Using hamsters to study
hemorrhagic fever

In light of the 2014 Ebola virus disease outbreak, viral hemorrhagic fevers have garnered much public interest. But not much is known about the molecular mechanisms underlying infection and progression of these diseases, so there are very few treatments and no vaccines.

Image courtesy of Sreejithk2000, a Wikimedia Commons user

The hemorrhagic fever viruses are a genetically diverse group and include Ebola, Marburg, Lassa, Hantavirus and others. They all have the same gross, even horrifying, symptoms — most notably, blood vessel damage leading to bleeding in internal organs and, in some cases, out of orifices. An article recently published in the journal Molecular & Cellular Proteomics reports molecular events throughout the course of infection in a model of hemorrhagic fever virus infection in hamsters. Understanding how cell-signaling networks change over the course of infection in this rodent virus, says Jason Kindrachuk, a staff scientist at the National Institutes of Health and corresponding author of the study, says could be a vital first step in the development of therapies for related viruses.

But, you might be wondering, what do hamsters have to do with Ebola and other hemorrhagic fever viruses? Pichinde virus is endemic to Colombian rice rats and causes viral hemorrhagic fever in laboratory rodents. The basic pathology of the Pichinde virus in hamsters is quite similar to that of Lassa virus in humans, and it is closely related, so it should to be a good model for recapitulating the molecular events of viral-host interactions. Plus, Pichinde virus doesn’t infect primates or require many of the safety precautions other more dangerous hemorrhagic fever viruses require, making it a good model for labs without high-containment facilities.

Kindrachuk’s team developed a novel hamster-specific kinome array to look at pathogenesis of Pichinde, trying to figure out what is actually going on at a molecular level. The kinome array detects changes in cell signaling networks at the level of kinase-mediated phosphorylation events. The team found that, while predictable immune-response signals were turned on during early infection and predictable cell-death and cell-survival signals were turned on late in the infection, the signals related to the formation of new blood vessels were turned on throughout the whole course of infection. Specifically, cellular responses related to vascular endothelial growth factor-mediated phosphorylation – which is a signal for blood vessel formation and widening of blood vessels – were upregulated one, three, five, and seven days after infection.

In addition, other signaling pathways related to blood-vessel formation, including those mediated by the angiopoietin receptor Tie2 and cell-motility regulator Rac1, were upregulated five and seven days after infection. These findings suggest that VEGF-mediated signaling plays a central role in host response to Pichinde viral infection and may contribute to the blood vessel leakiness seen in hemorrhagic fevers.

The team also found that the amount of proteins involved in binding cells together changed drastically over the course of the infection and corresponded to peak vascular leakage – that is, bleeding from everywhere. Two proteins, Claudin-1 and VE-cadherin, decreased as the infection progressed, while two others, intracellular adhesion molecule 1 and vascular cell adhesion molecule 1, increased. Most interestingly, this dysregulation of proteins involved in holding blood vessels together has been seen before in Hantavirus, another rodent-carried hemorrhagic fever virus.

Kindrachuk said he finds the unexpected similarity of molecular responses of infection between Pichinde viral infection and Hantavirus quite encouraging. If there is a conserved molecular hallmark among the genetically diverse hemorrhagic fever viruses, that opens up the possibility of a more general therapeutic approach. “If we could find therapeutics that are a little bit more broadly applicable and seem to attack some sort of conserved pathology within the infected individual, it gives us a better approach to dealing with these (outbreaks) as they come up in the future,” he said.

The next step for Kindrachuk’s team is to see how Ribavirin, an antiviral drug used to treat Lassa virus infections, or additional antiviral therapeutics, work at the molecular level. Kindrachuk says he would like to “try and pick apart the molecular mechanism for how that therapeutic is working.” Another possible future direction, he said, is to exploit this new knowledge about kinases important in Pichinde viral infection and try to repurpose known kinase inhibitors as novel antiviral drugs.

Mollie Rappe Mollie Rappe is an intern at ASBMB Today and a Ph.D. candidate in biophysics at Johns Hopkins University.