A polymorphism in TIM1 is associated with susceptibility to severe hepatitis A virus infection in humans
Hye Young Kim, … , Dale T. Umetsu, Sergio D. Rosenzweig
Hye Young Kim, … , Dale T. Umetsu, Sergio D. Rosenzweig
Published February 21, 2011
Citation Information: J Clin Invest. 2011;121(3):1111-1118. https://doi.org/10.1172/JCI44182.
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Research Article

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

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.

Authors

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

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Figure 2

HAV induces the activation of NKT cells.

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HAV induces the activation of NKT cells. (A) NKT cells constitutively ex...
(A) NKT cells constitutively express TIM-1. NKT cells were identified by flow cytometry by gating on 6B11+CD3+ NKT cells in total PBMCs (upper panels) or in an NKT cell line (lower panels). TIM-1 expression was then analyzed on gated NKT cells (right panels). The numbers in the dot plot represent the percentage of NKT cells after gating on lymphocytes. Shaded histogram represents background staining with isotype control (mIgG1). (B) NKT cells are cytotoxic for HAV-infected hepatoma cells. Naive or HAV-infected hepatoma cells were cocultured with NKT cell lines from different donors (black: homozygous short form of TIM-1 [n = 6], light gray: heterozygous form of TIM-1 [n = 10], and white: homozygous long form of TIM-1 [n = 2]). AST levels of noninfected and HAV-infected hepatoma cells cultured alone are shown. After 48 hours, culture supernatants were analyzed for AST level. Greater AST indicates greater hepatoma cell lysis. Data are given as mean ± SEM; *P < 0.05, ***P < 0.001 (ANOVA). (C) WT HAV is found at the cell surface of HAV-infected hepatoma cells. Human hepatoma Huh7-A-I cells were infected with WT HAV (HAV-infected) or mock infected (Naive) and examined with a cell surface ELISA using an anti-HAV mAb, detected with peroxidase-labeled anti-IgG. Absorbance at 450 nm was determined in an ELISA plate reader, and the mean absorbance of duplicate wells ± SD was plotted versus the anti-HAV mAb concentration (***P < 0.001 [ANOVA]). The assay was performed twice, and the data represent 1 experiment.