How Cells Recognize Viral Toxins

ScienceDaily (Mar. 25, 2010) — For many years it's been known that the
fever, achiness and other symptoms you feel during the flu are
triggered by a viral molecule that travels through the body acting like
a toxin.

But what scientists haven't understood is how this molecule -- known as
double-stranded RNA -- is recognized and taken up by cells.

New research from McMaster University has identified how specific
proteins on the surface of cells, known as class A scavenger receptors,
bind to double-stranded RNA and bring it into the cell, jumpstarting
the immune response to a virus.

This finding, published in the March 26 issue of the journal PLoS
Pathogens, could lead to the development of new antiviral therapies.

"Since the 1950s and '60s, it's been known that double-stranded RNA is
a viral toxin," said Karen Mossman, an associate professor in the
Department of Pathology and Molecular Medicine in the Michael G.
DeGroote School of Medicine. "But what we haven't known is how cells
recognize double-stranded RNA outside of the cell. We know how they
respond to it. We know they take it up. But we've never appreciated how
that happens."

Mossman, an investigator with the Michael G. DeGroote Institute for
Infectious Disease Research at McMaster University, led a research team
to investigate the "gatekeeper" function of scavenger receptors in both
human and mouse cells. Until now, it was thought that the role of
scavenger receptors was limited to the removal of foreign substances
and waste materials from the body.

The researchers examined the five members of the class A scavenger
receptor family and discovered that they all had overlapping functions
in mediating the response of a cell to double-stranded RNA. They also
found that no matter what type of cell they looked at -- including
those not thought to express scavenger receptors -- all had at least
two or three scavenger receptor family members.

"We found that they are ubiquitously expressed," Mossman said. "But
that make sense to us because nearly every cell type responds to
double-stranded RNA."

Previously, scavenger receptors were thought to be found only on white
blood cells, or macrophages, and a small population of other blood
cells. The McMaster research has shown that scavenger receptors are
also expressed on fibroblast cells, which play an important role in
healing wounds and maintaining the structural framework of tissue.

By identifying these receptors, the researchers have uncovered an ideal
target for antiviral drug therapies which could potentially decrease
the side effects associated with viral infections.

"Now that we know what to manipulate, we can start looking at how we
can manipulate it to be beneficial during a viral infection," Mossman
said. "Since all viruses make double-stranded RNA, targeting these
receptors should be effective against many different viral infections
including influenza and other pandemic viruses."

The research was supported with funds from the National Institutes of
Health (NIH) and the Canadian Institutes of Health Research (CIHR).

"Since double-stranded RNA is produced by many different viruses, Dr.
Mossman's findings may have a significant impact on the treatment of a
wide variety of infections," said Dr. Marc Ouellette, scientific
director of the Institute of Infection and Immunity at the Canadian
Institutes of Health Research. "Understanding the mechanism employed by
viruses to infect surrounding cells is important if we are to develop
more effective antiviral therapies, and prevent the spread of viral
infections to a wider population."

Stephanie DeWitte-Orr, a postdoctoral fellow in the Mossman lab, was
the lead author of the study. The research also involved other
collaborators in the Michael G. DeGroote Institute for Infectious
Disease Research at McMaster University