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January 12, 2018

For Dengue, Slow and Steady Wins the Replication Race

These cultured cells include one (center) that is infected with a common strain of dengue virus. The genomic material of the virus is highlighted in magenta and is localized to an area in the host cell where a specialized structure called the endoplasmic reticulum resides. [Jessica Child/Duke University Medical Center]

  • Rising global temperatures will allow diseases that are typically isolated to tropical climates to spread northward and dramatically increase the threat to public health. Clinicians have already begun to report on a spike in the number of cases of dengue in areas that have been devoid of the mosquito-borne disease previously. While the mortality rate for dengue is thankfully low, the morbidity associated with infections is extremely high, typically placing a huge economic burden on local communities and the healthcare system. A greater understanding of dengue virus’ molecular mechanisms once inside the host cell may hold the key to new therapeutic interventions.

    Now a team of investigators from Duke University has just released data revealing how dengue virus manages to reproduce itself in an infected person without triggering the body's normal defenses. Findings from the new study—published recently in the Journal of Virology, in an article entitled “Dengue Virus Selectively Annexes Endoplasmic Reticulum-Associated Translation Machinery As a Strategy for Co-Opting Host Cell Protein Synthesis”—shows that the virus pulls off this immune hoax by co-opting a specialized structure within host cells for its own purposes.

    "It is a remarkably clever thing for a mere ten kilobases of genetic information," remarked senior study investigator Christopher Nicchitta, Ph.D., professor of cell biology at Duke University School of Medicine. "The virus takes over the machinery and makes a ton of itself, but so slowly and inefficiently that it doesn't set off any of the sensors the host cell uses to detect when something is awry."

    Unlike other viruses that flagrantly disrupt the functions of the host in favor of their own needs, dengue appears to be more subtle. It slowly and surreptitiously takes over an accordion-shaped structure inside the cell called the endoplasmic reticulum, the production site for a small subset of host proteins, and steers clear of the larger fluid-filled space of the cell called the cytosol, where most cellular proteins are manufactured.

    According to the World Health Organization, approximately half of the world's population is at risk of dengue and each year, about 96 million people are sickened by it. No specific treatment for dengue fever currently exists. Decades of vaccine research have been met with disappointment, and recent reports indicate that a new vaccine for dengue could worsen the disease rather than prevent it.

    "If you can't make a vaccine, the approach you are left with involves understanding the precise molecular details of the life cycle of these viruses and how they are able to secure and manipulate the host machinery so that you can identify potential drug targets," Dr. Nicchitta explained. "It is a more difficult path, but we are beginning to map it out."

    Viruses like dengue are curious entities that exist in a realm between the living and the dead. Though they possess a few hallmarks of life—like proteins and genetic material (DNA or RNA)—they are missing a key one, the ability to reproduce (at least by themselves). That's where host cells come in. Shortly after a virus infects a living cell, it taps into the host's replication machinery to make more copies of itself. In the case of dengue, one infected host cell can churn out as many as 10,000 viral offspring.

    In the current study, Dr. Nicchitta and his colleagues infected tissue culture cells with a common strain of dengue virus. They subsequently sorted out the cell contents to focus on the two areas where proteins are typically synthesized, the endoplasmic reticulum and the neighboring cytosol. Using advanced molecular techniques, the researchers mapped out the location of the tiny factories known as ribosomes that produce proteins, as well as the RNA template that provides a blueprint for their production.

    Interestingly, the researchers found that all the action took place on the surface of the endoplasmic reticulum. The entire genome of the dengue virus is translated in one fell swoop and then cut up into ten separate proteins. Adding such a complex product to the workload of the endoplasmic reticulum would typically set off its stress sensors. But the researchers discovered that the viral RNA template was translated into protein in such an inefficient, lackadaisical manner, that it didn't trip those alarms.

    "There are features of the RNA that makes it inefficiently translated, so it doesn't turn on these stress pathways," Dr. Nicchitta concluded. "Dengue keeps the host cells happy as long as it can. At some point, it does gradually overburden the system, and the cells will die, but by then the virus has already made tens of thousands of copies of itself."

    The Duke researchers are currently trying to pinpoint which features of dengue—its sequence or structure, or both—that underlie the slow and steady approach. It may sound counterintuitive, but if the virus were translated more efficiently, it could no longer hide in plain sight. The host cell would notice, and the ruse would be over.

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