Comparative genomics to cast new light on other spirochete microbes

Three centuries after a pioneering Dutch microbiologist first observed the spiral-shaped oral pathogen Treponema denticola, scientists have deciphered the bacterium’s entire DNA sequence and used comparative genomics to cast new light on other spirochete microbes.

The study by scientists at The Institute for Genomic Research (TIGR) and collaborators at Baylor College of Medicine and the University of Texas Health Science Center at Houston found profound differences between the gene content of T. denticola, which is associated with periodontal (gum) disease, and of other spirochetes that cause syphilis and Lyme disease.

“This highlights the power of comparative genomics to help us understand how related pathogens can cause completely different diseases,” says Ian Paulsen, who led the sequencing along with fellow TIGR researcher Rekha Seshadri. Paulsen says the T. denticola genome “provides an excellent point of reference to study the biology of spirochetes.”

The researchers found that T. denticola has more than twice as many genes as the spirochete that causes syphilis, T. pallidum, and that there is virtually no conservation of gene order (synteny) between the genomes of the two related microbes. The authors say that indicates that the two spirochetes’ divergence from a common ancestor “was an ancient event” in contrast to the more recent divergence of many other groups of bacteria from their ancestral relatives.

The genome study is expected to help scientists find out more about how oral pathogens interact in dental plaque to cause gum disease. T. denticola tends to aggregate in such subgingival plaque with Porphyromonas gingivalis, a bacterium that is associated with periodontitis, a gum disease that affects an estimated 200 million Americans. Having the complete genomes of both microbes will help researches study their interactions and possibly provide molecular clues to find targets for drugs to treat gum disease.

TIGR scientists and collaborators sequenced the genome of P. gingivalis last year and are now deciphering the genomes of six other oral-cavity bacteria and conducting a “meta-genomic” assay of mouth microbes. Of the estimated 500 microbial species in the human mouth, only about 150 species have been cultured in laboratories.

“The genome sequence reveals mechanisms used by T. denticola to colonize and survive in the complex environment of oral biofilms,” says Seshadri, the study’s first author. TIGR’s collaborators in the PNAS study included Steven J. Norris at the UT Health Science Center at Houston and George M. Weinstock at Baylor College of Medicine’s Department of Molecular and Human Genetics.

In the PNAS paper, researchers reported that the genome of T. denticola “reflects its adaptations for colonization and survival” with other bacteria in plaque. Compared to other spirochetes (including an estimated 60 other treponomal species or phylotypes found in dental plaque), T. denticola is relatively easy to cultivate and manipulate genetically, making it an excellent model for spirochete research.

Spirochetes are distinguished by their spiral shapes and their ability to corkscrew their way through gel-like tissues, causing a number of different diseases. The father of microbiology, Antonie van Leeuwenhoek, had first sketched an oral spirochete – later named T. denticola – after viewing it through his primitive microscope in the 1670s. Even after three centuries, however, spirochetes are poorly understood in contrast to many other major types of bacteria.

So far, TIGR has sequenced the complete genomes of three spirochetes: T. denticola; T. pallidum, which causes syphilis; and Borellia burgdorferei, which causes Lyme disease. The genome of a fourth spirochete, Leptospira interrogans, which causes the disease Leptosporisis, was sequenced at the Chinese National Human Genome Center.

TIGR’s comparative analysis found that about half of T. denticola’s 2,786 genes are not present in the other three sequenced spirochetes. The 618 genes that all four spirochetes have in common include some genes that are not found in other types of microbes whose genomes have been sequenced.

“Having the genome sequences of several spirochetes provides a remarkable opportunity to study evolution,” says Norris, who says all spirochetes are cousins even though they live in a wide variety of environments, including mud, clams, termite guts, ticks, and humans. By comparing the DNA sequences of more spirochetes, he says, “we may be able to get at the root of what makes a bacterium cause disease, live free in the environment, or even be beneficial to its host.”

Claire M. Fraser, president of TIGR, says the sequence data “provide a new starting point” for exploring the molecular differences that may explain why and how T. denticola and T. pallidum cause such different diseases: “This study has revealed new insights into spirochete-specific biology as well as the evolutionary forces that have shaped these genomes.”

The Institute for Genomic Research (TIGR) is a not-for-profit research institute based in Rockville, Maryland. TIGR, which sequenced the first complete genome of a free-living organism in 1995, has been at the forefront of the genomic revolution since the institute was founded in 1992. TIGR conducts research involving the structural, functional, and comparative analysis of genomes and gene products in viruses, bacteria, archaea, and eukaryotes.