|Scientists Identify Factor Key to Severity of
Community-Associated Methicillin-Resistant Staph Infections
Newly described proteins in drug-resistant strains of the Staphylococcus
aureus bacterium attract and then destroy protective human
white blood cells — a key process ensuring that S.
aureus survives and causes severe disease, according to
scientists at the National Institute of Allergy and Infectious
Diseases (NIAID), part of the National Institutes of Health.
S. aureus disease is a global public health concern because
some strains, including community-associated methicillin resistant S.
aureus (CA-MRSA), have developed resistance to existing antibiotics.
The NIAID scientists hope to use this finding to advance development
of new therapeutic treatments.
In a study published online in Nature Medicine, Michael
Otto, Ph.D., and his colleagues at NIAIDís Rocky Mountain Laboratories
(RML) describe how novel members of the phenol-soluble modulin
(PSM) protein family help determine disease severity and eliminate
immune defense mechanisms against CA-MRSA.
"This elegant work helps reveal the complex strategy that S.
aureus has developed to evade our normal immune defenses," says
Anthony S. Fauci, M.D., NIAID director. "Understanding what
makes the infections caused by these new strains so severe and
developing new drugs to treat them are urgent public health priorities."
Up until a year ago, most scientists studying S. aureus believed
they had narrowed their search for the cause of severe CA-MRSA
infections, focusing on the Panton-Valentine leukocidin (PVL) toxin
produced by certain strains. But then last year, Dr. Otto and his
RML colleagues published a study indicating that PVL does not play
a major role in CA-MRSA infections (http://www3.niaid.nih.gov/news/newsreleases/2006/staphtoxin.htm).
Given the scope of the problem in the United States, Dr. Otto's
group continued its search to understand why the CA-MRSA strains
cause widespread and often severe infections in otherwise healthy
people. Until now, no one had examined what role PSMs have in Staphylococcus infection.
The RML group identified previously unknown PSMs secreted by S.
aureus and identified the genes that encode those PSM proteins.
They then compared PSM production between CA-MRSA and the most
prominent hospital-associated MRSA strains. The research team
found PSM genes in all MRSA strains, but production of the proteins
was typically higher in CA-MRSA strains known for severe virulence,
according to Dr. Otto.
To determine whether PSMs contribute to virulence, the scientists
developed test strains using the most widespread isolates of CA-MRSA,
called USA300 and USA400. Each test strain had a certain combination
of PSM-encoding genes removed so the researchers could ascertain
whether those genes affected virulence. The scientists then observed
how laboratory mice responded to the test strains. By doing so,
they pinpointed the psm-alpha gene cluster (which makes PSM-alpha protein)
as playing an essential role in determining CA-MRSA virulence and,
ultimately, disease severity.
To understand how PSMs contribute to virulence, Dr. Otto and colleagues
next examined the role of the molecules in S. aureus evasion
of human immune defenses. They observed that the psm-alpha genes
generated the most resistance activity and the PSM-alpha proteins
were best at destroying most immune cells that help protect against
infection and disease. In all instances, the PSM-alpha molecules
caused the greatest destruction of white blood cells, an effect
that occurred rapidly.
What was remarkable, says Dr. Otto, is that a specific sensing
mechanism likely enabled S. aureus to secrete PSMs at
the ideal time when host immune cells were weakest and most vulnerable
to destruction. Likewise, PSM production slowed when the bacterial
survival was most jeopardized.
"We're not saying the psm-alpha gene cluster is
the only element contributing to the virulence and survival of
CA-MRSA, but it is a major factor," says Dr. Otto.
Next, he and his RML colleagues will examine whether the simple
presence of the psm-alpha genes create havoc with the
immune system, or whether some unknown trigger causes these genes
to be expressed in a harmful way. Dr. Otto's group also is continuing
to study the molecular details of how PSMs function. Ultimately
they hope to identify new candidate therapeutics for CA-MRSA by
studying the roles of the different PSM genes.
News releases, fact sheets and other NIAID-related materials are
available on the NIAID Web site at http://www.niaid.nih.gov.
NIAID is a component of the National Institutes of Health. NIAID
supports basic and applied research to prevent, diagnose and treat
infectious diseases such as HIV/AIDS and other sexually transmitted
infections, influenza, tuberculosis, malaria and illness from potential
agents of bioterrorism. NIAID also supports research on basic immunology,
transplantation and immune-related disorders, including autoimmune
diseases, asthma and allergies.
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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 it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.