The Speaker News Journal

Significant improvements in Ebola research have been made possible by researchers at the University of North Carolina. The researchers have not only bred a mouse that can be used to better investigate the way Ebola symptoms develop in a human host, but have also identified several key genes that account for a variety of Ebola symptoms–in particular one gene, Tek, which accounts for a large amount of the symptom variation in individuals within a species.

“Laboratory mice have traditionally been unable to be infected by wild-type Ebola virus,” Martin Ferris, research assistant professor of genetics at UNC-Chapel Hill and one of the researchers on the project, told The Speaker.

Typical lab mice do not develop Ebola in the way that humans do–mice infected with Ebola don’t develop the fatal symptoms that present in human victims. The team considered, however, that some mice might be more susceptible than others, and bred a new mouse strain that could be infected with an Ebola virus and which displayed symptoms like those displayed by human Ebola victims.

“A mouse adapted strain of Ebola has been used for in vivo studies of Ebola pathogenesis for over 15 years,” said Ferris. “This mouse adapted Ebola virus was used in our studies.” Ferris clarified for us that the team did not infect mice with the active human strain of Ebola that is currently epidemic in West Africa. Nevertheless, strict medical precautions were taken.

“In general, adaptation of viruses to small animal models results in attenuated viruses as measured on human cell types–obviously there are no studies showing primary human infection. Often this is due to viral changes to utilize host-species specific cell receptors. That said, it is not clear whether the mouse adapted Ebola virus used in these studies would cause disease in a human. Therefore, to be safe, this virus was still handled under Biosafety Level 4 conditions, just like other Ebola virus strains.”

Read more: Ebola Genome Sequencing Being Undertaken by Harvard Team to Discover Weaknesses in Virus Genome, Which Has Already Mutated Hundreds of Times

The team bred together eight genetic mouse variants to create the new strain that could be infected and develop symptoms similar to those experienced by humans.

Ferris elaborated on how the process worked.

“Just as host genetic variants can impact disease susceptibility, so too can viral genetic variants. In other words, just as there is no single human from a genetic standpoint, there is no single Ebola virus from a genetic standpoint.

“In some cases specific mutations in a virus can be identified and characterized which allow for improved infection of a different species (e.g. mice instead of humans). In other cases, there are only associations of sequence variants in different stages of an epidemic. For example, as viruses that have typically resided in wild animal populations spend more and more time spreading within the human population, and eventually are maintained by human to human contact, we can see genetic variants selected for in the virus population. This is illustrated by the SARS-coronavirus epidemic in 2002-2003, where changes in the virus over the course of the outbreak allowed it to interact more efficiently with its receptor on human cells. This likely allowed the virus to infect humans more efficiently, thereby worsening the outbreak.”

The UNC study will aid researchers in fighting Ebola by providing them with a better tool for understanding how Ebola Ebola infection manifests in the body of a host, and by pointing to a gene that researchers can target in their investigations.

The team found that a combination of genes was involved in producing a range of disease symptoms, and linked genetic variation to symptom variety. Not only that: the researchers were able to identify a single gene that accounted for much of the variation in symptoms–a gene that codes for the protein Tek.

“Our study not only in gives an improved mouse model which recapitulates more of the severe Ebola disease seen in humans,” said Ferris, “but also in pointing to a gene, Tek, which has sequence variants that are strongly associated with disease outcome in these mice. This helps in two ways.

“Therapeutics and vaccines need to be shown to be both effective against viral infection, and also safe for individuals. By developing a mouse model that shows many aspects of severe Ebola disease, we have a better platform for quickly assessing how effective treatments might be.”

“We now have a genetic target (Tek),” continued Ferris, “and its associated pathway of host response genes where we can focus studies on. Having a specific pathway that differentiates resistant and susceptible mouse lines provides us with a good host pathway that can be targeted to develop Ebola virus therapies.”

Of particular importance is the way that a disease, such as Ebola, infects individuals within a species differently, and that means variants in a species genetic code need to be identified in order to combat the disease–exactly what was accomplished in the research.

“Host genes have a major impact on susceptibility to infection, and not just between species,” said Ferris. “The mice we used were related to each other, yet some were resistant to infection and others got hemorrhage in a very controlled experiment. This means variants in their genes played a major role in determining their disease outcomes.”

The UNC team has been working on the study since before Ebola made headlines earlier this year, and Ferris pointed out that disease, if it is to be successfully fought, must be studied before it becomes a problem.

“I think another critical point is that we cannot wait for a major outbreak to start research on potential human pathogens,” said Ferris. “We have been part of this collaborative study for over 2 years, and therefore started well before the current outbreak. Only by identifying pathogens and studying them before they cause pandemics can we hope to develop the tools needed to combat infection.”

The report, “Host genetic diversity enables Ebola hemorrhagic fever pathogenesis and resistance,” was authored by Angela L. Rasmussen, Atsushi Okumura, Martin T. Ferris, Richard Green, Friederike Feldmann, Sara M. Kelly, Dana P. Scott, David Safronetz, Elaine Haddock, Rachel LaCasse, Matthew J. Thomas, Pavel Sova, Victoria S. Carter, Jeffrey M. Weiss, Darla R. Miller, Ginger D. Shaw, Marcus J. Korth, Mark T. Heise, Ralph S. Baric, Fernando Pardo Manuel de Villena, Heinz Feldmann, and Michael G. Katze, and was published in Science Magazine.

By Dan Jackson

The same bizarre worm-like clams that create holes in driftwood may be a game-changes for fuel supplies in America, according to a joint research team that has just published their finding that shipworms have a totally unique digestive system–hitherto unknown–and possess the ability to create enzymes that break plant matter down into sugar and other fuel products.

“You don’t hear about the discovery of new diges­tive strate­gies very often,” said Dr Dan Distel, Director at the Ocean Genome Legacy Center of New England Biolabs Marine Science Center, Northeastern University, and a lead researcher on the study. “It just doesn’t happen.”

“This is why it’s so impor­tant that we as researchers look at oceans,” Distel said. “It yields so many unex­pected benefits.”

Shipworms aren’t worms–they’re clams that look like worms, and they burrow holes through wood using enzymes made by bacteria. They use the broken down wood matter as nutrition, similar to termites.

How shipworms break down wood is the matter of the teams recent, groundbreaking discovery: the bacteria doesn’t come from shipworms’ guts.

The enzymes that break down wood are made by bacteria that lives inside special cells in the clam’s gills, and are transported to the gut.

No other animal in the world uses bacteria produced outside its digestive system, Distel said. No other intracellular bacterium produces enzymes that function outside of the host.

“This is really unusual in that the bacteria that produce the enzymes are located in an organ outside the digestive system and in fact appear to be intracellula,” Distel told The Speaker. “The vast majority of animals use extracellular bacteria in the gut to help them digest. The lumen of the gut, if you think about it, is really part of the outside of the animal. There are some examples of animals ingesting enzymes produced by bacteria or fungi in their food, but I have not heard of another animal that has a special organ outside of the gut designed to house enzyme-producing bacteria.”

Because the team could find around 45 genes inside the guts of the shipworms that matched the 1000 genes found in the gills, the team believes they can find the enzymes that could be used in commercial biofuel production.

“This was a key finding,” Distel said, “because we can iden­tify the small number of enzymes that are actu­ally involved in breaking down wood in gut, and that gives us a list of can­di­dates that you can start to look at to find commercially-​​viable enzymes.”

The enzymes convert plant biomass–cellulose–into sugar, and sugar can be used to make ethanol and other biofuels.

Biofuel production is already a matter of US government policy. By 2022 36 billion gallons of cellulosic biofuel should be produced in the country, according to a government mandate, and the United States Department of Agriculture (USDA) expects that one-third of US transportation fuel could be met with cellulosic biomass.

The main obstacle to commercial success in cellulosic ethanol is finding the right enzymes to convert plant matter into sugar.

Distel told us that although it would be an overstatement to say that they had found the key to unlocking commerce in cellulosic ethanol, they had identified a new source of enzymes with potential commercial value.

Next for the research team is to investigate how shipworms’ digestive enzymes move from gills to gut, and to characterize each of the proteins the team found and evaluate their potential applications.

The research was a large cooperative effort undertaken with the help of colleagues at the Joint Genome Institute (DOE), New England Biolabs, and other collaborating institutions.

In addition to collaborative help, advances in science were also credited by Distel in the research.

“It has been known that bacteria are present in the gills since the 1970’s and it has been suspected for some time that they contribute to wood digestion by the host,” Distel told us, “but this is the first demonstration. I have been working on these critters for many years, but recently advances in genomics and proteomics have given us the tools to answer many questions that were previously tough to address. ”

Their research paper, “Gill bacteria enable a novel digestive strategy in a wood-feeding mollusk,” was published in Proceedings of the National Academy of Sciences Monday afternoon, and was authored by Roberta M. O’Connora of Tufts Medical Center, Jennifer M. Fung at Bolt Threads biotech company, Koty H. Sharp at Eckerd College, Jack S. Bennerd, Colleen McClungd, Shelley Cushing, Elizabeth R. Lamkin, Alexey I. Fomenkov, Bernard Henrissat, Yuri Y. Londer, Matthew B. Scholz, Janos Posfai, Stephanie Malfatt, Susannah G. Tringe, Tanja Woyke, Rex R. Malmstromh, Devin Coleman-Derrh, Marvin A. Altamia, Sandra Dedrick, Stefan T. Kaluziak, Margo G. Haygood, and Daniel L. Distel.

By Dan Jackson

Photos: Dan Distel, Korabel Cherv