COLUMBUS, Ohio -- Thanks to a total of $2.6 million in funding from the National Institutes of Health and the U.S. Department of Agriculture National Research Initiative, an Ohio State University researcher is helping crack the code that could lead to new vaccines and interventions against paramyxoviruses, responsible for the majority of acute viral respiratory infections in humans and animals.
The Paramyxoviridae family includes a number of pathogens, including those that cause measles and mumps. Although vaccines have been available for decades against those two childhood diseases, attempts at developing a vaccine for three related illnesses -- human metapneumovirus (hMPV), human respiratory syncytial virus (RSV) and human parainfluenza virus type 3 (hPIV3) -- have failed. Infants, children, the elderly and those with compromised immune systems are most subject to these illnesses.
The five-year NIH grant addresses hMPV. HMPV is a newly discovered human pathogen, first identified in 2001 in the Netherlands. Soon after its discovery, it was recognized as a globally prevalent pathogen. Epidemiological studies suggest that 5 to 15 percent of all respiratory tract infections in infants and young children are caused by hMPV, a proportion second only to that of RSV.
"By the age of 5, more than 95 percent of children have had hMPV," said Jianrong Li, the project's principal investigator. Li's co-investigator on the project is Stefan Niewiesk, associate professor in the College of Veterinary Medicine.
In addition, a related paramyxovirus, the avian metapneumovirus (aMPV), causes respiratory disease in turkeys and "swollen head syndrome" in chickens. This virus was discovered in South Africa in 1978, becoming prevalent in the U.S. in 1996. It causes significant economic losses in the turkey industry, including sharp drops in egg production, poor weight gain and mortality. The virus is very similar to its human counterpart, hMPV. Li received the USDA grant to study aMPV with co-investigator Mo Saif, director of the Food Animal Health Research Program at the university's Ohio Agricultural Research and Development Center (OARDC).
"There are no anti-virals nor vaccines for this type of virus," Li said. While some potential vaccines developed over the years showed promise initially, scientists found they prompted an increased risk of lung disease if the person later became infected with the same virus. Li is an assistant professor with a joint appointment in the College of Food, Agricultural, and Environmental Sciences and the College of Public Health, and he is also a scientist with OARDC.
Li, a virologist, has experience in tackling a number of different issues involving viruses. As a post-doctoral researcher at Harvard Medical School several years ago, Li helped identify what could be this particular organism's Achilles heel.
"When the virus infects humans, it attaches to a cell, enters the cell, then replicates inside the cell," Li said. "To be able to replicate, it needs to make more genomic RNA, and it needs to make more viral proteins, which come from viral mRNA. What if we stopped this process so the virus cannot replicate?"
The replication strategy of paramyxoviruses is unique in that a single complex called polymerase controls two types of viral RNA synthesis: replication to yield genomic RNA and transcription to yield mRNA. Li explains that mRNA, short for messenger RNA, translates genetic code in DNA and is necessary for protein synthesis. The mRNA in paramyxoviruses has a unique methylated cap structure that is essential for mRNA stability and viral protein translation.
"To generate the viral protein, the mRNA needs a cap, and the cap needs to be methylated," Li said. "If we can make the cap less methylated, then less viral protein is made. If we can find a chemical method to prevent the cap from forming at all, that's lethal to the virus."
To develop an antiviral agent, the team is focusing on the molecular mechanisms involved in the methylation of the cap. They have already determined that L-protein (a large protein) is involved, but they are not certain how. "If we can find out how it works, we can develop a way to prevent it from happening."
The researchers are also interested in examining how a single polymerase controls two distinct RNA synthesis pathways and determining what drives these pathways. "The mechanism isn't clear; it's poorly understood right now," Li said. "We need to better understand this process."
Next, the researchers want to generate a paramyxovirus that doesn't have a methylated cap -- such an organism could be used in a vaccine because without that unique structure, its ability to multiply would be seriously hampered, preventing it from causing illness.
Li is a scientist in Ohio State's Public Health Preparedness for Infectious Diseases (PHPID) program. PHPID is part of Ohio State's Targeted Investment in Excellence, which targets some of society's most pressing challenges with a major investment of university resources in programs with a potential for significant impact in their fields.