Nav: Home

Catch a virus by its tail

May 13, 2019

Viruses are masterful invaders. They cannibalize host cells by injecting their genetic material, often making thousands of copies of themselves in a single cell to ensure their replication and survival.

Some RNA viruses insert their genetic material as a single piece, while others chop it up into pieces. The latter are aptly named segmented viruses.

Such segmented RNA viruses--including several that cause human diseases like influenza--have been a longstanding enigma to researchers: How do they accomplish the precise copying and insertion of each segment? How do they ensure that individual segments are all copied by the same enzyme while ensuring that each segment can make different amounts of RNA? Such exquisite regulation is critical to make the correct levels of the viral proteins necessary for successful replication.

Now research by scientists at Harvard Medical School's Blavatnik Institute yields a surprising answer: The viral machinery in charge of this survival-ensuring maneuver becomes activated by an RNA from the opposite end of the segment where copying starts.

The findings, published May 9 in PNAS, identify new potential targets to inhibit the replication of segmented viruses. This group includes several emerging and highly fatal viruses such as Lassa fever virus, bunyaviruses like La Crosse and Rift Valley fever, as well as the better known and more common influenza viruses.

"Climate change has altered and intensified the spread of some serious and emerging viruses to new geographic regions, creating an acute challenge to global health. Our findings identify a critical mechanism that allows some of these pathogens to replicate and survive," said Sean P. J. Whelan, professor of microbiology at HMS and director of the Harvard Program in Virology.

Lassa fever infections, for example, are rarely fatal, but once actual disease develops, it can cause hemorrhages, or bleeding, in multiple organs in one out of five people. The mortality rate can reach 50 percent during epidemics, according to the Centers for Disease Control and Prevention.

In the study, Whelan and study co-author Jesse Pyle, a graduate student in Whelan's lab, worked with the Machupo virus, an arenavirus, which like Lassa virus infects rodents that in turn transmit the virus to humans where it causes fatal hemorrhagic fevers.

Unlike the flu virus, whose genome has eight segments, Machupo virus has only two segments--called small and large segments--offering a much simpler way to understand how different segments are copied in the correct amounts.

Previous clues about this mechanism came from research on influenza and La Crosse viruses that showed the viral protein responsible for copying the key segment--RNA-dependent RNA-polymerase (RdRP)--interacts with the 5' end of the segment, which is the exact opposite end to the location where the protein initiates copying. Yet, the importance of this interaction was not fully understood.

The experiments revealed that mixing short 13-nucleotide long RNAs from the 5' end of the Machupo virus segments with the RdRP--the catalyst that initiates RNA replication--in fact, stimulated the ability of this enzyme to copy the viral segment. The two-segment Machupo virus contains four subtly different 5' RNAs that each bind the RdRP enzyme. Remarkably, the scientists observed, those RNAs dictate which of the four different start sites the enzyme actually uses.

Whelan and Pyle say these results not only shed light on an important question in basic virology, but they also identify a new target that may illuminate how to develop of a new class of antiviral drugs that target this essential 5' RNA activation.

Most antiviral drugs currently on the market directly target viral enzymes involved in replicating genetic material or in the processing of viral proteins. None, however, interfere with the particular mechanism described in the current study.

"Our work demonstrates that both the 5' RNA and its binding site on the viral enzyme are potential new targets for inhibition of viral replication," Whelan said. "An important next goal would be to hunt for molecules that interfere with this process and set the stage for new drug design."
-end-
This research was funded by National Institutes of Health (grants AI133689, T32AI007245 and AI059371).

Paper DOI: https://doi.org/10.1073/pnas.1900790116

Harvard Medical School

Related Rna Articles:

A new, unified pathway for prebiotic RNA synthesis
Adding to support for the RNA world hypothesis, Sidney Becker and colleagues have presented what's not been shown before -- a single chemical pathway that could generate both the purine and pyrimidine nucleosides, the key building blocks of RNA.
Blue light for RNA control
Messenger RNA molecules contain genetic information and thus control the synthesis of proteins in living cells.
New ways to look at protein-RNA networks
For their vital tasks, all RNA molecules in our cells require proteins as binding partners.
We now know how RNA molecules are organized in cells
With their new finding, Canadian scientists urge revision of decades-old dogma on protein synthesis
RNA microchips
Ribonucleic acid (RNA) is, along with DNA and protein, one of the three primary biological macromolecules and was probably the first to arise in early life forms.
More Rna News and Rna Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Erasing The Stigma
Many of us either cope with mental illness or know someone who does. But we still have a hard time talking about it. This hour, TED speakers explore ways to push past — and even erase — the stigma. Guests include musician and comedian Jordan Raskopoulos, neuroscientist and psychiatrist Thomas Insel, psychiatrist Dixon Chibanda, anxiety and depression researcher Olivia Remes, and entrepreneur Sangu Delle.
Now Playing: Science for the People

#537 Science Journalism, Hold the Hype
Everyone's seen a piece of science getting over-exaggerated in the media. Most people would be quick to blame journalists and big media for getting in wrong. In many cases, you'd be right. But there's other sources of hype in science journalism. and one of them can be found in the humble, and little-known press release. We're talking with Chris Chambers about doing science about science journalism, and where the hype creeps in. Related links: The association between exaggeration in health related science news and academic press releases: retrospective observational study Claims of causality in health news: a randomised trial This...