Association of Mutations in Toll-like Receptor 2 Signaling Genes With Fulminant Form of Hepatitis B-Related Acute Liver Failure.
The fulminant form of hepatitis B-related acute liver failure (FHB-ALF) is a rare but highly fatal outcome of acute hepatitis B virus (HBV) infection. Its related host factors have not been studied to our knowledge.



To identify functionally relevant biological pathway(8) in FHB-ALF pathogenesis, pathway enrichment analysis was conducted on a data set of rare case-specific variants derived from exomic sequencing of 10 unrelated cases. Key variants in identified pathways were validated using 312 controls with HBV disease. Mechanistic studies of a recurrent Toll-like receptor (TLR) 2 gene (TLR2) variant were performed in vitro and in vivo.



The TLR signaling pathway was highly enriched, with associated variants found in 9 of the 10 cases. Notably, a rare heterozygous single-nucleotide variation causing F679I mutation in TLR2 was identified in 2 unrelated cases. In vitro analysis demonstrated F679I to cause loss of function. In both heterozygous and homozygous TLR2 knockout mice, injection of HBV replicon plasmid resulted in more prominent alanine aminotransferase elevations and hepatic necroinflammation than in wild-type mice. Mechanistic analyses demonstrated reduced regulatory T-cell percentages in postexposure TLR2 knockout mice.



TLR2 signaling is very likely impaired in patients with FHB-ALF. The recurrence of rare case-specific TLR2 variant strongly suggests mechanistic contribution to fulminancy in HBV infection.
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Yue
Y
Han
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Leilei
L
Gu
Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
Jing
J
Liu
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Xinhua
X
Li
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Mingjie
M
Wang
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
Qiming
Q
Gong
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Demin
D
Yu
Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Zhitao
Z
Yang
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Donghua
D
Zhang
Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
Huijuan
H
Yang
Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
Zhongliang
Z
Shen
Department of Pathology, Shanghai Medical College, Fudan University, China.
Hongguang
H
Zhu
Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
Youhua
Y
Xie
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Translational Medicine Research Center, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, China.
Xinxin
X
Zhang
D000328:Adult; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D006509:Hepatitis B / Q000150:complications*; D006512:Hepatitis B Core Antigens / Q000097:blood; D006515:Hepatitis B virus; D006801:Humans; D008099:Liver / Q000821:virology; D017114:Liver Failure, Acute / Q000235:genetics* / Q000821:virology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009154:Mutation; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000235:genetics*; D055815:Young Adult
D004279:DNA, Viral; D006512:Hepatitis B Core Antigens; D051195:Toll-Like Receptor 2; D000410:Alanine Transaminase
FHB-ALF; TLR2.; hepatitis B; pathway enrichment