Eastern equine encephalitis virus, which kills about half of the people it infects, uses a newly identified mechanism to “hijack” cells of its hosts in order to suppress an immune response.
“Anytime you understand how a virus causes a disease, you can find ways to interrupt that process,” says senior author William Klimstra, associate professor at the University of Pittsburgh’s Center for Vaccine Research. “And this discovery is particularly exciting because it is the first time that anyone has shown a virus using this particular strategy to evade its host’s immune system and exacerbate disease progression.”
The discovery, which is published in the journal Nature, could aid in the development of vaccines and treatments for eastern equine encephalitis virus (EEEV), a rare but deadly disease that is found primarily in the Atlantic and Gulf States. It also may be useful in efforts to inhibit other diseases, such as West Nile virus, dengue, rhinovirus, and SARS.
EEEV carries ribonucleic acid (RNA) as its genetic material. Klimstra and his colleagues discovered that EEEV evolved to have a binding site in its RNA that fits perfectly with a small piece of RNA, called microRNA, in the cells of the organism that the virus is invading. Typically, the host produces microRNAs to control its own cellular processes.
When the virus binds with the microRNA in certain cells involved in triggering an immune response in a human, it restricts its own replication. This allows the virus to evade an immune response because the viral replication in these cells is what would normally tip off the host’s immune system and induce it to mount an attack to rid the body of the virus.
Meanwhile, the virus is able to replicate and spread undetected in the cells of the host’s neurological system and cause overwhelming disease.
High fatality rate
EEEV causes inflammation of the brain that begins with the sudden onset of headache, high fever, chills, and vomiting and can quickly progress to disorientation, seizures, and coma.
There is no treatment for the disease, but it is rare, with about five to 30 cases reported in the US annually, according to the US Centers for Disease Control and Prevention. It has a 30 to 70 percent fatality rate, the highest of any North American mosquito-borne virus, and causes significant brain damage in most survivors.
It does not transmit easily to humans, and the mosquito species that typically carries it is usually found in swampy areas that aren’t highly populated, though it has been found in more common mosquitoes, spurring pesticide spraying, curfews, and outdoor event cancellations in recent years in states such as Massachusetts, where EEEV is more frequently found.
EEEV in the lab
In the laboratory, Klimstra and his colleagues created a mutant version of EEEV without the microRNA binding site, which allowed them to discover that the binding site is key to the virus evading detection.
When this manufactured mutant version was tested in the laboratory, the researchers found that the host’s immune system was able to mount an effective response to the mutant virus. Klimstra added that the studies were mostly done in the Regional Biocontainment Laboratory at the university.
“Viruses are constantly evolving and changing,” says Klimstra. “However, the genetic sequence that allows EEEV to bind to our microRNA has persisted. We find it in samples from the 1950s, which indicates tremendous evolutionary selection pressure to maintain this mechanism.
“Ultimately, these results suggest that the mutant virus could be used as an EEEV vaccine and that microRNA blockers could have potential for use as a therapeutic treatment for EEEV-infected patients who currently can be treated only with supportive care.”
The National institutes of Health supported the research.
Source: University of Pittsburgh