The extraordinary amounts of data generated in this systematic comparative genome analysis may prove to be an invaluable resource for those wanting to know how any bacterial species becomes pathogenic.
The extraordinary amounts of data generated in this systematic comparative genome analysis may prove to be an invaluable resource for those studying not only this particular genus of gram-negative, motile, spiral bacteria, commonly referred to as spirochetes, but also for those wanting to know how any bacterial species becomes pathogenic.
The results of the relatively large and ambitious Leptospira Genome Project, initiated in 2011, were recently published in PLoS Neglected Tropical Diseases.
Leptospira was selected for such detailed scrutiny for several reasons. Among them, members of this genus have been implicated as the cause of leptospirosis, which has a range of manifestations in infected individuals from a subclinical infection to severe multi-organ failure. Lead author Derrick E. Fouts, PhD, an Associate Professor at the J. Craig Venter Institute in Rockville, Maryland, described leptospirosis as, "an emerging and re-emerging globally important zoonotic infectious disease caused by spirochetes of the genus Leptospira."
The Leptospira genus is accurately described as complex, not only due to its number of species, but also because only certain members within it cause this potentially deadly disease. Although the study had many goals, perhaps the most important was to elucidate the mechanisms that underlie pathogenesis in some, but not all, species within the genus. Furthermore, an analysis of this scope would ideally identify common antigens for improving both leptospirosis diagnosis and vaccine development.
Fouts et al describe their study as a, "comprehensive cross-species genomic comparison of all known species of infectious and non-infectious Leptospira, with the goal of identifying genes related to pathogenesis and mammalian host adaptation," which they identify as, "a key gap in the field." To accomplish this, a pan-genus genomic analysis of the 20 Leptospira species known at the study's inception was conducted.
Results from this analysis addressed several separate but interconnected aspects of Leptospira biology. For example, the data demonstrated the evolutionary relationships between the different Leptospira clades, which is interesting in and of itself as a matter of taxonomy. Additionally, a variety of genetic factors related to virulence and pathogenesis of species within the genus were identified. More specifically, the analyses of the infectious Leptospira species revealed how they had become adapted to mammals. Two of the identified adaptations included the biosynthesis of sialic acid and the metabolism of pathogen-specific porphyrin. The pathogenic species within Leptospira were also found to be vitamin B12 autotrophs with the capacity to synthesize vitamin B12 from the amino acid precursor L-glutamine.
The authors also described a large and novel protein family of unknown function referred to as the Virulence Modifying proteins, which were unique to the pathogenic species within the genus. In a similar finding, the CRISPR/Cas system was only detected in pathogenic species. Collectively, this battery of findings is significant because it serves as definitive proof that unique genes found in infectious Leptospira are not found in non-infectious Leptospira.
The copious amounts of data generated in this research effort resulted in the identification of large scale changes between infectious and non-infectious Leptospira species, which shed new light on how pathogenic bacteria evolve from a non-pathologic ancestor. Additionally, results from this study can be applied to the study of leptospirosis pathogenesis and potential new therapeutic targets for its treatment. Fouts et al also note that, "More generally, it [the study] provides new insights into mechanisms by which bacterial pathogens adapt to mammalian hosts."
When drawing a broad conclusion based on the study's results, Fouts and colleagues state, "In summary, the large-scale comparative genomic analysis of 20 Leptospira species has provided broad insights into how infectious members of this genus acquired the genes necessary to acquire pathogenicity and virulence, placing these species within a definitive phylogeny."
It is important to note that the methods used to accrue the results of this study can serve as a roadmap for research on how any species of bacteria from any genus evolve to acquire pathogenicity and the ability to infect mammals. Future studies can build on information of this kind by identifying and exploiting potential therapeutic targets to treat infections caused by pathogenic species.
William Perlman, PhD, CMPP is a former research scientist currently working as a medical/scientific content development specialist. He earned his BA in Psychology from Johns Hopkins University, his PhD in Neuroscience at UCLA, and completed three years of postdoctoral fellowship in the Neuropathology Section of the Clinical Brain Disorders Branch of the National Institute of Mental Health.