Ever since Homo sapiens - modern mankind - got savvy enough to domesticate animals, some 10 thousand or 20 thousand years ago, their human descendants have been paying a heavy price for being all that sapient. The beasts of the field and wilderness that people tamed for food and power have fobbed off their disease-bearing pathogens onto their new human masters.
A case in point, of course, is the African chimpanzee, Pan troglodytes, caught in the act circa 1960 of transmitting the immunodeficiency virus, HIV-1, to human AIDS. HIV-2 is the legacy of a different African primate, the sooty mangabey monkey (Cercocebus atys.).
At genome sequencing laboratories around the world, 187 microbes from A to Y (Actinobacillus to Yersinia) are waiting in line to have their genomes sequenced. The list is compiled by TIGR - The Institute for Genomic Research in Rockville, Md. - which accounts for 47 of the 187 microorganisms on the sequencing list.
The latest of these to have its genome heralded is Streptococcus agalactiae, a member of the Streptococcal family of infectious pathogens that afflict the human species. The bug's two main perpetrators are S. pneumoniae and S. pyogenes.
"The original classification of S. agalactiae was made by American bacteriologist Rebecca Lancefield [1895-1981] in 1928," observed Harvard microbiologist Michael Cieslewicz. "It was initially a bovine pathogen that infected the udders of cows with mastitis," he told BioWorld Today, "and at some time made the jump to humans. In adult immunocompromised patients, we are seeing that this is becoming an important emerging pathogen in patients with cancer, chemotherapy or diabetes. They're going to be at risk for any bacterial infection."
Now the current Proceedings of the National Academy of Sciences (PNAS), released online Aug. 28, 2002, reports: "Complete genome sequence and comparative genomic analysis of an emerging human pathogen, serotype V Streptococccus agalactiae." Its senior author is Claire Fraser, president of TIGR, and its lead author, molecular biologist Hervé Tettelin, an associate investigator at TIGR.
Three Killer Bugs Measured For Genes
S. agalactiae is the leading cause of bacterial sepsis, pneumonia and meningitis in the U.S. and Europe. Its newly sequenced genome weighs in at 2,160,266 base pairs, encoding 2,176 genes (roughly the size of S. pneumoniae or S. pyogenes).
"The purpose of the whole PNAS article," Tettelin told BioWorld Today, "was to identify new potential vaccine candidates against the diseases caused by this organism. We found proteins that are exposed on the surface, confirmed by some experiments run in the lab by our collaborator, Chiron [Corp.]. Some that are unique to this S. agalactiae and its genes will be taken into experiments in the mouse and in humans later by the Chiron group to provide vaccine candidates."
Tettelin pointed out, "The experiments being performed so far by Chiron in Italy seek to know which proteins are expressed on the pathogen's cell surface, because they're the ones that will interact with the human host cells and be recognized by antibodies for vaccines.
"Another main finding," Tettelin noted, "is that we tried to understand the pathogenic virulence mechanism of S. agalactiae. To do this we again compared it to the other two pathogenic streptococci. And we found some virulence determinants that are shared by all three, and others specific to S. agalactiae, also known as Group B Streptococcus. This gives us insights into how this pathogen evolved to cause disease the way it does, occupying niches in the human body; also why it has become an emerging pathogen in recent decades. There are several Group B serotypes that cause disease. In the '80s it used to be IAa and III, and it has lately flipped to over 30 percent of the cases being serotype V.
"What we're doing now," Tettelin continued, "is sequencing a few other serotypes, including a couple of strains of pathogens isolated from bovine cases, to see how they relate to our genome. On top of which there is a Type III S. agalactiae being sequenced at the Pasteur Institute in France."
Chiron Partners With TIGR For Strep Vaccine
IRIS Chiron SpA, of Siena, Italy, is one member of the seven-institution consortium marshaled by TIGR for its sequencing feat. Vaccinologist John Telford, a coauthor, explained that " IRIS' is our friendly name for the Chiron vaccine research center in Italy. Its acronym in Italian translates as Immunobiological Research Institute of Siena.' This collaborative relationship we have with TIGR," he continued, "relates to analysis of the Group B Streptococcus genome. We are in the process of evaluating the antigens identified from its sequence. We have them in vitro and in vivo for testing the future vaccines. On the basis of the genome sequence, we have identified a number of proteins predicted to be on the surface of the bacteria, and thus potential vaccine candidates. IRIS has a pending patent application, submitted a year and a half ago. Its inventors," Telford concluded, "are from both TIGR and Chiron."
"Strep agalactiae colonizes a large fraction of women in the vaginal area," Tettelin pointed out. "Originally that was the main reason why it became a significant pathogen, because when those women were pregnant and gave birth, the baby went through a flood of S. agalactiae bugs, and was catching disease. It resulted in meningitis cases and septicemia - sometimes being lethal. But since '96," he added, "there is systematic administration of antibiotics to women at risk, and the cases of infection in newborns have greatly decreased.
"But in the meantime," Tettelin went on, "immunocompromised adults have now emerged to become the most prominent targets of the pathogen, which is also causing pneumonia, meningitis, septicemia and death."
How will this work redound to medical practice? "The vaccine," Tettelin suggested, "is one of these things. Hopefully, some follow-up studies may be done by us or our collaborators to identify new drug targets, based on the characterizations and annotations we've made of the proteins. We also hope that sometime in the future we may discover new drugs throughout - although we haven't particularly focused on that aspect so far. But the main impact," he concluded, "is a basic understanding of the bug's virulence determinants, which might also affect our ways of treating disease in the short term."