Immune Avoidance Mechanism Discovery Could Point to Treatments for Deadly Eastern Equine Encephalitis Mosquito-borne Virus

Eastern Equine Encephalitis (EEEV), is a rare but deadly mosquito-borne disease that kills about half of the people it infects. However, research by a team of scientists at the University of Pittsburgh Center for Vaccine Research (CVR), the University of Texas Medical Branch, and the Weizmann Institute of Science has discovered that the EEEV uses a never-before-documented mechanism to “hijack” one of the cellular regulatory systems of its hosts to suppress immunity holds promise for better outcomes.

The discovery, which will be published in the journal Nature and is funded by the National Institutes of Health (NIH), could aid in the development of vaccines and treatments for EEEV, which in the U.S. 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 fever, rhinovirus and SARS.

klimstra“Anytime you understand how a virus causes a disease, you can find ways to interrupt that process,” says senior author William Klimstra, Ph.D., associate professor at the Center for Vaccine Research in a University of Pittsburgh Medical Center (UPMC) Physician Resources release. “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.”

BST3The central research focus at Dr. Klimstra’s CVR laboratory is to define host and viral factors that determine success or failure of the innate immune response to infection with arthropod-borne viruses. The specific approach is to examine at the single cell level, the molecular mechanisms that determine host cell permissivity to the alphaviruses (e.g., Sindbis virus [SB], Venezuelan equine encephalitis virus [VEEV], eastern equine encephalitis virus [EEEV], western equine encephalitis virus [WEEV], Chikungunya virus [CHIKV] and Ross River virus [RRV]) and the contribution of replication in specific cells to the pathogenesis of viral disease).

BioNews Texas’s Wendy Gaisford reported last August that an outbreak of EEEV in humans was reported in the eastern Panamanian province of Darien in 2010, raising questions as to how the virus crossed the species barrier, noting that scientists were convinced that unlike the Venezuelan equine encephalitis (VEEV) viruses, this virus was fundamentally different in its ability to infect humans. Researchers from the Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston collaborated with Panamanian scientists to investigate this outbreak and results published that month in the New England Journal of Medicine confirmed 13 human cases of EEEV and one case of dual infection of both Eastern and Venezuelan equine encephalitis. In that study, researchers highlighted that the occurrence of EEEV in humans in Latin America may be the result of ecologic changes where human contact with these viruses and their enzootic transmission cycles have increased. Researchers also proposed that genetic changes in strains of this virus may have resulted in an altered host range and increased human virulence.

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Eastern Equine Encephalitis

Photo Credit: Anastasija Popova/Shutterstock

A University of Texas Medical Branch at Galveston release notes that the mosquito-borne virus that causes EEEV is found all over the Americas, and infects horses throughout its range. Human infections are diagnosed every year in North America and are taken quite seriously; they carry a 50 percent chance of mortality, and can result in lifelong neurological damage. But 2010 marked a dramatic change in the way the virus behaved in Latin America.

Professor Scott Weaver, Director of the Institute for Human Infections and Immunity, head of the UTMB study group, and senior author of the paper on the epidemic that appeared in the August 22. 2013 issue of the New England Journal of Medicine, highlighted that, ”although only about a one in 10 case-fatality rate in Panama was observed, which is low by U.S. standards, concerns are being raised about whether this virus has changed and become more virulent for people,” and stressed: “we need to know, number one, is it going to spread to other parts of Latin America or number two, are other Latin American strains likely to do the same thing?”

“Until the Darien outbreak, we had become convinced that the virus in South America was fundamentally different in its ability to infect people and cause serious disease,” said University of Texas Medical Branch at Galveston professor Scott Weaver, “This epidemic broke that dogma’s back very quickly.”

UTMB researchers collaborated with Panamanian scientists to investigate the outbreak, testing samples from 174 patients and many horses. In the end, they confirmed 13 human cases of eastern equine encephalitis and one case of dual infection of both eastern and Venezuelan equine encephalitis.

Weaver also noted that earlier studies have shown that the eastern equine encephalitis virus is common in many Latin American locations where human exposure to virus-carrying mosquitoes is high. Since the virus is constantly mutating, it’s possible that a strain like the one seen in 2010 in Panama could take hold in an ecosystem in nearby Colombia, Ecuador or the Peruvian Amazon.

“With a situation where a lot of people are being exposed to the virus, there would be the potential for a lot of new disease,” observed Dr. Weaver. “So it’s important to understand what’s happening in Panama both for the Panamanians and for people all over Latin America.”

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Upon introduction into a susceptible host, alphaviruses initially replicate within cells of the dendritic cell (DC) and macrophage lineages. In young animals, this replication is unrestrained and leads to induction of a toxic proinflammatory cytokine response. However, in adults virus replication and cytokine induction are restricted by one or more as yet uncharacterized mechanisms. These mechanisms likely involve changes in host cell permissivity to virus infection.

Dr. Klimstra’s Webpage notes that ongoing studies at the lab include determination of the relationship between infection of DC/macrophage and induction of the systemic inflammatory response, identification and characterization of cellular receptors that promote virus infection and identification of host innate immune mechanisms that control virus replication within individual cells. Furthermore, since the extent of virus replication, viral cellular tropism and the host response to infection are critical factors in stimulation of robust and appropriate immune responses to immunogens, we also strive to translate information gained from pathogenesis studies into strategies for improvement of alphavirus-based gene delivery systems.

horse in the snow

Photo Credit: Anastasija Popova/Shutterstock

The UPMCEEEV Physician Resources release explains that EEEV carries ribonucleic acid (RNA) as its genetic material, and Dr. Klimstra and his colleagues have 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, microRNAs are produced by the host 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, including brain inflammation that begins with sudden onset of headache, high fever, chills and vomiting, and can quickly progress to disorientation, seizures and coma.

There is no specific treatment for the disease, which is addressed medically with symptoms-management, but it is mercifully rare, with about five to 30 cases reported in the U.S. annually according to the U.S. Centers for Disease Control and Prevention. It has a 30 to 70 percent fatality rate, the highest of any North American mosquito-borne virus, with significant brain damage in most survivors.

EEEV 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.
In the laboratory, Dr. Klimstra and his colleagues created a mutant version of EEEV without the microRNA binding site, facilitating their discovery 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. Dr. Klimstra adds that the studies were mostly done in the Regional Biocontainment Laboratory at Pitt, a unique, high-security facility constructed with Pitt and NIH funds.

“Viruses are constantly evolving and changing,” Dr. Klimstra observes. “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.”
Co-authors on this research are Derek W. Trobaugh, Ph.D., Cristina L. Gardner, Ph.D., Chengqun Sun, Ph.D., and Kate D. Ryman, Ph.D., all of the University of Pittsburgh Center for Vaccine Research and Department of Microbiology & Molecular Genetics; Andrew D. Haddow, Ph.D., Eryu Wang, Ph.D., and Scott C. Weaver, Ph.D., all of the University of Texas Medical Branch; and Elik Chapnik, Ph.D., and Alexander Mildner, Ph.D., both of the Weizmann Institute of Science.

This work was supported by NIH grants AI049820-10, AI060525-08, AI083383, AI095436, U54 AI081680.
Sources:
University of Pittsburgh Medical Center (UPMC)
University of Pittsburgh Center for Vaccine Research (CVR)
University of Texas Medical Branch at Galveston
Image Credits:
University of Pittsburgh Medical Center
University of Pittsburgh Center for Vaccine Research (CVR)

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