Researchers have sequenced the entire genome of a virulent strain of Streptococcus pneumoniae, a bacterium that readily moves from the throat to invade the lungs, blood, or brain, and kills millions of children and elderly people every year. The work should help provide targets for better drugs against S. pneumoniae, which is increasingly becoming resistant to existing therapies, as well as vaccines.
A team led by Claire Fraser and Hervé Tettelin of The Institute for Genomic Research (TIGR) in Rockville, Maryland, began the sequencing project in 1996, but progress was slowed by a series of technical problems and a split with the institute's original sponsor, Human Genome Sciences of Rockville, Maryland, that caused a temporary funding drought. Although TIGR made most of the raw sequence data available in 1997, the team took several more years to finish the sequencing and characterize the genes, a process called annotation.
Meanwhile, several companies were busy sequencing other S. pneumoniae strains. GlaxoSmithKline's Damien McDevitt predicts that "there are at least 10 genomes out there from different companies." So far, however, only two have been made public. A team led by Jose García-Bustos of GlaxoSmithKline's molecular microbiology division in Tres Cantos, Spain, published the annotated but incomplete genome of a virulent, antibiotic-resistant S. pneumoniae strain in the June issue of Microbial Drug Resistance. A team at Eli Lilly published an incomplete genome of a widely studied, nonvirulent lab strain in 1998, and a more complete version is in press at the Journal of Bacteriology.
Comparing multiple genomes is key for stopping S. pneumoniae, because 92 strains infect humans--and researchers would like to protect against them all. In their paper, which appears in this week's issue of Science, the TIGR team has taken a step in that direction by comparing its strain with the two incomplete published ones. This revealed that about 10% of the genes in the virulent TIGR strain are missing in the other two. That and sequence analysis pointed to several genes that may be important for infection.
Among those are a group that encode enzymes that the microbe uses to weaken biological membranes, which may help it invade tissues and spread throughout the body. The analysis also showed that the bacterium seems very adept at shuffling its genes--an ability that may help it evade the immune system. This "thrilling view" of the S. pneumoniae genome offers "a [new] glimpse into the lifestyle of the organism," says microbiologist Alexander Tomasz of Rockefeller University in New York City.
The Streptococcus pneumoniae Genome Diversity Project
More information about S. pneumoniae, on a site supported by vaccine manufacturer Wyeth-Lederle
List of the more than 45 microbial genomes so far completed, with links to others still in progress