Leptospira Genomics and Human Health

Leptospirosis is the most common and widespread zoonotic disease worldwide, caused by more than 250 different serovars of the genus Leptospira that are primarily spread through contact with water contaminated by urine of infected animals. Millions of people are estimated to be infected annually, but little is known regarding the true incidence of leptospirosis because of limitations of diagnosis. Leptospiral infections are common in tropical environments, in agricultural areas with high densities of livestock and rodents, and in areas supporting large and diverse wildlife populations where warm and humid conditions facilitate survival of the organism in the environment. Clinical manifestations range from asymptomatic infections recognizable only by seroconversion without illness, to severe, potentially fatal infections involving renal, liver and/or respiratory complications (including pulmonary hemorrhage) with case fatality rates as high as 25% in affected locales despite the most advanced medical care. The epidemiological pattern of leptospirosis has been changing in recent years in association with increasing urbanization and changes in the relationship between the environment and human activities.

Obtaining whole genome sequences of a diverse and representative set of globally significant Leptospira isolates is a major priority of the leptospirosis community. This comprehensive set of genome data will directly facilitate the improvement of public health through the judicious and well-considered application of fundamental scientific discovery. Leptospira strains for whole genome analysis will be chosen to address the following major scientific goals:

1. To identify a minimal number of molecular markers for multilocus sequence typing that can differentiate leptospires species directly from human samples without the need for bacterial isolation. Markers will be identified by sequencing 9 known pathogenic Leptospira species, 5 intermediate Leptospira species, and 6 saprophytic Leptospira species. Conserved protein markers that are the targets of antibody recognition or antigen detection will be identified.
2. To delineate taxonomic and phylogenetic relationships among Leptospira species. The genomic data obtained will provide precise insights into the genetic basis of lipopolysaccharide O-antigen structure, which determines serovar identify without the need for serological typing. Complete genome sequence of reference strains used for serological diagnosis will facilitate the development of molecular-based serovar typing and help to optimize diagnosis of infection.
3. To understand the mechanisms of leptospirosis pathogenesis and determinants of clinical outcome. Correlations of genetic polymorphisms and virulence will be identified between isolates at the species, serovar, and strain level. This will require sequencing of isolates associated with distinct clinical presentations and outcomes. This data will provide the fundamental basis for hypothesis-driven research to determine virulence factors and for vaccine development.

Strains to be sequenced

We plan to sequence up to 200 Leptospira species/new serovars using 454 Titanium with 8 kb paired-end libraries in order to generate high-quality draft genomes to serve as reference genomes for downstream mapping of Illumina reads and to gain an understanding of their genome structure. In addition, we plan to sequence up to 252 additional Leptospira serovars using the Illumina platform.

White Paper Access

The initial white paper submitted can be downloaded here. Since white papers are not always approved exactly as submitted, this document may not exactly describe the final form of the project. Please contact gsc@jcvi.org if you have any questions.

Funding