Genome Comparison Reveals Leptospira’s Infectious Traits

Researchers at UCSD and the J. Craig Venter Institute have identified genetic traits uniquely associated with disease-causing bacteria by comparing the genomes of all 20 species within the genus Leptospira. The findings, published online in the Feb. 18 issue of PLOS Neglected Tropical Diseases, provide clues to its evolutionary history and to potential treatment approaches to Leptospirosis, a common, globally widespread bacterial disease.

Leptospirosis can affect livestock, companion animals and humans who come into contact with the urine of infected animals, either directly or by way of contaminated water or soils. The disease is caused by infectious bacteria of Leptospira and can lead to kidney damage, respiratory complications and death if left untreated.

Not all species of Leptospira contribute to this disease, however, and the distinction between infectious and noninfectious species lies in genetic differences. To determine the specific genomic features of those disease-causing bacteria, scientists compared the complete genome sequences of the different species, both pathogenic and nonpathogenic, within Leptospira

This project stems from the Leptospira Genome Project, a large genome-sequencing effort funded by the National Institutes of Allergy and Infectious Diseases. Derrick Fouts, JCVI associate professor and first author, explained to the UCSD Guardian that the team’s objectives for the study were to generate a dataset that improves treatment approaches to Leptospirosis.

“We conducted this research project to gain a better understanding, through genomics, of the genetic differences that enable certain species of Leptospira infectious to humans while others are harmless environmental inhabitants,” Fouts said. “We sequenced over 300 Leptospira isolates with the goal of generating a comprehensive dataset of Leptospira genome sequences that can be used to develop better diagnostics, vaccines and to better understand molecular mechanisms of pathogenesis that relate to different clinical outcomes.”

The group of scientists employed bioinformatics to identify genetic differences within species of Leptospira. Fouts describes how a program he helped develop has allowed the team to identify genes and functions that were exclusively found in the genome of the pathogenic species.

“Using a new computer program called PanOCT, written by me and colleague Granger Sutton, we were able to identify several genetic features that collectively were only observed in isolates that cause human disease,” Fouts said in an email to the Guardian. “Some examples include genes for adhesion to host cells, production of vitamin B12 (which is required for survival, but typically unavailable to bacteria inside the human body), and protection against host defenses.”

Another significant finding was the discovery of a system present in the infectious species that serves to confer resistance to foreign genetic elements. Haritha Adhikarla, an associate research scientist in epidemiology at Yale University and co-author of the study, describes the specific traits this system might be responsible for in disease-causing Leptospira.

“One important finding of this study was discovery of the CRISPR-Cas genetic machinery only in pathogenic Leptospira, but not in the intermediate or non-infectious groups of the genus,” Adhikarla told the Guardian. “CRISPR elements provide [pathogenic Leptospira] a form of acquired immunity and could be responsible for limited transformability of pathogenic species; additionally, they might have some evolutionary significance which needs to be investigated.”

Fouts clarified that the machinery might provide pathogenic Leptospira resistance to bacteriophages, viruses that infect bacteria, and suggested that Leptospira species that reside within the human host might be exposed to more bacteriophages. 

While the significance of this observation requires further research, the presence of CRISPR-Cas may serve as one of several key adaptations found in infectious species of Leptospira. Adhikarla added that the team also discovered a large, novel protein family whose function is currently unknown — termed the Virulence Modifying proteins — in pathogenic Leptospira.

While there is currently no approved Leptospira vaccine for human use, Fouts predicted that the team’s genomic dataset will generate a better understanding of the mechanisms of infectious species and contribute to future vaccine development.

“Having the genetic map of these bacterial pathogens, and many of the features that define them, will focus future research towards better diagnostics and vaccines,” said Fouts. “I plan to continue using genomics and other techniques to validate our predictions and apply them to answer questions pertaining to environmental sources of infection and asymptomatic human carriage.”