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Leptospira Genome Project Yields Clues to Pathogenesis

NEW YORK (GenomeWeb) – A comparative genomics study published online today in PLOS Neglected Tropical Diseases is spelling out the gene and pathway differences that distinguish Leptospira species capable of infecting humans and other mammals from non-infectious species that grow on dead organic matter.

As part of the Leptospira Genome Project, an international team led by investigators at the University of California at San Diego, the J. Craig Venter Institute, and elsewhere compared and contrasted genome sequences from 20 Leptospira species in an effort to understand their relationships to one another, the correct taxonomic classifications for these spirochete bacteria, and capacity for infection.

"This work compares the complete genome sequences of all known species of Leptospira to discover which genes make this bacterium a pathogen," senior author Joseph Vinetz, an infectious diseases researcher at UCSD and director of the university's Center for Tropical Medicine and Travelers Health, said in a statement. "It provides a roadmap for future research, including finding new ways to diagnose infection and vaccine development."

For example, results from the team's analysis highlighted several key metabolic pathways, virulence factors, and host response systems present in Leptospira species that infect animals, but absent in saprophytic species surviving on decaying material. The new genomic resource is also expected to provide a framework for ongoing research into Leptospira pathogenesis, approaches for diagnosing infections approaches, and vaccine development strategies.

While saprophytic Leptospira species are typically harmless to mammals, other species have been implicated in leptospirosis infections in livestock, pets, and humans that can range in severity from barely detectable to severe.

In animals, for example, leptospirosis can prompt injury to the liver, lung, or kidneys and may cause fetal loss. Human cases, which can crop up due to contact with infected animal urine, contaminated water or soil, may involve features ranging from fever to kidney failure, bleeding, meningitis, and death.

To delve into the genomic relationships between infectious and non-infectious Leptospira, the researchers did whole-genome sequencing on 20 species, including nine pathogens, five species classified as intermediate pathogens, and six saprophytic species. Three of the genomes were sequenced and reported previously, they noted, while collaborators at JCVI sequenced the remaining 17 species with Illumina HiSeq and Roche 454 FLX Titanium instruments.

A tenth pathogen, L. santarosai serovar Sherman, was discovered while the work was in progress and was not included in the analysis.

The researchers estimated that the species contained some 3,932 to 4,582 predicted protein-coding genes apiece, housed in genomes spanning between 3.89 million and 4.71 million bases. At its conserved core, the Leptospira genome contained 1,764 protein-coding genes, though almost 17,500 genes were identified across the genera.

Along with a Leptospira family trees that it put together with conserved protein sequences, 16S ribosomal RNA genes, and other gene sequences, the team scoured the complete genome sequence for clues to Leptospira biology and pathogenesis, when applicable.

The pathogenic species had distinct metabolic capabilities, such as the ability to produce sialic acid and vitamin B12, which their non-infectious counterparts lacked. The pathogens also carried sequences coding for virulence factors, virulence-modifying proteins, and systems for secreting proteins.

And while components of the CRISPR/Cas bacterial defense system were missing in the saprophytic, genomes of pathogenic and intermediately pathogenic Leptospira species contained sequences corresponding to new and known CRISPR/Cas elements.

"The evolutionary acquisition of novel CRISPR elements, which are only in pathogenic Leptospira, probably hastened adaptation to human infection," Vinetz said, though he cautioned that "[t]he significance of this observation remains to be explored."