pediatrics
Record Identifier: 9984003420602771

Metrics

36 Record Views

67 Times Cited - Web of Science

See more details