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      Genetic diversity of Leptospira strains circulating in humans and dogs in France in 2019-2021

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          Abstract

          Leptospirosis is a bacterial zoonotic disease. Humans and dogs are susceptible hosts, with similar clinical manifestations ranging from a febrile phase to multiple organ dysfunction. The incidence of leptospirosis in mainland France is relatively high, at about 1 case per 100,000 inhabitants, but our knowledge of the strains circulating in humans and dogs remains limited. We studied the polymorphism of the lfb1 gene sequences in an exhaustive database, to facilitate the identification of Leptospira strains. We identified 46 species-groups (SG) encompassing the eight pathogenic species of Leptospira. We sequenced the lfb1 gene amplification products from 170 biological samples collected from 2019 to 2021: 110 from humans and 60 from dogs. Epidemiological data, including vaccination status in dogs, were also collected. Three Leptospira species displaying considerable diversity were identified: L. interrogans, with eight lfb1 species-groups (including five new lfb1 species-groups) in humans and dogs; L. kirschneri, with two lfb1 species-groups in humans and dogs; and L. borgpetersenii, with one lfb1 species-group in humans only. The lfb1 species-group L. interrogans SG1, corresponding to serovar Icterohaemorrhagiae or Copenhageni, was frequently retrieved from both humans and dogs ( n=67/110; 60.9% and n=59/60; 98.3% respectively). A high proportion of the affected dogs developed the disease despite vaccination ( n=30/60; 50%). Genotyping with the polymorphic lfb1 gene is both robust and simple. This approach provided the first global picture of the Leptospira strains responsible for acute infections in mainland France, based on biological samples but without the need for culture. Identification of the Leptospira strains circulating and their changes over time will facilitate more precise epidemiological monitoring of susceptible and reservoir species. It should also facilitate the monitoring of environmental contamination, making it possible to implement preventive measures and to reduce the burden of this disease.

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          Most cited references43

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          Global Morbidity and Mortality of Leptospirosis: A Systematic Review

          Background Leptospirosis, a spirochaetal zoonosis, occurs in diverse epidemiological settings and affects vulnerable populations, such as rural subsistence farmers and urban slum dwellers. Although leptospirosis is a life-threatening disease and recognized as an important cause of pulmonary haemorrhage syndrome, the lack of global estimates for morbidity and mortality has contributed to its neglected disease status. Methodology/Principal Findings We conducted a systematic review of published morbidity and mortality studies and databases to extract information on disease incidence and case fatality ratios. Linear regression and Monte Carlo modelling were used to obtain age and gender-adjusted estimates of disease morbidity for countries and Global Burden of Disease (GBD) and WHO regions. We estimated mortality using models that incorporated age and gender-adjusted disease morbidity and case fatality ratios. The review identified 80 studies on disease incidence from 34 countries that met quality criteria. In certain regions, such as Africa, few quality assured studies were identified. The regression model, which incorporated country-specific variables of population structure, life expectancy at birth, distance from the equator, tropical island, and urbanization, accounted for a significant proportion (R2 = 0.60) of the variation in observed disease incidence. We estimate that there were annually 1.03 million cases (95% CI 434,000–1,750,000) and 58,900 deaths (95% CI 23,800–95,900) due to leptospirosis worldwide. A large proportion of cases (48%, 95% CI 40–61%) and deaths (42%, 95% CI 34–53%) were estimated to occur in adult males with age of 20–49 years. Highest estimates of disease morbidity and mortality were observed in GBD regions of South and Southeast Asia, Oceania, Caribbean, Andean, Central, and Tropical Latin America, and East Sub-Saharan Africa. Conclusions/Significance Leptospirosis is among the leading zoonotic causes of morbidity worldwide and accounts for numbers of deaths, which approach or exceed those for other causes of haemorrhagic fever. Highest morbidity and mortality were estimated to occur in resource-poor countries, which include regions where the burden of leptospirosis has been underappreciated.
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            Revisiting the taxonomy and evolution of pathogenicity of the genus Leptospira through the prism of genomics

            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.
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              Leptospira as an emerging pathogen: a review of its biology, pathogenesis and host immune responses.

              Leptospirosis, the most widespread zoonosis in the world, is an emerging public health problem, particularly in large urban centers of developing countries. Several pathogenic species of the genus Leptospira can cause a wide range of clinical manifestations, from a mild, flu-like illness to a severe disease form characterized by multiorgan system complications leading to death. However, the mechanisms of pathogenesis of Leptospira are largely unknown. This article will address the animal models of acute and chronic leptospire infections, and the recent developments in the genetic manipulation of the bacteria, which facilitate the identification of virulence factors involved in pathogenesis and the assessment of their potential values in the control and prevention of leptospirosis.
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                Author and article information

                Contributors
                Journal
                Front Cell Infect Microbiol
                Front Cell Infect Microbiol
                Front. Cell. Infect. Microbiol.
                Frontiers in Cellular and Infection Microbiology
                Frontiers Media S.A.
                2235-2988
                17 August 2023
                2023
                : 13
                : 1236866
                Affiliations
                [1] 1 Biology of Spirochetes Unit, National Reference Center for Leptospirosis, Institut Pasteur , Paris, France
                [2] 2 USC 1223-RS2GP, Laboratory of Leptospira and Veterinary Analysis, VetAgro Sup, University of Lyon , Marcy l’Etoile, France
                [3] 3 Department of Infectiology, Eurofins Biomnis , Lyon, France
                [4] 4 Cerba Laboratory , Saint-Ouen L’Aumône, France
                Author notes

                Edited by: Tao Lin, Baylor College of Medicine, United States

                Reviewed by: Béla Dénes, University of Veterinary Medicine Budapest, Hungary; Rigoberto Hernandez-Castro, Hospital General Dr. Manuel Gea Gonzalez, Mexico

                *Correspondence: Pascale Bourhy, pbourhy@ 123456pasteur.fr
                Article
                10.3389/fcimb.2023.1236866
                10469827
                37662012
                880f7040-2d53-4a15-ac47-56fc794d51b0
                Copyright © 2023 Garcia-Lopez, Lorioux, Soares, Trombert-Paolantoni, Harran, Ayral, Picardeau, Djelouadji and Bourhy

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 08 June 2023
                : 21 July 2023
                Page count
                Figures: 3, Tables: 3, Equations: 0, References: 44, Pages: 13, Words: 5603
                Funding
                Funded by: Institut Pasteur , doi 10.13039/501100003762;
                Funded by: VetAgro Sup , doi 10.13039/501100011073;
                This study was supported and financed by the Pasteur Institute of Paris and the Veterinary Analysis Laboratory (LAV) at VetAgro Sup, Lyon, France.
                Categories
                Cellular and Infection Microbiology
                Original Research
                Custom metadata
                Molecular Bacterial Pathogenesis

                Infectious disease & Microbiology
                leptospirosis,zoonotic disease,human,dog,france,lfb1 gene
                Infectious disease & Microbiology
                leptospirosis, zoonotic disease, human, dog, france, lfb1 gene

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