As reported in this week's issue of the journal Nature, scientists have
determined the entire order of paired chemical building blocks that make up
the DNA of the deadly cholera bacterium, an ancient infectious foe. The
comma-shaped microbe, Vibrio cholerae, causes a severe diarrheal disease
that has been endemic in southern Asia for at least 1,000 years. Since
1817, it has spread worldwide to cause seven pandemics. Between outbreaks,
the organism thrives in brackish waters in both harmless and disease-causing
"Determining the genomic sequence of medically important pathogens such as
Vibrio cholera holds enormous promise for helping us fight some of the
world's most intractable infectious diseases," comments Anthony S. Fauci,
M.D., director of the National Institute of Allergy and Infectious Diseases
(NIAID), which funded the project. "Besides contributing to our
understanding of how a microbe causes disease and survives in the
environment, sequencing studies enable scientists to locate genes that may
lead to potential new targets for vaccine candidates, drugs and diagnostic
"Cholera has been extensively studied by many people, yet important new
discoveries continue to be made," he adds. "Having the sequence available
will facilitate these efforts immensely."
A talented team of cholera and genome sequencing experts contributed to the
success of the project. They include John Mekalanos, Ph.D., of Harvard
Medical School, a renowned microbiologist who probes how bacterial virulence
factors cause disease; National Science Foundation Director Rita Colwell,
Ph.D., of the University of Maryland, an expert in how V. cholerae persists
in the environment; and genomics experts Claire M. Fraser, Ph.D., and John
Heidelberg, Ph.D., of The Institute for Genomic Research (TIGR) in
Rockville, Maryland .
The project began in late 1996, one of the earliest microbial genome
sequencing efforts financed by NIAID, and its outcome has been long-awaited.
Since that time, NIAID has rapidly expanded its portfolio of such grants,
and they now number more than 30.
One of the most unusual findings of the cholera project is that instead of
having one circular chromosome, like most bacteria, the organism has two,
notes Dennis Lang, Ph.D., NIAID's bacterial and viral enteric diseases
program officer. "When the team became aware of new research indicating
that cholera strains may have two chromosomes, they rapidly assembled the
final sequence into two separate elements."
The larger chromosome, comprising nearly 3 million base pairs, contains most
of the organism's critical genes, including those coding for disease-causing
toxins and proteins that carry out essential cell functions. The smaller
chromosome is roughly one-third its size. "Both chromosomes are essential,"
says Dr. Lang. "You couldn't do away with either one of them and have the
organism be viable."
Besides illuminating the bacterium's role in disease, the sequence
information will enable scientists to investigate specific questions about
how V. cholerae survives and persists in the environment, which it sometimes
does by colonizing algae and other sea life. "Hundreds of different strains
of the bacterium exist, and how they interact and evolve is largely a
mystery," Dr. Lang notes.
Dr. Colwell and others have long believed that the bacterium enters a
quiescent state where, much like bacterial spores, it is alive but fails to
multiply unless triggered by specific environmental conditions. "The
authors of the Nature paper found some genes in the cholera genome," Dr.
Lang says, "that appear to be related to genes from sporulating bacteria.
What role these cholera genes may play in that quiescent state, if it
exists, remains to be seen, but this information will provide much fodder
for that research."
The V. cholerae strain that was sequenced, a virulent El Tor strain used for
many years in clinical studies, is also a strain that NIAID has produced in
quantity and supplies to investigators worldwide for vaccine studies.
Cholera has a rapid onset and most often occurs in epidemics spread through
contaminated water. Oral rehydration is an effective treatment, but left
untreated, cholera causes severe diarrhea that has a high mortality rate,
particularly in young children. According to information reported to the
World Health Organization in 1999, nearly 8,500 people died and another
223,000 were sickened with cholera worldwide.