Comparative genomics of two Leptospira interrogans serovars reveals novel insights into physiology and pathogenesis

Abstract

Leptospira species colonize a significant proportion of rodent populations worldwide and produce life-threatening infections in accidental hosts, including humans. Complete genome sequencing of Leptospira interrogans serovar Copenhageni and comparative analysis with the available Leptospira interrogans serovar Lai genome reveal that despite overall genetic similarity there are significant structural differences, including a large chromosomal inversion and extensive variation in the number and distribution of insertion sequence elements. Genome sequence analysis elucidates many of the novel aspects of leptospiral physiology relating to energy metabolism, oxygen tolerance, two-component signal transduction systems, and mechanisms of pathogenesis. A broad array of transcriptional regulation proteins and two new families of afimbrial adhesins which contribute to host tissue colonization in the early steps of infection were identified. Differences in genes involved in the biosynthesis of lipopolysaccharide O side chains between the Copenhageni and Lai serovars were identified, offering an important starting point for the elucidation of the organism's complex polysaccharide surface antigens. Differences in adhesins and in lipopolysaccharide might be associated with the adaptation of serovars Copenhageni and Lai to different animal hosts. Hundreds of genes encoding surface-exposed lipoproteins and transmembrane outer membrane proteins were identified as candidates for development of vaccines for the prevention of leptospirosis.

FIG. 1.

Inversion of L. interrogans serovars Copenhageni and Lai CI chromosomes. (A) Nucleotide alignment obtained by using MUMmer, which relies on exact matches of at least 20 bp. Each dot in the figure is one such match. The dark lines on the two main diagonals result from the high density of points with sequence identity along chromosome I of the two serovars. The scattered points outside the main diagonals represent other short regions of sequence identity. (B) Scheme showing predicted genes flanking the inversion breakpoints. Pairs of ortholog genes have the same pattern code. The black arrows represent IS elements.

FIG. 2.

Schematic representation of a region with clusters of several predicted genes encoding membrane-associated proteins in the genome of serovar Copenhageni (top) and the equivalent region in the genome of serovar Lai (bottom). The open arrows represent genes encoding membrane-associated proteins, and the cross-hatched arrows represent hypothetical genes; the hatched arrow represents a predicted nuclease gene, and the filled arrows represent transposases unique to these regions. The large gray box encompasses identical equivalent regions in both serovars.

FIG. 3.

Comparative distribution of IS1501 and ISlin1 on CI chromosome of L. interrogans serovars Copenhageni and Lai.