Tuesday, September 27, 2011

Research Yields Unprecedented Insight into Antiviral Immune Response

The study, "Structural basis of RNA recognition and activation by innate immune receptor RIG-I," was chosen for advanced online publication in Nature on September 25, 2011, and can be found online at: http://www.nature.com/nature/journal/vaop/ncurrent/full/nature10537.html

The research was supported with funding from the National Institutes of Health.

"This work provides unprecedented insights on the molecular mechanism of viral RNA recognition by RIG-I," said Barbara Gerratana, PhD, who oversees enzyme catalysis grants at the National Institute of General Medical Sciences of the National Institutes of Health. "As a result, we have a deeper understanding of how the human body fights viral infections and a structural basis for the development of new antiviral therapeutics."

The research team investigated the structure of RIG-I which is made up of a helicase enzyme, which works in conjunction with a repressor domain to recognize the viral RNA. This is the first step for sensing viruses and initiating synthesis of interferon molecules that "interfere" with viral infection, thereby preventing the spread of viral RNA. This work reveals at the atomic level the details of how RIG-I forms a capped ring around double-stranded RNA and how this structure formation activates RIG-I to initiate immune response.

RIG-I is a receptor that recognizes differences in molecular pathways in order to separate viral RNA from cellular RNA. Unlike DNA, RNA is normally made up of a single strand of nucleotides. However, viral RNA is double-stranded similar to the double-helical shape of DNA. Upon recognition of viral, double-stranded RNA, RIG-I initiates a signaling cascade to induce anti-immune and anti-inflammatory defenses within the cell.

"With the structure in hand, we will be able to design molecules to activate RIG-I or inhibit RIG-I depending on whether we want to fight viral infections or control inflammation," said Joseph Marcotrigiano, PhD, assistant professor of chemistry and chemical biology at Rutgers University, whose lab specializes in determining structures of biomolecules including proteins, RNA, and DNA. Dr. Marcotrigiano also is a member of the Center for Advanced Biotechnology and Medicine, a joint institute of Robert Wood Johnson Medical School and Rutgers University.

"RIG-I is a very important protein that provides us with our first line of defense against viral infections, and prior to this work, there was little information on how RIG-I recognized viral RNAs," said Smita Patel, PhD, professor of biochemistry at Robert Wood Johnson Medical School, whose lab specializes in the mechanics of biomolecules and the activity of enzymes. "A failure of RIG-I to identify viral RNA can lead to alterations of the cell, including cell death, inflammation, autoimmune diseases and cancer."

Many viruses infecting humans including influenza virus, hepatitis C virus, West Nile virus, rabies and measles viruses contain a ribonucleic acid (RNA) genome. These viruses are dependent on RNA as genetic information and they duplicate in human cells to make copies, thereby infecting other cells and spreading the virus. Researchers from UMDNJ-Robert Wood Johnson Medical School and Rutgers, The State University of New Jersey, led by principal investigators Joseph Marcotrigiano and Smita Patel, show, for the first time, the structure of retinoic-acid-inducible gene-I, or RIG-I. RIG-I is a human protein that detects whether the RNA comes from a virus (viral RNA) and, if so, initiates an auto-immune response. Isolating the structure of RIG-I with RNA bound is the first step in developing broad-based therapies against viral infections.

http://www.infectioncontroltoday.com/news/2011/09/research-yields-unprecedented-insight-into-antiviral-immune-response.aspx

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