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For The First Time, A Vaccine Against Fungal Infection
For the first time, scientists have used recombinant DNA technology to
create a live vaccine that protects against a fungal infection in
mice.
This new vaccine is safer than live vaccines made without recombinant
technology and more effective than "killed" vaccines. Many fungal
diseases are on the rise in the United States, and this recombinant
live vaccine approach could be used to protect against them.
Mycologist Bruce Klein, M.D., and colleagues at the University of
Wisconsin-Madison report their results in today's issue of the Journal
of Clinical Investigation. The effort was supported by a grant from
the National Institute of Allergy and Infectious Diseases (NIAID).
"This work achieves what many would have thought highly unlikely, if
not impossible," comments Dennis M. Dixon, Ph.D., chief of the
bacteriology and mycology branch at NIAID. "It validates the concept
of a vaccine approach for disease-causing fungi."
Developing an anti-fungal vaccine is extremely difficult because fungi
are complex organisms with large numbers of genes. The immune system
must respond to a fungal infection with an equally complex set of
defenses.
A live vaccine is the best way to achieve this response for
blastomycosis thus far, experts say, but rendering a pathogenic fungus
harmless so that it can be used as a live vaccine is no easy task.
To do so, scientists must find and inactivate a "virulence" gene --
one that allows an organism to cause disease. To give an idea of the
relative difficulty of this search, the fungus used in this study has
a genome of 25 million base pairs of DNA; a bacterium such as
Escherichia coli has only 4.6 million base pairs, and HIV has under
10,000.
Klein and his team worked with a fungus called Blastomyces
dermatiditis, which causes a sometimes fatal lung infection,
blastomycosis, even in people with healthy immune systems.
The researchers identified a particular virulence gene, WI-1. When
they knocked out the WI-1 gene with recombinant DNA technology, they
found that the altered B. dermatiditis strain could no longer cause
disease in laboratory mice.
Furthermore, they discovered that exposure to the harmless engineered
strain induced a T-cell response that fully immunized the mice against
all strains tested of the lethal, naturally occurring fungus.
"The WI-1 gene codes for a surface protein molecule that allows the
fungus to stick and stay in the lung," explains Dr. Klein.
In addition, the WI-1 protein actively interferes with the immune
response by disrupting the balance of defensive molecules called
cytokines produced by the immune system. The WI-1 protein is probably
the major reason B. dermatiditis is so potent -- a mere 10 to 100
cells of the organism are enough to cause fatal infection in healthy
mice.
A previous live vaccine, for the fungus Coccidioides immitis, used a
variant form of the organism that did not cause disease. However,
there is always a chance that such variants will spontaneously revert
to the disease-causing form, Dr. Klein explains, a risk that is
eliminated by using recombinant DNA technology to irreversibly knock
out a virulence gene.
Blastomycosis is not common in humans. Various studies report anywhere
from one to 40 cases per 100,000 people in areas where B. dermatiditis
commonly lives: the South Eastern, South Central and upper Midwestern
United States. Like many fungi, this one lives in the soil, especially
around waterways, and can cause pneumonia when people inhale its
spores into their lungs. Current treatments with anti-fungal drugs
usually take six months to be effective.
However, other disease-causing fungi similar to B. dermatiditis are
much more common, and Dr. Dixon hopes the new recombinant live vaccine
might encourage researchers to develop vaccines against other fungi.
For example, Coccidioides immitis caused an epidemic of San Joaquin
Valley Fever in the California area in 1992. And Histoplasma
capsulatum, which can cause the lung infection histoplasmosis, is
endemic to the Ohio and Mississippi River Valley, where it infects
most of the population by age 20. The majority of these infections are
benign, but in about 10 percent of individuals the infection can
produce life-threatening symptoms such as inflammation of the
membranes around the heart. Researchers are working to develop
vaccines against these organisms as well.
In addition, so-called "opportunistic" fungal infections, caused by
organisms such as Aspergillus and Candida, are on the rise. This
increase is caused in part by the growing number of people with
impaired immune systems due to AIDS, chemotherapy, bone marrow
transplants or surgical procedures.
The B. dermatiditis vaccine may have a more immediate use as a
veterinary vaccine, because blastomycosis affects a large number of
dogs. Dr. Klein is studying how the vaccine works in dogs, and this
work should help him further refine his vaccine method. - By Jeff
Minerd
(Reference: M W=FCthrich, et al. Mutation of the WI-1 gene yields an
attenuated Blastomyces dermatiditis strain that induces host
resistance. Journal of Clinical Investigation 106(11):1381-89 (2000).)
[Contact: Jeff Minerd]
30-Nov-2000
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