Environmental change and viral mutations combine to fuel outbreaks of a deadly mosquito-borne disease

Environmental change and viral mutations have combined to fuel outbreaks of a deadly mosquito-borne disease that have plagued South and Central America for the last 100 years, a new study by University of Texas Medical Branch at Galveston (UTMB) and Colorado State University researchers reports.

The scientists discovered that a single common genetic mutation can turn a harmless virus circulating among rodents in New World tropical forests into a strain of deadly Venezuelan equine encephalitis (VEE) virus that strikes humans, horses, donkeys and mules. Because viruses mutate constantly, those with the potential to cause epidemic VEE are constantly present among populations of mosquitoes that feed on the rodents. All that's needed to set the stage for an outbreak is the transformation of parts of the forest into farms and ranches, which brings susceptible horses and other equines into contact with mosquitoes feeding on rodents in neighboring areas of intact forest.

The key viral mutation causes a small change in one virus protein, but that's enough to turn a largely benign virus into a fast-moving killer if enough horses, donkeys and mules and mosquitoes are available. The mutated virus multiplies very rapidly in these equine species, spreading quickly via mosquitoes to other equines and humans.

"The critical thing is really the presence of vulnerable equine species on these ranches in areas that used to be forests," said UTMB pathology professor Scott Weaver, senior author of a paper on the study which appears in the Proceedings of the National Academy of Sciences (PNAS).

An effective equine vaccine for VEE is available, but because long periods may elapse between outbreaks (as much as 20 years), ranchers often don't inoculate their animals. When a VEE epidemic takes off, the results can be devastating - hundreds of thousands of human and equine cases can occur over a wide area. For example, one outbreak that started in Guatemala and El Salvador in 1969 eventually reached South Texas, killing an estimated 100,000 horses in its path and sickening thousands of people. The last major VEE outbreak, which occurred in 1995, infected between 70,000 and 100,000 people in northern Venezuela and Colombia.

The UTMB and CSU researchers made their discovery by genetically manipulating a virus that does not cause disease in horses but is the closest known relative of a strain of VEE that was isolated after a 1992-1993 epidemic in western Venezuela. By deliberately introducing mutations into the genetic code of this relatively harmless virus, they were able to determine how much change was needed to create a virus that reproduced at high enough levels to cause disease in horses. All that was required was one mutation, producing a change in one amino acid in a protein in the virus' envelope - its outer coating - which enables the virus to slip into cells and use their genetic machinery to reproduce itself.

"It was very surprising - I thought it would take a combination of mutations," Weaver said. "But a single mutation makes it much easier, and since these viruses are very mutable, this is something that must be happening all the time."

Weaver's co-authors on the paper include UTMB researchers Michael Anischenko, Ivorlyne P. Greene and Slobodan Paessler, as well as Richard A. Bowen and Laura Austgen of Colorado State University. The work was supported by grants from the National Institutes of Health and the Centers for Disease Control and Prevention.