Infection with flaviviruses requires BCLXL for cell survival.

Abstract

BCL2 family proteins including pro-survival proteins, BH3-only proteins and BAX/BAK proteins control mitochondria-mediated apoptosis to maintain cell homeostasis via the removal of damaged cells and pathogen-infected cells. In this study, we examined the roles of BCL2 proteins in the induction of apoptosis in cells upon infection with flaviviruses, such as Japanese encephalitis virus, Dengue virus and Zika virus. We showed that survival of the infected cells depends on BCLXL, a pro-survival BCL2 protein due to suppression of the expression of another pro-survival protein, MCL1. Treatment with BCLXL inhibitors, as well as deficient BCLXL gene expression, induced BAX/BAK-dependent apoptosis upon infection with flaviviruses. Flavivirus infection attenuates cellular protein synthesis, which confers reduction of short-half-life proteins like MCL1. Inhibition of BCLXL increased phagocytosis of virus-infected cells by macrophages, thereby suppressing viral dissemination and chemokine production. Furthermore, we examined the roles of BCLXL in the death of JEV-infected cells during in vivo infection. Haploinsufficiency of the BCLXL gene, as well as administration of BH3 mimetic compounds, increased survival rate after challenge of JEV infection and suppressed inflammation. These results suggest that BCLXL plays a crucial role in the survival of cells infected with flaviviruses, and that BCLXL may provide a novel antiviral target to suppress propagation of the family of Flaviviridae viruses.

• Authors: Tatsuya Suzuki, Toru Okamoto, Hiroshi Katoh, Yukari Sugiyama, Shinji Kusakabe, Makoto Tokunaga, Junki Hirano, Yuka Miyata, Takasuke Fukuhara, Masahito Ikawa, Takashi Satoh, Sachiyo Yoshio, Ryosuke Suzuki, Masayuki Saijo, David C S Huang, Tatsuya Kanto, Shizuo Akira, Yoshiharu Matsuura
• Journal: PLoS pathogens (PLoS Pathog) Vol. 14 Issue 9 Pg. e1007299 (09 2018) ISSN: 1553-7374 [Electronic] United States
• PMID: 30261081 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BCL2L1 protein, human
• Bcl2l1 protein, mouse
• Myeloid Cell Leukemia Sequence 1 Protein
• bcl-X Protein

Topics

• Animals
• Apoptosis (genetics, physiology)
• Cell Line
• Cell Survival (genetics, physiology)
• Chlorocebus aethiops
• Dengue Virus (pathogenicity, physiology)
• Encephalitis Virus, Japanese (pathogenicity, physiology)
• Flavivirus (pathogenicity, physiology)
• Flavivirus Infections (genetics, pathology, physiopathology)
• Gene Knockout Techniques
• HEK293 Cells
• Host-Pathogen Interactions (genetics, physiology)
• Humans
• Immunity, Innate
• Mice
• Mice, Knockout
• Models, Biological
• Myeloid Cell Leukemia Sequence 1 Protein (antagonists & inhibitors, genetics, physiology)
• U937 Cells
• Vero Cells
• Virus Replication (physiology)
• Zika Virus (pathogenicity, physiology)
• bcl-X Protein (antagonists & inhibitors, genetics, physiology)