Autophagy-mediated downregulation of AXL and TIM-1 promotes sustained Zika virus infection.

in Proceedings of the National Academy of Sciences of the United States of America by Jingyou Yu, Yi-Min Zheng, Megan A Sheridan, Pei Li, Toshihiko Ezashi, R Michael Roberts, Shan-Lu Liu

TLDR

  • ZIHK downregulates AXL and TIM-1 to facilitate sustained viral replication and spread, with autophagy involved in the process.
  • The study's findings have implications for understanding ZIKV infection and developing strategies to control it.
  • Future research could explore therapeutic targets and strategies to combat ZIKV infection.

Abstract

Zika virus (ZIKV) infection can lead to a variety of clinical outcomes, including severe congenital abnormalities. The phosphatidylserine receptors AXL and TIM-1 are recognized as critical entry factors for ZIKV in vitro. However, it remains unclear whether and how ZIKV regulates these receptors during infection. In this study, we investigated AXL and TIM-1 expression in human lung adenocarcinoma epithelial A549 cells, glioblastoma U87 cells, and embryonic stem cell-derived trophoblasts following ZIKV infection. We found that both the Asian strain FSS13025 and the African strain MR766 of ZIKV downregulate AXL, with a milder effect on TIM-1. We identified several ZIKV proteins, notably envelope (E), NS2A, NS3, and NS4B, that contribute to this downregulation. Notably, treatment with lysosomal inhibitor NHCl or the autophagy inhibitor 3-methyladenine mitigated the AXL/TIM-1 downregulation, indicating autophagy's involvement in the process. Importantly, this downregulation facilitates sustained viral replication and promotes viral spread by preventing superinfection and limiting cell death, which is also associated with impaired innate immune signaling. Our findings uncover a mechanism by which ZIKV downregulates entry factors to enhance prolonged viral replication and spread.

Overview

  • The study investigated how Zika virus (ZIKV) regulates phosphatidylserine receptors AXL and TIM-1 during infection in human cells.
  • ZIWK downregulates AXL and TIM-1 in human lung adenocarcinoma epithelial A549 cells, glioblastoma U87 cells, and embryonic stem cell-derived trophoblasts.
  • The study aimed to understand the mechanism by which ZIKV regulates these receptors to enhance prolonged viral replication and spread.

Comparative Analysis & Findings

  • The Asian strain FSS13025 and the African strain MR766 of ZIKV downregulate AXL, with a milder effect on TIM-1.
  • Several ZIKV proteins, including envelope (E), NS2A, NS3, and NS4B, contribute to the downregulation of AXL and TIM-1.
  • Treatment with lysosomal inhibitor NHCl or the autophagy inhibitor 3-methyladenine mitigated the AXL/TIM-1 downregulation, indicating autophagy's involvement in the process.

Implications and Future Directions

  • The study's findings highlight the importance of understanding how ZIKV regulates its entry factors to promote prolonged viral replication and spread.
  • Future studies could investigate the role of autophagy in other viral infections and explore potential therapeutic strategies targeting autophagy to control ZIKV replication.
  • The study's findings could also inform the development of vaccines or antiviral therapies that target ZIKV's entry factors or its regulation of autophagy.
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