Despite ongoing public health efforts, E. coli outbreaks continue to
infiltrate the food supply, annually causing significant sickness and death
throughout the world. But the research community is gaining ground.
In a major finding, published
today in the scientific journal Nature, researchers from the La Jolla Institute
for Allergy & Immunology have discovered a molecule's previously unknown
role in fighting off E. coli and other bacterial infections, a discovery that
could lead to new ways to protect people from these dangerous microorganisms.
"We've found that a certain molecule,
known as HVEM, expressed by the cells lining the surface of the lung and
intestine, is critical to protecting the body from E. coli, pneumococcus and
other bacterial infections that enter our bodies through the lining of our
respiratory or intestinal tracts," said Mitchell Kronenberg, Ph.D., La
Jolla Institute's president and chief scientific officer, who led the research
team.
"We discovered that HVEM acts in these
cells like a border guard that responds to the presence of invasive bacteria and
signals the immune system to send in more troops. Without its involvement as
part of the epithelial protective barrier, the body could be overrun by certain
disease causing bacteria," said Dr. Kronenberg, adding that he is hopeful
the discovery will advance efforts toward developing new treatments or vaccines
against bacterial infections.
"People knew that epithelial cells
protect the body's mucosal borders from infection," said Dr. Kronenberg.
"But what wasn't known was that HVEM is critically important in turning on
the epithelial cell anti-bacterial response." Epithelial cells line the
body's mucosal borders, which include the mouth, nose, intestines and lungs and
are the most common entry points for infectious pathogens.
"We found that HVEM and another receptor
(the receptor for IL-22) have to act together in the epithelial cells to
trigger immune protection. Without these two receptors acting in concert, the
body couldn't withstand the infection," said Dr. Kronenberg.
Richard S. Blumberg, M.D., a professor of
medicine at Harvard Medical School and chief of the division of
Gastroenteroogy, Hepatology and Endoscopy at Brigham and Women's Hospital,
called the finding important on many levels.
"It is of great biological interest
because it shows how this very novel pathway has an important role to play in
the management of infections at the epithelial boundaries, which is the entry
point for the vast majority of infectious diseases," he said. "At the
most fundamental levels, it gives us new insights into the way in which our
host immune response engages and enables protection mechanisms at that portal
of entry. From a therapeutic standpoint, better understanding of these pathways
will enable researchers to explore ways to therapeutically manipulate the immune
response to prevent and eradicate infectious pathogens at these critical body
sites."
While the study, "HVEM signaling at
mucosal barriers provides host defense against pathogenic bacteria,"
focused on E. coli and pneumococcus (also known as Streptococcus pneumoniae),
Dr. Kronenberg said the HVEM mechanism is likely involved in protecting the
body from many other dangerous bacteria and other microorganisms. In fact, HVEM
stands for herpes virus entry mediator, and it is a protein that herpes virus
uses to enter cells. In the study, the researchers used mice genetically
engineered not to have HVEM.
When these mice were exposed to pneumococcus
or a mouse pathogen very similar to E. coli, the HVEM deficiency led to a much
greater susceptibility to infection, higher bacterial burdens and significantly
compromised the mucosal barrier.
"It is striking how similar the
responses in the lung and the intestine were," said Dr. Kronenberg.
"The mice without HVEM were unable to respond effectively at either site,
and the deficit was not only major but also nearly immediate, within two days
of exposure to the microorganisms."
"In the present era of ever increasing
antibiotic resistance, innovative approaches to treatment of bacterial
infections are urgently needed," commented Victor Nizet, M.D., a professor
of Pediatrics and Pharmaceutical Sciences at the University of California San
Diego. "These importantly include new approaches to strengthen immune
resistance to infection, and the discovery by the La Jolla Institute scientists
reveals HVEM as a candidate drug target with relevance to multiple pathogens
and multiple sites of infection."
Pneumococcus is the most common cause of
bacterial pneumonia and meningitis in children. According to the World Health
Organization, pneumonia is the single largest cause of death in children
worldwide, annually killing an estimated 1.4 million children under the age of
five.
While cases among U.S. children have declined
significantly due to the introduction of a pneumococcal vaccine in 2000, the
bacteria remains a significant problem, particularly among U.S. children under
two years, the elderly and throughout the developing world.
Escherichia coli (abbreviated as E. coli) are
a large and diverse family of bacteria. Although most strains of E. coli are
harmless, some can be deadly. E. coli creeps into the food supply through
contamination by tiny (usually invisible) amounts of human or animal feces.
Many people may develop mild symptoms, but
some suffer severe complications that can lead to kidney failure and death. In
2011, an E. coli outbreak centered in Germany sickened more than 4,000 people,
ultimately killing 50 people in 15 countries. The outbreak was eventually
traced to contaminated bean sprouts.
Provided
by La
Jolla Institute for Allergy and Immunology
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