The study, published this week in the on-line version of the Proceedings of the National Academy of Sciences (PNAS), not only determined the pathogen's genetic makeup but also compared it to other isolates of the same microbe. That analysis shed light onto why S. agalactiae -- which is found in the digestive or genital tracts of many healthy people - has emerged in recent years as a more widespread and virulent cause of illness in certain adults.
"We were surprised to find so many differences among the isolates of this important pathogen," said Hervé Tettelin, an associate investigator at The Institute for Genomic Research (TIGR) who led the sequencing project. "Those differences could help explain why some strains of S. agalactiae are much more virulent than others."
Tettelin and other TIGR scientists did the comparative genomics analysis in cooperation with a research group led by Dennis L. Kasper at Harvard Medical School and a team led by Guido Grandi at the vaccine research division of Chiron, S.p.A., a biomedical company that funded the research project. The research was supported by Chiron and by grants from the National Institutes of Health.
"Completion of the genome sequence represents an important milestone in the study of this organism," said Kasper. "We anticipate that many investigators will take advantage of the S. agalactiae genome sequence to identify new virulence determinants and potential targets for vaccine development."
"We wanted the genome information to identify proteins which can be used in a vaccine," said Guido Grandi, head of Biochemistry and Molecular Biology at Chiron vaccine research. "We have used this new genomic approach already to make a type B meningococcal meningitis vaccine which is now being tested in people. So we know that the strategy works."
To find out more about the molecular reasons for the virulence of what is known as the "serotype V" isolate of S. agalactiae, the authors of the study compared that genome to the genetic makeup of other S. agalactiae strains and also with two different species of streptococci that cause human diseases: S. pneumoniae, which causes pneumonia, meningitis and septicemia, and S. pyogenes, which among other illnesses causes the "strep throat" that can lead to acute rheumatic fever.
Tettelin said the microarray experiments that compared those related genomes found numerous differences, even among strains with the same serotype - that is, the type of polysaccharides that make up the capsule (outer coat) that surrounds each bacterium. The genetic diversity indicates that S. agalactiae has mechanisms (including acquisition, duplication and re-assortment of genes) that have allowed it "to adapt to new environmental niches and to emerge as a major human pathogen."
They also said in silico (computer) analysis showed that S. agalactiae's genome differed from that of other streptococci in several of the microbe's metabolic pathways and in related transport systems through the bacterium's cell membrane. Those differences probably relate to how S. agalactiae adapted to distinct niches in its human and bovine hosts, the paper suggests. The researchers also found genes unique to S. agalactiae that likely play a role in colonization or in disease: genes related to surface proteins, capsule synthesis, and the hemolysin enzyme that clears the path for microbes to invade other parts of the body and cause disease.
The researchers chose to sequence type V because it is the most common capsule type that is associated with invasive infection among adults other than pregnant women. And the emergence of type V strains over the last decade appears to parallel the increase in S. algalactiae-related diseases among those adults.
While S. agalactiae is normally a harmless organism when it colonizes the human gastrointestinal or genital tracts, the microbe can cause life-threatening invasive infection in susceptible hosts, which include newborn infants, pregnant women, and adults with underlying chronic illnesses. The number of neonatal S. agalactiae infections has dropped since physicians began prescribing antibiotics during delivery for high-risk pregnant women in 1996, but invasive infections in adults with deficient immune systems have increased.
S. agalactiae has a circular genome of about 2.16 million base pairs. Researchers predicted that there are 2,176 genes in that genome, and about 65% of the proteins expressed by those genes were of known function. The authors of the study found that the three streptococcal species shared 1,060 genes--about half of their genes-- but that 683 genes are unique to S. agalactiae.
"This study is important because it sheds light on the virulence mechanism of one of the last major human pathogens whose genome had not yet been sequenced," said Claire M. Fraser, TIGR's president. "This should help researchers find vaccine candidates or drug targets to fight a pathogen with broad impact on human health."
The Institute for Genomic Research (TIGR) in Rockville, Maryland, is widely regarded as the world's leading research center for microbial genomics. Founded in 1992, TIGR is a not-for-profit research institute whose primary research interests are in structural, functional and comparative analysis of genomes and gene products from a wide variety of organisms, including viruses, eubacteria, archaea, and eukaryotes.
The Channing Laboratory is a multidisciplinary research division of Brigham and Women's Hopital and Harvard Medical School. Areas of investigation include pathogenic bacteriology and vaccine development, chronic disease epidemiology, and virology.
Chiron Corporation, headquartered in Emeryville, California, is a leading biotechnology company that participates in three global healthcare markets: biopharmaceuticals, vaccines and blood testing. The company is applying a broad and integrated scientific approach to the development of innovative products for preventing and treating cancer, infectious diseases and cardiovascular diseases.
Chiron Vaccines is a global business, based in Europe, dedicated to supplying conventional vaccines and developing its range through the skills in genetic engineering, gene delivery system, genomics, proteomics, adjuvants and infectious disease biology. Chiron Vaccines' presence is strongest in Germany and Italy, where it is a market leader. The company also sells its products to multinational health organizations and local distributors worldwide, and works closely with the global science community and research institutes.
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