|Researchers Discover How Compounds Prevent Viruses From Entering
Compounds called defensins — known to prevent viruses from entering cells — appear
to do so by preventing the virus from merging to cells’ outer membrane, according
to a study by researchers at the National Institute of Child Health and Human
Development and the National Heart Lung and Blood Institute, both of the National
Institutes of Health, and the University of California at Los Angeles.
The study, appearing in the September 11 Nature Immunology, also received
funding from NIH’s National Center for Research Resources.
“This discovery provides a basic understanding of a first-line defense against
such viruses as HIV and the influenza virus,” said Duane Alexander, M.D., Director
of the NICHD. “This finding may ultimately lead to new strategies for preventing
viral illness, and to increased understanding of why some individuals are more
resistant to certain kinds of viral infection than are other individuals.”
The means by which many viruses infect a cell is a two-step process, said the
study’s senior author, Leonid V. Chernomordik, Ph.D., Head of NICHD’s Section
on Membrane Biology in the Laboratory of Cellular and Molecular Biophysics. First,
the membrane of the virus’ outer coating, or envelope, must attach, or bind to,
the outer membrane of the cell. After this attachment has taken place, the viral
envelope membrane combines with, or fuses to, the cell membrane. After the two
membranes have fused, the virus inserts its genetic material into the cell.
Defensins are produced by cells that are among the first to come in contact
with viruses, Dr. Chernomordik explained. Such cells include leukocytes, a type
of immune cell, and epithelial cells, which line the surfaces of many organs
In the current study, the researchers studied epithelial cells from the inner
surface of the lungs. The researchers discovered that defensins block the influenza
virus entry into cells by preventing the fusion of viral and cell membranes.
Specifically, the researchers studied the antiviral effects of two different
classes of defensins, theta-defensin and beta defensin.
Membranes-the outer covering of cells and of many kinds of viruses-are coated
with a layer of molecules called glycoproteins. The glycoproteins protrude from
the membranes’ surface, in somewhat the same way bristles stick out of a hairbrush.
(See figure 1 at http://www.nichd.nih.gov/new/releases/defensins.cfm.) When the
virus first infects the cell, glycoproteins on both the cell surface and on the
virus spread apart, as the viral membrane approaches the cell membrane. To extend
the hairbrush comparison, it’s as if you could slide the bristles to the side,
and leave bare patches on each hairbrush. At the bare patches, both the cell
membrane and the viral envelope come together, and membrane fusion takes place.
Defensins, the researchers discovered, bind crosswise to glycoproteins, preventing
the viral and cell glycoproteins from spreading apart. In keeping with the hairbrush
comparison, it’s as if the bristles of the hairbrushes were bound together with
numerous small rubber bands. (See figure 2 at http://www.nichd.nih.gov/new/releases/defensins.cfm.)
“Defensins do not kill the virus, they just prevent it from entering the cell,” Dr.
Chernomordik said. “Viruses that are not allowed to enter the cells can then
be destroyed by the cells of the immune system.”
Dr. Chernomordik and his colleagues also studied the activity of mannan-binding
lectin, a compound produced by the liver. Like defensins, mannan-binding lectin
also protects against viral infection. The researchers discovered that mannan-binding
lectin prevents viral infection in the same way that defensins do, by binding
crosswise to glycoproteins.
Future studies of defensins may yield new strategies for preventing viral diseases,
Dr. Chernomordik added. For example, by learning more about how defensins bind
to glycoproteins, researchers one day may be able to devise new drugs that prevent
viruses from entering cells.
Similarly, researchers might explore whether potential differences in defensin
production might affect the ability to resist viral infection, Dr. Chernomordik
theorized. For example, slight variations in the genes for defensins might make
the molecules either more, or less, effective, at combating viruses. Similarly,
some individuals may produce more defensins than do others.
Other authors of the paper were Eugenia Leikina, Helene Delanoe-Ayari, Kamran
Melikov, and Andrew Chen of the NICHD; Myoung-Soon Cho, of the NHLBI; and Alan
J. Waring, Wei Wang, Yongming Xie, Joseph A. Loo and Robert I. Lehrer of the
University of California at Los Angeles.
The NICHD is part of the National Institutes of Health (NIH), the biomedical
research arm of the federal government. NIH is an agency of the U.S. Department
of Health and Human Services. The NICHD sponsors research on development, before
and after birth; maternal, child, and family health; reproductive biology and
population issues; and medical rehabilitation.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U. S. Department of Health and Human Services. It is the primary Federal
agency for conducting and supporting basic, clinical, and translational medical
research, and investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.