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Researchers Examine Evolution of Genes that Trigger the Body's Immune Response to Viral Infection
October 22, 2008Virginia Commonwealth University Institute of Molecular Medicine researchers have traced the evolutionary origin of two genes that serve as primary cellular sensors of infection with RNA viruses, such as influenza, poliovirus, West Nile virus, and HIV, which may ultimately provide researchers with insight into a possible new pathway for the development of innate immunity.
Recent studies by other investigators have provided information on exactly how humans respond to virus infection and the role of innate immunity in protection from viral pathogenesis. Induction of innate immunity is closely associated with the production of type I interferons. Interferons are a class of proteins that are secreted by the body in response to a viral infection such as rhinovirus, the cause of the common cold.
In the study, published online in the Early Edition of the Proceedings of the National Academy of Sciences the week of October 20-24, the VCU team reported that melanoma differentiation associated gene-5 (MDA-5) and retinoic acid inducible gene-I (RIG-I) originated specifically in mammals. These genes induce the production of type I interferons.
"Understanding how these unique genes developed and evolved provides a unique opportunity to understand the origins of innate immunity and to develop ways of exploiting this process to develop new types of therapies for pathogenic viruses," said lead investigator Paul B. Fisher, M.Ph., Ph.D., professor and chair of the Department of Human and Molecular Genetics and director of the VCU Institute of Molecular Medicine in the VCU School of Medicine.
According to Fisher, MDA-5, but not RIG-I, orthologs are found in fish, indicating that MDA-5 might have evolved before RIG-I. The unique domain arrangement of MDA-5 and RIG-I evolved independently by domain grafting and not by a simple gene-duplication event of the entire four-domain arrangement. This process may have been initiated by differential sensitivity of these proteins to viral infection.
"Our studies provide insights into the shuffling of gene regions, which culminated in a unique mechanism for protection against viral infection. Additionally, our phylogenetic analyses of these domains provides one of the first direct insights into the temporal pathways of development of innate immunity," said Fisher.
According to Fisher, expression of both MDA-5 and RIG-I can limit viral replication post-entry in cells. In this context, identifying drugs that can effectively turn on either or both of these genes offers promise for decreasing virus-induced pathogenesis.
In related work, the team has identified the promoter region, which controls expression of MDA-5 and RIG-I. Studies are now under way at the VCU Institute of Molecular Medicine and the Burnham Institute for Medical Research in La Jolla, Calif., to use these promoters as part of a screening paradigm to identify small molecules that can be developed into drugs to treat infectious diseases.
This work was supported by grants from the National Institutes of Health.
Fisher, who is the first incumbent of the Thelma Newmeyer Corman Endowed Chair in Cancer Research and researcher with the VCU Massey Cancer Center, worked with VCU School of Medicine researcher Devanand Sarkar, Ph.D., assistant professor at the VCU Massey Cancer Center, VCU Institute of Molecular Medicine and Department of Human and Molecular Genetics; and Rob DeSalle, curator and director of comparative genomics at the American Museum of Natural History in New York.
Virginia Commonwealth University
"Understanding how these unique genes developed and evolved provides a unique opportunity to understand the origins of innate immunity and to develop ways of exploiting this process to develop new types of therapies for pathogenic viruses," said lead investigator Paul B. Fisher, M.Ph., Ph.D., professor and chair of the Department of Human and Molecular Genetics and director of the VCU Institute of Molecular Medicine in the VCU School of Medicine.
According to Fisher, MDA-5, but not RIG-I, orthologs are found in fish, indicating that MDA-5 might have evolved before RIG-I. The unique domain arrangement of MDA-5 and RIG-I evolved independently by domain grafting and not by a simple gene-duplication event of the entire four-domain arrangement. This process may have been initiated by differential sensitivity of these proteins to viral infection.
"Our studies provide insights into the shuffling of gene regions, which culminated in a unique mechanism for protection against viral infection. Additionally, our phylogenetic analyses of these domains provides one of the first direct insights into the temporal pathways of development of innate immunity," said Fisher.
According to Fisher, expression of both MDA-5 and RIG-I can limit viral replication post-entry in cells. In this context, identifying drugs that can effectively turn on either or both of these genes offers promise for decreasing virus-induced pathogenesis.
In related work, the team has identified the promoter region, which controls expression of MDA-5 and RIG-I. Studies are now under way at the VCU Institute of Molecular Medicine and the Burnham Institute for Medical Research in La Jolla, Calif., to use these promoters as part of a screening paradigm to identify small molecules that can be developed into drugs to treat infectious diseases.
This work was supported by grants from the National Institutes of Health.
Fisher, who is the first incumbent of the Thelma Newmeyer Corman Endowed Chair in Cancer Research and researcher with the VCU Massey Cancer Center, worked with VCU School of Medicine researcher Devanand Sarkar, Ph.D., assistant professor at the VCU Massey Cancer Center, VCU Institute of Molecular Medicine and Department of Human and Molecular Genetics; and Rob DeSalle, curator and director of comparative genomics at the American Museum of Natural History in New York.
Virginia Commonwealth University
Molecular Current Events and Molecular News RSSScientists unlock clues for tailoring corn plant for food, energy needs
Scientists have long known that the offspring of two inbred strains tend to be superior to both their parents. Now, a team of researchers including a University of Florida geneticist has discovered clues to why that might be the case for one of the most important crops in the world: corn.
WPI Researchers Take Aim at Hard-to-Treat Fungal Infections
A team of researchers at the Worcester Polytechnic Institute (WPI) Life Sciences and Bioengineering Center at Gateway Park has developed a new model system to study fungal infections.
Scripps research scientists find new link between insulin and core body temperature
A team led by scientists at The Scripps Research Institute have discovered a direct link between insulin-a hormone long associated with metabolism and metabolic disorders such as diabetes-and core body temperature.
New research into the mechanisms of gene regulation
A team led by Penn State's Ross Hardison, T. Ming Chu Professor of Biochemistry and Molecular Biology, has taken a large step toward unraveling how regulatory proteins control the production of gene products during development and growth.
New map of variation in maize genetics holds promise for developing new varieties
A new study of maize has identified thousands of diverse genes in genetically inaccessible portions of the genome. New techniques may allow breeders and researchers to use this genetic variation to identify desirable traits and create new varieties that were not easily possible before.
Common pain relief medication may encourage cancer growth
Although morphine has been the gold-standard treatment for postoperative and chronic cancer pain for two centuries, a growing body of evidence is showing that opiate-based painkillers can stimulate the growth and spread of cancer cells.
Saliva proteins change as women age
In a step toward using human saliva to tell whether those stiff joints, memory lapses, and other telltale signs of aging are normal or red flags for disease, scientists are describing how the protein content of women's saliva change with advancing age.
Scientists find molecular trigger that helps prevent aging and disease
Researchers at Mount Sinai School of Medicine set out to address a question that has been challenging scientists for years: How do dietary restriction-and the reverse, overconsumption-produce protective effects against aging and disease?
Texas A&M Researchers Examine How Viruses Destroy Bacteria
Viruses are well known for attacking humans and animals, but some viruses instead attack bacteria. Texas A&M University researchers are exploring how hungry viruses, armed with transformer-like weapons, attack bacteria, which may aid in the treatment of bacterial infections.
UCLA researchers create 'fly paper' to capture circulating cancer cells
Just as fly paper captures insects, an innovative new device with nano-sized features developed by researchers at UCLA is able to grab cancer cells in the blood that have broken off from a tumor.
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