HMGB1 mediates HAdV-7 infection-induced pulmonary inflammation in mice.

Abstract

Human adenovirus (HAdV) is a common respiratory pathogen in children, with no safe and effective treatment currently available. HAdV type 7 (HAdV-7), in particular, causes severe pediatric pneumonia with a high incidence of sequelae and mortality. Clinical data and animal experiments suggest that HAdV-7-induced pneumonia promotes cell necrosis, releasing a large number of inflammatory mediators. In recent years, the high mobility group box-1 (HMGB1) protein, released by necrotic cells, has been shown to play important roles in several viral infections. Here, we show that HMGB1 levels gradually increased in the media supernatants of HAdV-7 infected A549 cells, starting at 12 h post-infection. In vivo, HMGB1 levels in BALF and mRNA levels in lung tissues significantly increased after 3 days of HAdV-7 infection. Among the HMGB1 receptor genes, TLR-4 and TLR-9 expression increased, and so did the receptor for advanced glycation end-products (RAGE). Interestingly, NF-κB levels also increased concomitantly. Conversely, when HMGB1 was blocked, the pathological scores from lung tissues, inflammatory mediator levels, and viral copy number all were reduced significantly; in addition, HMGB1-related signaling pathway molecules, namely TLR-4, TLR-9, RAGE, and NF-κB were also reduced. We conclude that HMGB1 promotes HAdV-7 replication and signals through TLR-4, TLR-9, and RAGE receptors to activate NF-κB, stimulating the release of inflammatory mediators and contributing to adenoviral pathology. Thus, HMGB1 could be used as a therapeutic target in HAdV-7 infection.

• Authors: Zhengzhen Tang, Na Zang, Yangxi Fu, Zhixu Ye, Sisi Chen, Shi Mo, Luo Ren, Enmei Liu
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 501 Issue 1 Pg. 1-8 (06 18 2018) ISSN: 1090-2104 [Electronic] United States
• PMID: 29571731 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018. Published by Elsevier Inc.

Chemical References

• Ager protein, mouse
• Antibodies, Monoclonal
• HMGB1 Protein
• HMGB1 protein, human
• HMGB1 protein, mouse
• Inflammation Mediators
• NF-kappa B
• RNA, Messenger
• Receptor for Advanced Glycation End Products
• Tlr4 protein, mouse
• Tlr9 protein, mouse
• Toll-Like Receptor 4
• Toll-Like Receptor 9

Topics

• A549 Cells
• Adenovirus Infections, Human (etiology, genetics, metabolism)
• Adenoviruses, Human (pathogenicity, physiology)
• Animals
• Antibodies, Monoclonal (administration & dosage)
• Disease Models, Animal
• Female
• HMGB1 Protein (antagonists & inhibitors, genetics, metabolism)
• Humans
• Inflammation Mediators (metabolism)
• Lung (metabolism, pathology)
• Mice
• Mice, Inbred BALB C
• NF-kappa B (metabolism)
• Pneumonia, Viral (etiology, genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• Receptor for Advanced Glycation End Products (genetics, metabolism)
• Signal Transduction
• Toll-Like Receptor 4 (genetics, metabolism)
• Toll-Like Receptor 9 (genetics, metabolism)
• Up-Regulation
• Virus Replication