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Mouse Study Shows Host Genetics May Influence Response to Ebola Infection

NEW YORK (GenomeWeb) – Host genetics appear to play a role in response to Ebola virus infection, researchers reported in a paper appearing online in Science today.

Researchers led by Michael Katze at the University of Washington infected mice from varied genetic backgrounds with the mouse-adapted Ebola virus. How these mice responded to infection varied based on their genetic background.

"The frequency of different manifestations of the disease across the lines of these mice screened so far are similar in variety and proportion to the spectrum of clinical disease observed in the 2014 West African outbreak," first author Angela Rasmussen from UW said in a statement.

The first cases of the 2014 West African Ebola outbreak were reported in March in Guinea, and the disease has spread to neighboring countries including Sierra Leone and Liberia. According to the US Centers for Disease Control and Prevention, as of earlier this week nearly 11,150 people have been infected in this outbreak and 4,922 people have died.

Because standard lab mice infected with mouse-adapted Ebola virus die from the disease, but don't exhibit the hemorrhagic symptoms of the disease, Rasmussen, Katze, and their colleagues drew on mice from the Collaborative Cross, a collection of genetically diverse mice developed through crosses of eight inbred founder mouse strains — strains that represent some 90 percent of common genetic variation in the main three mouse subspecies — to examine if they had different responses to Ebola virus infection.

In this study, the researchers infected eight Collaborative Cross founders with either the mouse-adapted Ebola virus or the wild-type Mayinga strain of the virus. The mouse-adapted strain differs from the published wild-type Ebola virus strain by 13 nucleotide changes, the researchers said. Despite the lethality of the disease, these mice, too, didn't exhibit hemorrhagic disease.

But in 47 CC-RIX lines — Collaborative Cross mice that have then been interbred — infected with mouse-adapted Ebola virus, the researchers observed a range of phenotypes, including Ebola hemorrhagic fever and death as well as resistance to disease.

The researchers then focused on a disease-susceptible and a disease-resistant line. Mice from both these lines lost weight upon infection with the virus, though the resistant mice gained their lost weight back within two weeks while the susceptible came down with Ebola hemorrhagic fever some five days post infection and died.

Despite these phenotypic differences, both lines had similar levels of viral RNA in their livers, as gauged by quantitative real-time PCR, indicating to the researchers that resistance likely was due to an inability of the virons to assemble, be secreted, or be post-transcriptionally processed.

The virus, though, appeared to infect different types of hepatocytes in the two mouse strains. And the infected strains exhibited differences in coagulation time after infection.

These pathological symptoms, Katze and his colleagues noted, are similar to those observed in patients of the current Ebola outbreak in West Africa.

Sequence analysis, they added, indicated no difference in viral genomes between the mouse lines.

Additionally, neither strain developed disease after infection with the wild-type Mayinga strain of Ebola, suggesting to the researchers that it cannot replicate in these mice.

The two lines also had a number of genes that were differentially expressed in response to mouse-adapted Ebola virus infection, as compared to each other and to mock-infected samples.

Susceptible mice had between a 10- and 100-fold increase in differentially expressed genes, and genes associated with Ebola infection were differentially induced. For instance, the researchers noticed that one day after infection in susceptible mice, there was an enrichment of p38 MAPK and ERK signaling as well as increased NfκB expression and the induction of proinflammatory processes.

In particular, the researchers reported that the endothelial tyrosine kinases Tie1 and Tek, along with other genes related to vascular integrity, were enriched in susceptible mice at days three and five post-infection. At day five — the onset of coagulopathy — Tie1 and Tek were expressed at lower levels in susceptible mice than in mock-infected mice.

Tie1 and Tek signaling, the researchers noted, promotes the activation of coagulation factors like thrombin and protease activated receptors that have been implicated in coagulopathies mediated by Ebola and other viruses.

Tie1 and Tek expression, they added, is elevated in the spleens of resistant mice.

Across the Collaborative Cross founder lines, Katze and his colleagues found that the Tie1 alleles are highly divergent, while the Tek alleles in the Collaborative Cross founder lines are derived from two subspecies.

Various Tek alleles, they added, have been linked in the past to inflammatory coagulopathies and vascular dysfunction. They also uncovered statistically significant relationships between Tek alleles and the onset of weight loss, day of death, and mortality in the mice.

This, Katze said, suggests "genetic factors play a significant role in disease outcome." He noted, though, Ebola survivors from the ongoing outbreak in humans could have had an immunity to this or a related virus that may have helped them survive.

Still, the researchers said that the mouse model could be used to find additional genetic influences as well as evaluate drugs to treat Ebola.

"We hope that medical researchers will be able to rapidly apply these findings to candidate therapeutics and vaccines," Katze said.