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Bioinformatics Screen Uncovers Host Receptor for Ebola, Marburg Viruses

By Andrea Anderson

NEW YORK (GenomeWeb News) – In the early, online version of the Proceedings of the National Academy of Sciences last night, American researchers reported that they have tracked down a cell surface receptor exploited by Ebola and Marburg viruses.

Using a bioinformatics screen, the team found clues that a protein encoded by the T-cell immunoglobulin and mucin domain 1 gene TIM-1 serves as a receptor for the Ebola virus strain Zaire ebolavirus in some cell types. Through a series of follow-up functional studies, they verified this interaction and showed that TIM-1 can also act as a cellular port of entry for another hemorrhagic-fever causing virus: Lake Victoria marburgvirus.

Because TIM-1-expressing cells seem to turn up in some tissues most vulnerable to Ebola and Marburg infection, researchers say, the findings hint that targeting TIM-1 might eventually help prevent some hemorrhagic infections, since their experiments suggest blocking the receptor prevents Ebola movement into cells expressing the receptor.

"In cells that express TIM-1, when you block availability of TIM-1 you block infection," senior author Wendy Maury, a microbiology researcher at the University of Iowa, told GenomeWeb Daily News.

Ebola and Marburg belong to a family of viral pathogens known as filoviruses, which can cause serious hemorrhagic fevers — characterized by symptoms such as fever, muscle pain, vomiting, and excessive bleeding — in humans and other primates. Infections are fatal in between roughly half to 90 percent of cases.

Extensive research has been done to try figure out how Ebola and Marburg viruses infiltrate and act in human cells. Although a few proteins have been shown to ramp up the odds of filovirus infection, helping viruses stick to the outside of host cells, researchers explained, the actual cellular receptors for the viruses had not yet been found.

"There are several proteins that have been identified that clearly serve to enhance infection," Maury said. "But there has been nothing demonstrated prior to this study that had actually demonstrated that the receptor binding domain [of Ebola] was physically interacting with a cellular protein."

Rather than searching for viral receptors through a classical virological approach — for instance, using cDNA libraries to look for proteins that convert cells from non-permissive to permissive for a specific virus — Maury and her colleagues relied on a bioinformatics-based screen pioneered by National Institute of Dental and Craniofacial Research investigator and co-author John Chiorini.

The approach brings together gene expression data on characterized cell lines found in the NCI-60 human tumor cell panel with information on how efficiently viruses move into these cell lines.

For the current study, researchers exposed 54 of the NCI-60 lines to Ebola "pseudovirions" — slightly modified versions of glycoproteins found in the Ebola virus envelope.

Using the COMPARE algorithm from the NCI Developmental Therapeutic Program web site, Maury and her co-workers then looked at how Ebola pseudovirion transduction efficiency related to known expression patterns for each cell line.

When they sifted through possible viral receptors whose expression corresponded with viral glycoprotein entry into cells, they found TIM-1 amongst the top hits, Maury explained.

And follow-up experiments supported the notion that TIM-1 acts as a cellular receptor for Ebola in at least some cell types, she said.

For instance, the team verified physical interactions between the viral glycoprotein receptor domains and bits of the TIM-1 protein. Moreover, they found, ramping up the expression of TIM-1 intensified Ebola infection, whereas curbing TIM-1 expression with RNA interference rendered normally susceptible cells much more Ebola resistant.

Notably, the team found that they could block Ebola entry into TIM-1 expressing cells by interfering with the receptor using either small interfering RNA or a monoclonal antibody against TIM-1 known as ARD5.

The same strategy also curbed Marburg virus in these cells, Maury noted, consistent with past research showing that Marburg and Ebola use the same strategy to infect cells.

Together, the results hint that it may be possible to develop treatments against both types of filoviruses using small molecules or antibodies targeting TIM-1 — at least in cells expressing TIM-1.

And while those involved in the study emphasized that there are likely additional receptors for Ebola and Marburg viruses, since these viruses can infect some cell types that don't express TIM-1, the researchers were encouraged to find that the receptor is highly expressed in tissues from some of the most filovirus-vulnerable parts of the human body: mucus membranes in parts of the eye and the lining of the lungs.

"Both of those routes have been touted as possible routes of transmission of the virus — aerosolization as well as hand-to-eye contact," Maury said. "So this receptor, indeed, is at the locations one would predict, if in fact those routes are important."

The team is continuing to hunt for alternative Ebola and Marburg receptors in cells that don't employ TIM-1 receptors, she added. They also plan to do more detailed studies on the interactions between Ebola virus glycoproteins and TIM-1, along with pathogenesis studies in mice missing the protein.

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