Exosomes mediate the cell-to-cell transmission of IFN-a-induced antiviral activity.

Jianhua Li, Kuancheng Liu, Yang Liu1, Yan Xu, Fei Zhang, Huijuan Yang, Jiangxia Liu, Tingting Pan, Jieliang Chen, Min Wu, Xiaohui Zhou & Zhenghong Yuan.

Nature Immunology (2013) VOLUME 14 NUMBER 8,793-803

Speaker: Shih-Chuan Li (李世詮)                        Time: 14:00~15:00, Dec 3, 2014

Commentator: Dr. Pin Ling (凌斌 博士)             Place: Room 601

Abstract:

        Type-1 interferons, including interferon-α (IFN-α) and IFN-β play important role in controlling viral replication during early stage of viral infection. After binding to the interferon receptor, IFN-α and IFN-β signal through a kinase of the Jak family to the signal-transduction-and-activator-of-transcription (STAT) pathway to activate the transcription of the interferon-stimulated genes (ISGs). The expresses products of ISGs could establish the antiviral state of the targeted cells. However, some viral proteins could target several steps of the type-1 interferon pathway and resist from the anti-viral activity of the permissive cells¹. The host cells might develop mechanism to induce the transfer of viral resistance from nonpermissive cells to cell that able to viral replication, via intercellular communication. Exosomes are membrane vesicles with diameters of 40-100 nm that originate in the endosomal compartment from the inward budding of endosomal membranes which forming intracellular multivesicular bodies (MVBs). Exosomes are packaged in the MVBs and been released into the extracellular environment after the fusion between the MVBs and plasma membrane. The vesicles might transfer functional proteins, mRNA, and microRNA (miRNA) to locally cells and become the mediator of intercellular communication. Hepatitis B virus (HBV) exclusively infects hepatocytes, there are approximately 400 million people chronically infected with HBV worldwide. It’s found that IFN-α cannot or only modestly inhibit HBV replication in human hepatocyte-derived cell lines. This is phenomenon might be due to the blockage of the IFN-α signaling pathway by the inactivation of STAT1 and STAT2 induced by the HBV viral proteins². The liver organ is composed of both liver parenchymal cells (hepatocytes) and nonparechymal cells (LNPCs), and the LNPCs includes Kupffer cells (the resident macrophage of liver), liver sinusoidal endothelial cells (LSECs) and lymphocytes. The researchers investigated whether the anti-viral activity of IFN-α can be transferred from LNPCs to hepatocytes which are infected by the HBV via exosomes and then restored the antiviral state of hepatocytes.

Reference:

1.      Randall, R.E. & Goodbourn, S. Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J. Gen. Virol. 89, 1–47 (2008).

2.     Lutgehetmann, M. et al. Hepatitis B virus limits response of human hepatocytes to interferon-α in chimeric mice. Gastroenterology 140, 2074–2083 (2011).