INFLUENZA A VIRUS CAN UNDERGO MULTIPLE CYCLES OF REPLICATION WITHOUT M2 ION CHANNEL ACTIVITY
Figure 1-Influenza A Virus
Influenza A virus is an 8 piece segmented, negative stranded RNA virus enclosed in an envelope. There is a helical nucleoprotein (NP) closely associated with the genome of the virus. Three proteins: HA (hemagglutinin), NA (neuraminidase), and M2 are associated with the envelope. (Fig 1 and Fig 2) All three proteins work together and are necessary for the attachment of the virus to the host cell preparing the next step in viral infection: penetration of the viral genome into the host cell.
Courtesy of http://www.psc.edu/science/Herlocher/Herlocher.html Figure 3-HA with associated particles Courtesy of © Paul Digard, Dept Pathology, University of Cambridge. HA is a TM transmembrane protein consisting of a trimer (3 molecules) each of which possesses the receptor binding site for influenza A virus. (Fig 3). The receptor for HA is sialic acid (N-acetyl neuraminic acid) found on most epithelial cells of a host. Stop and think....What advantage and disadvantage does this have for the virus? Advantage It can infect most cells throughout the body Disadvantage The virus binds to various types of cell debris and other cells with a glycoprotein attached Influenza A mainly affects the cells of the upper and lower respiratory tract. HA binds to the sialic acid and fusion begins between the viral membrane and the host membrane resulting in the formation of an endosome.
Courtesy of © Paul Digard, Dept Pathology, University of Cambridge.
HA is a TM transmembrane protein consisting of a trimer (3 molecules) each of which possesses the receptor binding site for influenza A virus. (Fig 3). The receptor for HA is sialic acid (N-acetyl neuraminic acid) found on most epithelial cells of a host. Stop and think....What advantage and disadvantage does this have for the virus?
Advantage It can infect most cells throughout the body
Disadvantage The virus binds to various types of cell debris and other cells with a glycoprotein attached
Influenza A mainly affects the cells of the upper and lower respiratory tract. HA binds to the sialic acid and fusion begins between the viral membrane and the host membrane resulting in the formation of an endosome.
NA (Fig 1, 2, and 3) is an enzyme responsible for reversing the binding of influenza A. NA specifically cleaves sialic acid from the sugar side chains, (glycoproteins), of the host receptor. While the virus is inside the endosome, HA stays bound to the active site (siliac acid) making it nearly impossible for that particular molecule to bind to another receptor. After the virus has been replicated with its virions, the newly made NA cleaves the sialic acid moiety thereby releasing the virus to go and infect other cells. M2 is a transmembrane protein that possesses ion channel activity. (Fig 2,3). The receptor bound virus is taken into the cell via endocytosis. Once inside the endosome, the pH drops and the virus HA conformation changes and fusion between the viral membrane and the vesicle membrane begins. The M2 ion channel activity permits protons to flow from the endosome into the virion interior to disrupt the acid-labile M1 protein-ribonucleoprotein complex (RNP) interactions thereby releasing RNP into the cytoplasm. This chain of events leads to the uncoating of the viral genome and replication begins when the genome enters the nucleus of the host. Thus the M2 protein is thought to play an essential role in uncoating the viral RNA. Amantidine is a drug that targets the M2 protein and stops viral replication. It prevents proton flow across the virus membrane and blocks virion release into the cytoplasm of the host cell. In essence it is directly involved in the blockage of the 'uncoating' process. Without M2 it is believed that viral replication would be inhibited because the M1 would not dissociate from the ribonucleoproteins. This paper tested the hypothesis that M2 and its ionic activity is essential for viral replication. They completed this study by using mutant strains of M2 and measured their effects on viral replication.
M2 is a transmembrane protein that possesses ion channel activity. (Fig 2,3). The receptor bound virus is taken into the cell via endocytosis. Once inside the endosome, the pH drops and the virus HA conformation changes and fusion between the viral membrane and the vesicle membrane begins. The M2 ion channel activity permits protons to flow from the endosome into the virion interior to disrupt the acid-labile M1 protein-ribonucleoprotein complex (RNP) interactions thereby releasing RNP into the cytoplasm. This chain of events leads to the uncoating of the viral genome and replication begins when the genome enters the nucleus of the host. Thus the M2 protein is thought to play an essential role in uncoating the viral RNA. Amantidine is a drug that targets the M2 protein and stops viral replication. It prevents proton flow across the virus membrane and blocks virion release into the cytoplasm of the host cell. In essence it is directly involved in the blockage of the 'uncoating' process. Without M2 it is believed that viral replication would be inhibited because the M1 would not dissociate from the ribonucleoproteins.
This paper tested the hypothesis that M2 and its ionic activity is essential for viral replication. They completed this study by using mutant strains of M2 and measured their effects on viral replication.
This module explores work reported by T. Watanabe, S. Watanabe, H. Ito, H. Kida, and Y. Kawaoka from the Journal of Virology, June 2001, p. 5656-5662. "Influenza A Virus Can Undergo Multiple Cycles of Replication without M2 Ion Channel Activity."
Module was done by James Waters and Joan Williams for Biol 426 Spring 2002 taught by Dr. J. Kandel, PhD California State University, Fullerton