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Key Points Leptospira spp. belong to the bacterial phylum Spirochaetes, which contains evolutionary and structurally unique bacteria. The genus Leptospira is composed of saprophytic and pathogenic bacterial species that are fastidious and slow growing. Leptospirosis is an emerging zoonotic disease that has a worldwide distribution, with more than a million cases reported annually. Compared with other bacterial species, the genetic data for leptospires and the determination of the molecular basis of their pathogenesis are in their infancy. Pathogenic leptospires are the bacterial agents of leptospirosis, which is an emerging zoonotic disease that affects both animals and humans worldwide. In this Review, the recent advances in our understanding of the epidemiology, taxonomy, genomics and the molecular basis of virulence in leptospires, and of how these properties contribute to the pathogenesis of leptospirosis, are discussed. Pathogenic leptospires are the bacterial agents of leptospirosis, which is an emerging zoonotic disease that affects animals and humans worldwide. The success of leptospires as pathogens is explained by their spiral shape and endoflagellar motility (which enable these spirochetes to rapidly cross connective tissues and barriers), as well as by their ability to escape or hijack the host immune system. However, the basic biology and virulence factors of leptospires remain poorly characterized. In this Review, we discuss the recent advances in our understanding of the epidemiology, taxonomy, genomics and the molecular basis of virulence in leptospires, and how these properties contribute to the mechanism of pathogenesis of leptospirosis.

  Water-associated exposures (recreational water activities in developed countries and floods and heavy seasonal rainfall in tropical countries) are the main risk factors. Both papers emphasize the scarcity of data on the surveillance and epidemiology of leptospirosis, as well as a lack of consensus on definitions of cases and risk factors, study design, and adequate methods of data analysis.

Leptospira is a highly heterogeneous bacterial genus that can be divided into three evolutionary lineages and >300 serovars. The causative agents of leptospirosis are responsible of an emerging zoonotic disease worldwide. To advance our understanding of the biodiversity of Leptospira strains at the global level, we evaluated the performance of whole-genome sequencing (WGS) as a genus-wide strain classification and genotyping tool. Herein we propose a set of 545 highly conserved loci as a core genome MLST (cgMLST) genotyping scheme applicable to the entire Leptospira genus, including non-pathogenic species. Evaluation of cgMLST genotyping was undertaken with 509 genomes, including 327 newly sequenced genomes, from diverse species, sources and geographical locations. Phylogenetic analysis showed that cgMLST defines species, clades, subclades, clonal groups and cgMLST sequence types (cgST), with high precision and robustness to missing data. Novel Leptospira species, including a novel subclade named S2 (saprophytes 2), were identified. We defined clonal groups (CG) optimally using a single-linkage clustering threshold of 40 allelic mismatches. While some CGs such as L. interrogans CG6 (serogroup Icterohaemorrhagiae) are globally distributed, others are geographically restricted. cgMLST was congruent with classical MLST schemes, but had greatly improved resolution and broader applicability. Single nucleotide polymorphisms within single cgST groups was limited to <30 SNPs, underlining a potential role for cgMLST in epidemiological surveillance. Finally, cgMLST allowed identification of serogroups and closely related serovars. In conclusion, the proposed cgMLST strategy allows high-resolution genotyping of Leptospira isolates across the phylogenetic breadth of the genus. The unified genomic taxonomy of Leptospira strains, available publicly at http://bigsdb.pasteur.fr/leptospira, will facilitate global harmonization of Leptospira genotyping, strain emergence follow-up and novel collaborative studies of the epidemiology and evolution of this emerging pathogen.

Key Points Leptospira spp. belong to the bacterial phylum Spirochaetes, an evolutionarily and structurally unique group of bacteria. The genus Leptospira is composed of saprophytic and pathogenic species that are all fastidious and slow-growing bacteria. Leptospirosis is a zoonotic disease with a worldwide distribution. More than half a million cases are reported annually. Acute disease and chronic colonization can be reproduced in experimental animal models. Determination and comparison of the genome sequences of saprophytic and pathogenic strains could shed light on the virulence determinants involved in disease. Compared to other bacterial species, work to gather genetic data for leptospires and to elucidate the molecular basis of the pathogenesis of these organisms is in its infancy. Further development of genetic tools should allow a better understanding of the virulence and survival mechanisms that are used by these bacteria to ensure their persistence in different ecological niches. Leptospirosis is a neglected disease that has emerged as a widespread problem in impoverished populations in developing countries and tropical regions. Here, Picardeau and colleagues discuss the progress that has been made in our understanding of the pathogenesis of leptospirosis as a result of the recent availability of complete genome sequences for Leptospira spp. and the development of genetic tools for the analysis of this zoonotic species. Leptospirosis is a zoonotic disease that has emerged as an important cause of morbidity and mortality among impoverished populations. One hundred years after the discovery of the causative spirochaetal agent, little is understood about Leptospira spp. pathogenesis, which in turn has hampered the development of new intervention strategies to address this neglected disease. However, the recent availability of complete genome sequences for Leptospira spp. and the discovery of genetic tools for their transformation have led to important insights into the biology of these pathogens and their pathogenesis. We discuss the life cycle of the bacterium, the recent advances in our understanding and the implications for the future prevention of leptospirosis.

The causative agents of leptospirosis are responsible for an emerging zoonotic disease worldwide. One of the major routes of transmission for leptospirosis is the natural environment contaminated with the urine of a wide range of reservoir animals. Soils and surface waters also host a high diversity of non-pathogenic Leptospira and species for which the virulence status is not clearly established. The genus Leptospira is currently divided into 35 species classified into three phylogenetic clusters, which supposedly correlate with the virulence of the bacteria. In this study, a total of 90 Leptospira strains isolated from different environments worldwide including Japan, Malaysia, New Caledonia, Algeria, mainland France, and the island of Mayotte in the Indian Ocean were sequenced. A comparison of average nucleotide identity (ANI) values of genomes of the 90 isolates and representative genomes of known species revealed 30 new Leptospira species. These data also supported the existence of two clades and 4 subclades. To avoid classification that strongly implies assumption on the virulence status of the lineages, we called them P1, P2, S1, S2. One of these subclades has not yet been described and is composed of Leptospira idonii and 4 novel species that are phylogenetically related to the saprophytes. We then investigated genome diversity and evolutionary relationships among members of the genus Leptospira by studying the pangenome and core gene sets. Our data enable the identification of genome features, genes and domains that are important for each subclade, thereby laying the foundation for refining the classification of this complex bacterial genus. We also shed light on atypical genomic features of a group of species that includes the species often associated with human infection, suggesting a specific and ongoing evolution of this group of species that will require more attention. In conclusion, we have uncovered a massive species diversity and revealed a novel subclade in environmental samples collected worldwide and we have redefined the classification of species in the genus. The implication of several new potentially infectious Leptospira species for human and animal health remains to be determined but our data also provide new insights into the emergence of virulence in the pathogenic species.

Disruption of host cell barriers is a fundamental strategy enabling pathogens to establish a paracellular infection. Here, using dual RNA-Seq, we determine the in vivo host-pathogen transcriptomic landscape upon infection by the extracellular pathogen Leptospira interrogans and uncover a mechanism of cell–cell junction disruption. We demonstrate that, upon infection, an increase in intracellular calcium triggers tight junction destabilization, by activating the calmodulin and myosin light chain kinase signalization. We identify two bacterial effectors of the Virulence-Modifying (VM) proteins family, structurally related to toxin-like proteins, that promote modulation of calcium homeostasis and disruption of cell–cell junctions, thereby allowing Leptospira translocation across epithelium barriers, tissue colonization and pathogenicity. Furthermore, we demonstrate that at least one of these VM proteins is secreted and associates with host cells. Altogether, these findings reveal a unique strategy by which an extracellular pathogen secretes toxin-like proteins to exploit host calcium signaling for breaching epithelial barriers. Here, the authors use in vivo dual RNA sequencing to determine the host-pathogen transcriptomic landscape upon infection by Leptospira interrogans , revealing alterations in pathways associated with paracellular permeability, like cell–cell junctions.

Pathogenic Leptospira are spirochete bacteria which cause leptospirosis, a re-emerging zoonotic disease of global importance. Here, we use a recently described lineage of environmental-adapted leptospires, which are evolutionarily the closest relatives of the highly virulent Leptospira species, to explore the key phenotypic traits and genetic determinants of Leptospira virulence. Through a comprehensive approach integrating phylogenomic comparisons with in vitro and in vivo phenotyping studies, we show that the evolution towards pathogenicity is associated with both a decrease of the ability to survive in the environment and the acquisition of strategies that enable successful host colonization. This includes the evasion of the mammalian complement system and the adaptations to avoid activation of the innate immune cells by the highly-virulent Leptospira species (also called P1+ species), unlike other species belonging to the phylogenetically related P1- and P2 groups, as well as saprophytes. Moreover, our analysis reveals specific genetic determinants that have undergone positive selection during the course of evolution in Leptospira , contributing directly to virulence and host adaptation as demonstrated by gain-of-function and knock-down studies. Taken together, our findings define a new vision on Leptospira pathogenicity, identifying virulence attributes associated with clinically relevant species, and provide insights into the evolution and emergence of these life-threatening pathogens.

Leptospirosis is a zoonotic disease of increasing importance in French Guiana. It particularly affects subjects living in precarious conditions. We aimed to determine the seroprevalence and the risk of exposure to leptospirosis among inhabitants of three informal settlements in French Guiana. A serological investigation was conducted in 2022 in three informal settlements in the area of Cayenne, the main city of French Guiana. Leptospirosis exposure factors were assessed in volunteers aged > 15 through a standardized questionnaire. Leptospirosis seroprevalence was evaluated with Microscopic Agglutination Test (MAT) using 17 pathogenic Leptospira antigens with a reactivity threshold of 1:100. In 266 participants, median [IQR] age was 42 [34-52] and male to female sex ratio was 0.9. Most participants were migrants (96%), mainly from Haiti (83%), and lived in the study area for at least 2 years (82%). Household rodent exposure (89%) and use of other water sources than collective standpoint (92%) were common. An at-risk occupation was reported for 68% of working participants. Leptospirosis seroprevalence was 7.5% (95% CI [4.7-11.4]) with Ballum and Icterohaemorrhagiae as the main serogroups. Foot skin exposure in wet environments was associated with reactive serum (OR 7.6, 95% CI [1.1 - 326.7]). Despite a high theoretical risk of leptospirosis exposure among informal settlements inhabitants, only a few participants were seroreactive for Leptospira. This may suggest that despite at-risk exposures the effective transmission of leptospirosis remains limited within the study area. Broader serological surveys and environmental studies should clarify the areas of at-risk leptospirosis transmission in French Guiana.

Background Leptospirosis is a widespread zoonosis with global impact, particularly among vulnerable populations in resource-poor settings in tropical countries. Rodents have been considered to be the main reservoir of the disease; however, a wide variety of mammals can act as hosts as well. Here we examine the genetic diversity of Leptospira strains from biological samples of patients and animals in French Polynesia (FP) from 2011 to 2019. Methodology/Principal findings From 2011 to 2019, we have collected 444 blood samples from patients diagnosed as having leptospirosis. The limited volume of clinical material and low amount of leptospiral DNA in blood samples led us to develop a nested PCR targeting the secY locus that enabled us to amplify and sequence 244 samples (55%). In addition, 20 Leptospira strains recovered from the blood of patients from 2002 to 2011 were sequenced and fully characterized at the serogroup level and used as reference strains for the association of different phylogenetic branches with respective serogroups. The secY sequences were compared with publicly available sequences from patients and animal reservoirs in FP (n = 79). We identified rats as the main source of infection for L. borgpetersenii serogroup Ballum and L. interrogans serogroup Icterohaemorrhagiae, dogs as the main source of infection for L. interrogans serogroup Australis, and farm pigs as the main source of infection for L. interrogans serogroups Pomona or Canicola. L. interrogans was associated with the most severe infections with 10 and 5 fatal cases due to serogroups Icterohaemorrhagiae and Australis, respectively. Mortality was significantly associated with older age (p-value < 0.001). Conclusions/Significance We described the population dynamics of leptospires circulating among patients in FP, including two patients who were reinfected with unrelated Leptospira genotypes, and clarified the local role of the animal reservoirs in the transmission route of leptospirosis to humans. Routine Leptospira genotyping directly on biological samples should allow the epidemiological follow-up of circulating strains and assess the impact of control interventions on disease transmission.

The isolation of pathogenic Leptospira is fundamental for a comprehensive characterization of circulating strains in endemic regions. Unfortunately, culture methods of Leptospira spp. are laborious and challenging. Here, we present a method for the isolation of these pathogenic bacteria from non-fresh serum samples, previously stored at 4–8 °C for several days. Briefly, 730 serum samples collected from leptospirosis-suspected patients (presenting acute signs) were screened for Leptospira DNA by real-time PCR. Thirty-one PCR-positive sera were then assessed for Leptospira isolation on specialized media for up to 6 months. Using this methodology, 11 Leptospira isolates were obtained, resulting in an isolation rate of 35.4% (11/31). Through whole-genome analysis, ten strains were identified as Leptospira santarosai and one strain as Leptospira borgpertersenii . The isolates were classified into six different serogroups, namely Hebdomadis, Shermani, Tarassovi, Pyrogenes, Ballum, and Grippotyphosa, demonstrating a wide diversity of Leptospira strains circulating in Costa Rica. This study reveals that serum is a suitable sample for Leptospira isolation in patients with positive PCR results, even after maintenance at cold conditions, promoting the use of serum for Leptospira isolation in reference laboratories around the world.