"This is an interesting finding that underscores how basic
research in one disease area often leads to discoveries in
another area," says NIAID Director Anthony S. Fauci, M.D.
"It also is a good example of how pathogenesis research -
the study of how pathogens interact with the host to cause
disease - creates opportunities for applied research."
Approximately 2,500 babies with cystic fibrosis are born
each year in the United States. Before the 1950s, most
children with the disease died by age 1 or 2. Today,
with better methods for managing the disease, the average
survival of these individuals is about 30 years.
"In most cases of inherited disease with high rates of
childhood mortality, the defective gene does not remain
in the gene pool," says Dr. Pier. "The disease and the
gene causing it literally die out. When that doesn't
happen, we find that it is because carriers - healthy
people with one good copy and one bad copy of the disease
gene - have some enhanced survival advantage." For
example, Dr. Pier notes that individuals with a single
copy of the sickle cell disease gene are more resistant
to malaria infection than people who do not have the gene.
Scientists have speculated that cystic fibrosis carriers
also have enhanced protection against an infectious
agent, but until now, they didn't know which one.
Cystic fibrosis develops in children who inherit two
mutant copies - one from each parent - of the gene that
encodes a protein known as cystic fibrosis transmembrane
conductance regulator (CFTR). In these children, abnormal
CFTR blocks the movement of chloride ions and water in the
lungs, gastrointestinal tract, and other tissues and causes
them to secrete large amounts of mucus. As mucus accumulates
in their lungs, these children become increasingly susceptible
to life-threatening respiratory infections.
Infection with Pseudomonas aeruginosa is one of the primary
clinical features of cystic fibrosis. Last year, Dr. Pier
and his colleagues reported that the normal CFTR protein acts
as a receptor for P. aeruginosa and helps clear this bacterium
from the lung. When CFTR protein is abnormal or missing, it
does not bind and ingest this bacterium, and lifelong
infections are thus established in many individuals with
The researchers hypothesized that other bacteria might
interact with CFTR in a similar manner. Finding no other
lung pathogens that use the CFTR entry pathway, Dr. Pier
and his colleagues turned their attention to the
gastrointestinal tract, since its tissues also are affected
directly in people with cystic fibrosis.
Dr. Pier and his colleagues showed that normal CFTR protein
also acts as a receptor for Salmonella typhi, the
gastrointestinal pathogen that causes typhoid fever. In
tissue culture experiments, they found that human cells
expressing normal CFTR took up significantly more S. typhi
than did cells expressing mutant CFTR. The researchers then
added to the cells antibodies and synthetic molecules designed
to bind to a segment of the CFTR molecule that protrudes from
the cell membrane. These agents blocked the uptake of S.
typhi by CFTR, thus identifying the protruding CFTR segment
as the S. typhi binding site through which it enters cells.
"Uptake and ingestion of S. typhi by epithelial cells is
part of the body's normal protective response," explains
Dr. Pier. "Epithelial cells ingest the bacterium, then
slough off of the epithelial surface. New epithelial
cells soon take their place. At low concentrations of
S. typhi, this process prevents infection. High
concentrations, however, can overwhelm this protective
response. After S. typhi-ingesting epithelial cells
have been shed from the epithelial surface, any excess
S. typhi are free to attack the underlying tissue, which
lacks this defense mechanism."
Since abnormal CFTR binds poorly to S. typhi, cystic fibrosis
gene carriers would be protected from this infectious process
and thus spared the high mortality associated with typhoid
fever. Dr. Pier notes that before 1900, typhoid fever was
a major infectious disease in the United States that killed
about 15 percent of infected individuals. It remains a
serious problem in countries that lack adequate sewage
treatment facilities, since contaminated water is a major
source of S. typhi transmission.
Dr. Pier speculates that, in addition to advancing the
understanding of how pathogens interact with host tissues
to cause disease, this finding could have relevant
applications in vaccine research, particularly in ongoing
efforts to develop S. typhi-based vaccine delivery vehicles.
S. typhi stripped of its ability to cause disease is an
attractive tool for vaccine researchers. Vaccines based
on this gastrointestinal pathogen would be delivered orally,
and thus might be useful for stimulating immunity at the
mucosal surfaces that line the stomach and gut. AIDS
researchers supported by NIAID recently initiated a clinical
trial of an experimental vaccine composed of a weakened
form of S. typhi into which a gene for a human
immunodeficiency virus (HIV) protein had been inserted.
"Our work provides an understanding of how S. typhi gets
into the tissues of the host's immune system," says Dr.
Pier. "By manipulating S. typhi or other organisms to
deliver antigens via the CFTR-uptake pathway, we may be
able to develop better vaccines."
In future studies, he and his colleagues will try to
define the S. typhi surface molecules that bind to CFTR.
"It may be possible to use this structure to make non-
living antigen delivery vehicles that target antigens to
the immune system following oral ingestion."
NIAID supports research on AIDS, tuberculosis, malaria
and other infectious diseases, as well as allergies and
immunology. In addition to NIAID, the National Heart,
Lung and Blood Institute (NHLBI) supports Dr. Pier's
current research. NIAID and NHLBI are components of the
National Institutes of Health (NIH). NIH is an agency
of the U.S. Department of Health and Human Services.
Press releases, fact sheets and other NIAID-related
materials are available on the Internet via the NIAID
Web site at http://www.niaid.nih.gov.