Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Virulence of the zoonotic agent of leptospirosis: still terra incognita?

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.

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Cell morphology and envelope architecture of L. interrogans.
Figure 2: Schematic representation of the endoflagellum of Leptospira spp.
Figure 3: The distribution of virulence-associated genes in pathogenic, intermediate and saprophytic Leptospira species.
Figure 4: Initial stages of infection by pathogenic leptospires.

Similar content being viewed by others

References

  1. Inada, R., Ido, Y., Hoki, R., Kakeno, R. & Ito, H. The etiology, mode of infection and specific therapy of Weil's disease (Spirochaeta icterohaemorrhagiae). J. Exp. Med. 23, 377–403 (1916). A landmark paper that describes the discovery of Leptospira spp. as the aetiological agents of leptospirosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ellis, W. A. in Leptospira and Leptospirosis (ed. Adler, B.) 99–137 (Springer, 2014).

    Google Scholar 

  3. Dietrich, M., Mühldorfer, K., Tortosa, P. & Markotter, W. Leptospira and bats: story of an emerging friendship. PLoS Pathog. 11, e1005176 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Mgode, G. F. et al. Leptospira serovars for diagnosis of leptospirosis in humans and animals in Africa: common Leptospira isolates and reservoir hosts. PLoS Negl. Trop. Dis. 9, e0004251 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Jobbins, S. E. & Alexander, K. A. Evidence of Leptospira sp. infection among a diversity of African wildlife species: beyond the usual suspects. Trans R. Soc. Trop. Med. Hyg. 109, 349–351 (2015).

    Article  CAS  PubMed  Google Scholar 

  6. Mwachui, M. A., Crump, L., Hartskeerl, R., Zinsstag, J. & Hattendorf, J. Environmental and behavioural determinants of leptospirosis transmission: a systematic review. PLoS Negl. Trop. Dis. 9, e0003843 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  7. De Oliveira, D. et al. Leptospira in breast tissue and milk of urban Norway rats (Rattus norvegicus). Epidemiol. Infect. 44, 2420–2429 (2016).

    Article  Google Scholar 

  8. Trueba, G., Zapata, S., Madrid, K., Cullen, P. & Haake, D. Cell aggregation: a mechanism of pathogenic Leptospira to survive in fresh water. Int. Microbiol. 7, 35–40 (2004).

    PubMed  Google Scholar 

  9. Andre-Fontaine, G., Aviat, F. & Thorin, C. Water borne leptospirosis: survival & preservation of the virulence of pathogenic Leptospira spp. in fresh water. Curr. Microbiol. 71, 136–142 (2015).

    Article  CAS  PubMed  Google Scholar 

  10. Ristow, P. et al. Biofilm formation by saprophytic and pathogenic leptospires. Microbiology 154, 1309–1317 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Vinod Kumar, K., Lall, C., Vimal Raj, R., Vedhagiri, K. & Vijayachari, P. Molecular detection of pathogenic leptospiral protein encoding gene (lipL32) in environmental aquatic biofilms. Lett. Appl. Microbiol. 62, 311–315 (2016).

    Article  CAS  PubMed  Google Scholar 

  12. Ko, A. I., Goarant, C. & Picardeau, M. Leptospira: the dawn of the molecular genetics era for an emerging zoonotic pathogen. Nat. Rev. Microbiol. 7, 736–747 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Torgerson, P. R. et al. Global burden of leptospirosis: estimated in terms of disability adjusted life years. PLoS Negl. Trop. Dis. 9, e0004122 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Allan, K. J. et al. Epidemiology of leptospirosis in Africa: a systematic review of a neglected zoonosis and a paradigm for 'one health' in Africa. PLoS Negl. Trop. Dis. 9, e0003899 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Costa, F. et al. Global morbidity and mortality of leptospirosis: a systematic review. PLoS Negl. Trop. Dis. 9, e0003898 (2015). This study provides a recent update on the global burden of leptospirosis.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Dufour, B., Moutou, F., Hattenberger, A. M. & Rodhain, F. Global change: impact, management, risk approach and health measures — the case of Europe. Rev. Sci. Tech. 27, 529–550 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Pijnacker, R. et al. Marked increase in leptospirosis infections in humans and dogs in the Netherlands, 2014. Euro Surveill. 21, 30211 (2016).

    Article  Google Scholar 

  18. Fouts, D. E. et al. What makes a bacterial species pathogenic?: comparative genomic analysis of the genus Leptospira. PLoS Negl. Trop. Dis. 10, e0004403 (2016). This study details the first genomic analysis of the entire Leptospira genus.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Xu, Y. et al. Whole genome sequencing revealed host adaptation-focused genomic plasticity of pathogenic Leptospira. Sci. Rep. 6, 20020 (2016). A comprehensive analysis of the evolution of Leptospira spp. from saprophytic ancestors to pathogens.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Caro-Quintero, A., Ritalahti, K. M., Cusick, K. D., Löffler, F. E. & Konstantinidis, K. T. The chimeric genome of Sphaerochaeta: nonspiral spirochetes that break with the prevalent dogma in spirochete biology. mBio 3, e00025-12 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Haake, D. A. & Matsunaga, J. Leptospira: a spirochaete with a hybrid outer membrane. Mol. Microbiol. 77, 805–814 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Slamti, L., de Pedro, M. A., Guichet, E. & Picardeau, M. Deciphering morphological determinants of the helix-shaped Leptospira. J. Bacteriol. 193, 6266–6275 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jutras, B. L. et al. Lyme disease and relapsing fever Borrelia elongate through zones of peptidoglycan synthesis that mark division sites of daughter cells. Proc. Natl Acad. Sci. USA 113, 9162–9170 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Motaleb, M. A. et al. Borrelia burgdorferi periplasmic flagella have both skeletal and motility functions. Proc. Natl Acad. Sci. USA 97, 10899–10904 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhao, X., Norris, S. J. & Liu, J. Molecular architecture of the bacterial flagellar motor in cells. Biochemistry 53, 4323–4333 (2014).

    Article  CAS  PubMed  Google Scholar 

  26. Moon, K. H. et al. Spirochetes flagellar collar protein FlbB has astounding effects in orientation of periplasmic flagella, bacterial shape, motility, and assembly of motors in Borrelia burgdorferi. Mol. Microbiol. 102, 336–348 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Raddi, G. et al. Three-dimensional structures of pathogenic and saprophytic Leptospira species revealed by cryo-electron tomography. J. Bacteriol. 194, 1299–1306 (2012). This study details the use of cryo-electron tomography to describe the native ultrastructure of Leptospira spp.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Malmström, J. et al. Proteome-wide cellular protein concentrations of the human pathogen Leptospira interrogans. Nature 460, 762–765 (2009). This study uses cutting-edge proteomics to determine the concentration (copy number) of proteins per cell.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Charon, N. W. & Goldstein, S. F. Genetics of motility and chemotaxis of a fascinating group of bacteria: the spirochetes. Annu. Rev. Genet. 36, 47–73 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Lambert, A. et al. FlaA proteins in Leptospira interrogans are essential for motility and virulence but are not required for formation of the flagellum sheath. Infect. Immun. 80, 2019–2025 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wunder, E. A. Jr et al. A novel flagellar sheath protein, FcpA, determines filament coiling, translational motility and virulence for the Leptospira spirochete. Mol. Microbiol. 101, 457–470 (2016). This study describes a novel flagellar protein that is essential for the coiled structure of endoflagella.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Goldstein, S. F. & Charon, N. W. Motility of the spirochete Leptospira. Cell Motil. Cytoskeleton 9, 101–110 (1988).

    Article  CAS  PubMed  Google Scholar 

  33. Nakamura, S., Leshansky, A., Magariyama, Y., Namba, K. & Kudo, S. Direct measurement of helical cell motion of the spirochete Leptospira. Biophys. J. 106, 47–54 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Goldstein, S. F. & Charon, N. W. Multiple-exposure photographic analysis of a motile spirochete. Proc. Natl Acad. Sci. USA 87, 4895–4899 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Beck, M. et al. Visual proteomics of the human pathogen Leptospira interrogans. Nat. Methods 6, 817–823 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Costa, T. R. et al. Secretion systems in Gram-negative bacteria: structural and mechanistic insights. Nat. Rev. Microbiol. 13, 343–359 (2015).

    Article  CAS  PubMed  Google Scholar 

  37. Abby, S. S. et al. Identification of protein secretion systems in bacterial genomes. Sci. Rep. 6, 23080 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bulach, D. M. et al. Genome reduction in Leptospira borgpetersenii reflects limited transmission potential. Proc. Natl Acad. Sci. USA 103, 14560–14565 (2006). This work shows that the genome of L. borgpetersenii has undergone reduction, which seems to have impaired its ability to survive in the external environment.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Bierne, H., Sabet, C., Personnic, N. & Cossart, P. Internalins: a complex family of leucine-rich repeat-containing proteins in Listeria monocytogenes. Microbes Infect. 9, 1156–1166 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Miras, I. et al. Structural characterization of a novel subfamily of leucine-rich repeat proteins from the human pathogen Leptospira interrogans. Acta Crystallogr. D Biol. Crystallogr. 71, 1351–1359 (2015).

    Article  CAS  PubMed  Google Scholar 

  41. Lehmann, J. S. et al. Pathogenomic inference of virulence-associated genes in Leptospira interrogans. PLoS Negl. Trop. Dis. 7, e2468 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Satou, K. et al. Complete genome sequences of low-passage virulent and high-passage avirulent variants of pathogenic Leptospira interrogans serovar Manilae strain UP-MMC-NIID, originally isolated from a patient with severe leptospirosis, determined using PacBio single-molecule real-time technology. Genome Announc. 3, e00882-15 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Toma, C., Okura, N., Takayama, C. & Suzuki, T. Characteristic features of intracellular pathogenic Leptospira in infected murine macrophages. Cell. Microbiol. 13, 1783–1792 (2011). This paper shows that Leptospira spp. are able to survive, replicate and exit macrophages.

    Article  CAS  PubMed  Google Scholar 

  44. Barocchi, M. A., Ko, A. I., Reis, M. G., McDonald, K. L. & Riley, L. W. Rapid translocation of polarized MDCK cell monolayers by Leptospira interrogans, an invasive but nonintracellular pathogen. Infect. Immun. 70, 6926–6932 (2002). This study finds that leptospires rapidly translocate across polarized cell monolayers by invading host cells and transiently residing in the cytoplasm.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Li, S. et al. Replication or death: distinct fates of pathogenic Leptospira strain Lai within macrophages of human or mouse origin. Innate Immun. 16, 80–92 (2010).

    Article  PubMed  Google Scholar 

  46. Asoh, T. et al. Natural defense by saliva and mucosa against oral infection by Leptospira. Can. J. Microbiol. 60, 383–389 (2014).

    Article  CAS  PubMed  Google Scholar 

  47. Charon, N. W., Greenberg, E. P., Koopman, M. B. H. & Limberger, R. J. Spirochete chemotaxis, motility, and the structure of the spirochetal periplasmic flagella. Res. Microbiol. 143, 597–603 (1992).

    Article  CAS  PubMed  Google Scholar 

  48. Fraga, T. R., Barbosa, A. S. & Isaac, L. Leptospirosis: aspects of innate immunity, immunopathogenesis and immune evasion from the complement system. Scand. J. Immunol. 73, 408–419 (2011).

    Article  CAS  PubMed  Google Scholar 

  49. Kassegne, K. et al. Identification of collagenase as a critical virulence factor for invasiveness and transmission of pathogenic Leptospira species. J. Infect. Dis. 209, 1105–1115 (2014).

    Article  CAS  PubMed  Google Scholar 

  50. Wunder, E. A. J. et al. Real-time PCR reveals rapid dissemination of Leptospira interrogans after intraperitoneal and conjunctival inoculation of hamsters. Infect. Immun. 84, 2105–2115 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Athanazio, D. A. et al. Rattus norvegicus as a model for persistent renal colonization by pathogenic Leptospira interrogans. Acta Trop. 105, 176–180 (2008).

    Article  PubMed  Google Scholar 

  52. Pinne, M. & Haake, D. A. LipL32 is a subsurface lipoprotein of Leptospira interrogans: presentation of new data and reevaluation of previous studies. PLoS ONE 8, e51025 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Murray, G. L. The molecular basis of leptospiral pathogenesis. Curr. Top. Microbiol. Immunol. 387, 139–185 (2015). Together with reference 12, this article highlights the virulence factors that have been discovered in Leptospira spp.

    CAS  PubMed  Google Scholar 

  54. Fernandes, L. G. et al. Leptospira spp.: novel insights into host–pathogen interactions. Vet. Immunol. Immunopathol. 176, 50–57 (2016).

    Article  CAS  PubMed  Google Scholar 

  55. Matsunaga, J. et al. Pathogenic Leptospira species express surface-exposed proteins belonging to the bacterial immunoglobulin superfamily. Mol. Microbiol. 49, 929–945 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ptak, C. P. et al. NMR solution structure of the terminal immunoglobulin-like domain from the Leptospira host-interacting outer membrane protein, LigB. Biochemistry 53, 5249–5260 (2014).

    Article  CAS  PubMed  Google Scholar 

  57. Choy, H. A. et al. Physiological osmotic induction of Leptospira interrogans adhesion: LigA and LigB bind extracellular matrix proteins and fibrinogen. Infect. Immun. 75, 2441–2450 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Choy, H. A. et al. The multifunctional LigB adhesin binds homeostatic proteins with potential roles in cutaneous infection by pathogenic Leptospira interrogans. PLoS ONE 6, e16879 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Castiblanco-Valencia, M. M. et al. Leptospiral immunoglobulin-like proteins interact with human complement regulators factor H, FHL-1, FHR-1, and C4BP. J. Infect. Dis. 205, 995–1004 (2012).

    Article  CAS  PubMed  Google Scholar 

  60. Ching, A. T. et al. Leptospira interrogans shotgun phage display identified LigB as a heparin-binding protein. Biochem. Biophys. Res. Commun. 427, 774–779 (2012).

    Article  CAS  PubMed  Google Scholar 

  61. Croda, J. et al. Targeted mutagenesis in pathogenic Leptospira: disruption of the ligB gene does not affect virulence in animal models of leptospirosis. Infect. Immun. 76, 5826–5833 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Figueira, C. P. et al. Heterologous expression of pathogen-specific genes ligA and ligB in the saprophyte Leptospira biflexa confers enhanced adhesion to cultured cells and fibronectin. BMC Microbiol. 11, 129 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Castiblanco-Valencia, M. M. et al. Acquisition of negative complement regulators by the saprophyte Leptospira biflexa expressing LigA or LigB confers enhanced survival in human serum. Immunol. Lett. 173, 61–68 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Robbins, G. T. et al. Evaluation of cell binding activities of Leptospira ECM adhesins. PLoS Negl. Trop. Dis. 9, e0003712 (2015). This paper provides a comparative analysis of previously described adhesins.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Breiner, D. D., Fahey, M., Salvador, R., Novakova, J. & Coburn, J. Leptospira interrogans binds to human cell surface receptors including proteoglycans. Infect. Immun. 77, 5528–5536 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Evangelista, K., Franco, R., Schwab, A. & Coburn, J. Leptospira interrogans binds to cadherins. PLoS Negl. Trop. Dis. 8, e267 (2014).

    Google Scholar 

  67. Eshghi, A. et al. Pathogenic Leptospira interrogans exoproteins are primarily involved in heterotrophic processes. Infect. Immun. 83, 3061–3073 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Narayanavari, S. A., Lourdault, K., Sritharan, M., Haake, D. A. & Matsunaga, J. Role of sph2 gene regulation in hemolytic and sphingomyelinase activities produced by Leptospira interrogans. PLoS Negl. Trop. Dis. 9, e0003952 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Gasque, P. & Jaffar-Bandjee, M. C. The immunology and inflammatory responses of human melanocytes in infectious diseases. J. Infect. 71, 413–421 (2015).

    Article  PubMed  Google Scholar 

  70. Li, L., Ojcius, D. M. & Yan, J. Comparison of invasion of fibroblasts and macrophages by high- and low-virulence Leptospira strains: colonization of the host-cell nucleus and induction of necrosis by the virulent strain. Arch. Microbiol. 188, 591–598 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Jin, D. et al. Leptospira interrogans induces apoptosis in macrophages via caspase-8- and caspase-3-dependent pathways. Infect. Immun. 77, 799–809 (2009).

    Article  CAS  PubMed  Google Scholar 

  72. Merien, F., Baranton, G. & Perolat, P. Invasion of Vero cells and induction of apoptosis in macrophages by pathogenic Leptospira interrogans are correlated with virulence. Infect. Immun. 65, 729–738 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Toma, C. et al. Leptospiral outer membrane protein LMB216 is involved in enhancement of phagocytic uptake by macrophages. Cell. Microbiol. 16, 1366–1377 (2014).

    Article  CAS  PubMed  Google Scholar 

  74. Zhang, L. et al. The mammalian cell entry (Mce) protein of pathogenic Leptospira species is responsible for RGD motif-dependent infection of cells and animals. Mol. Microbiol. 83, 1006–1023 (2012).

    Article  CAS  PubMed  Google Scholar 

  75. Xue, F. et al. Responses of murine and human macrophages to leptospiral infection: a study using comparative array analysis. PLoS Negl. Trop. Dis. 7, e2477 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Castiblanco-Valencia, M. M. et al. Plasmin cleaves fibrinogen and the human complement proteins C3b and C5 in the presence of Leptospira interrogans proteins: a new role of LigA and LigB in invasion and complement immune evasion. Immunobiology 221, 679–689 (2016).

    Article  CAS  PubMed  Google Scholar 

  77. Fraga, T. R. et al. Immune evasion by pathogenic Leptospira strains: the secretion of proteases that directly cleave complement proteins. J. Infect. Dis. 209, 876–886 (2014).

    Article  CAS  PubMed  Google Scholar 

  78. Fernandes, L., de Morais, Z., Vasconcellos, S. & Nascimento, A. Leptospira interrogans reduces fibrin clot formation by modulating human thrombin activity via exosite I. Pathog. Dis. 73, ftv001 (2015).

    Article  PubMed  CAS  Google Scholar 

  79. Scharrig, E. et al. Neutrophil extracellular traps are involved in the innate immune response to infection with Leptospira. PLoS Negl. Trop. Dis. 9, e0003927 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Srikram, A. et al. Cross-protective immunity against leptospirosis elicited by a live, attenuated lipopolysaccharide mutant. J. Infect. Dis. 203, 870–879 (2011). In this study, a LPS mutant was used as a live-attenuated vaccine; this resulted in cross-protective immunity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Nally, J. E., Chow, E., Fishbein, M. C., Blanco, D. R. & Lovett, M. A. Changes in lipopolysaccharide O antigen distinguish acute versus chronic Leptospira interrogans infections. Infect. Immun. 73, 3251–3260 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Nahori, M. A. et al. Differential TLR recognition of leptospiral lipid A and lipopolysaccharide in murine and human cells. J. Immunol. 175, 6022–6031 (2005). This paper shows that Leptospira spp. have unusual LPS that uses TLR2, rather than TLR4, for signalling in human cells.

    Article  CAS  PubMed  Google Scholar 

  83. Goris, M. G. A. et al. Potent innate immune response to pathogenic Leptospira in human whole blood. PLoS ONE 6, e18279 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Chassin, C. et al. TLR4- and TLR2-mediated B cell responses control the clearance of the bacterial pathogen, Leptospira interrogans. J. Immunol. 183, 2669–2677 (2009).

    Article  CAS  PubMed  Google Scholar 

  85. Needham, B. D. & Trent, M. S. Fortifying the barrier: the impact of lipid A remodelling on bacterial pathogenesis. Nat. Rev. Microbiol. 11, 467–481 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Eshghi, A., Henderson, J., Trent, M. S. & Picardeau, M. Leptospira interrogans lpxD homologue is required for thermal acclimatization and virulence. Infect. Immun. 83, 4314–4321 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Picardeau, M. in Leptospira and Leptospirosis (ed. Adler, B.) 43–63 (Springer-Verlag Berlin Heidelberg, 2015).

    Google Scholar 

  88. Adler, B., Lo, M., Seemann, T. & Murray, G. L. Pathogenesis of leptospirosis: the influence of genomics. Vet. Microbiol. 153, 73–81 (2011).

    Article  CAS  PubMed  Google Scholar 

  89. Lo, M., Cordwell, S. J., Bulach, D. M. & Adler, B. Comparative transcriptional and translational analysis of leptospiral outer membrane protein expression in response to temperature. PLoS Negl. Trop. Dis. 3, e560 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Matsunaga, J., Schlax, P. J. & Haake, D. A. Role for cis-acting RNA sequences in the temperature-dependent expression of the multiadhesive lig proteins in Leptospira interrogans. J. Bacteriol. 195, 5092–5101 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Schons-Fonseca, L. et al. Analysis of LexA binding sites and transcriptomics in response to genotoxic stress in Leptospira interrogans. Nucleic Acids Res. 44, 1179–1191 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Lourdault, K., Cerqueira, G. M., Wunder, E. A. Jr & Picardeau, M. Inactivation of clpB in the pathogen Leptospira interrogans reduces virulence and resistance to stress conditions. Infect. Immun. 79, 3711–3717 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. King, A. M. et al. High-temperature protein G is an essential virulence factor of Leptospira interrogans. Infect. Immun. 82, 1123–1131 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Lo, M. et al. Transcriptional response of Leptospira interrogans to iron limitation and characterization of a PerR homolog. Infect. Immun. 78, 4850–4859 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Caimano, M. J. et al. A model system for studying the transcriptomic and physiological changes associated with mammalian host-adaptation by Leptospira interrogans serovar Copenhageni. PLoS Pathog. 10, e1004004 (2014). The paper is the first to describe the transcriptome of L. interrogans in the mammalian host.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Eshghi, A. et al. Leptospira interrogans catalase is required for resistance to H2O2 and for virulence. Infect. Immun. 80, 3892–3899 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Eshghi, A. et al. Methylation and in vivo expression of the surface-exposed Leptospira interrogans outer-membrane protein OmpL32. Microbiology 158, 622–635 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Cao, X. J. et al. High-coverage proteome analysis reveals the first insight of protein modification systems in the pathogenic spirochete Leptospira interrogans. Cell Res. 20, 197–210 (2010).

    Article  CAS  PubMed  Google Scholar 

  99. Witchell, T. D. et al. Post-translational modification of LipL32 during Leptospira interrogans infection. PLoS Negl. Trop. Dis. 8, e3280 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Ricaldi, J. N., Matthias, M. A., Vinetz, J. M. & Lewis, A. L. Expression of sialic acids and other nonulosonic acids in Leptospira. BMC Microbiol. 12, 161 (2012).

    Article  CAS  PubMed  Google Scholar 

  101. Lindow, J. C. et al. Cathelicidin insufficiency in patients with fatal leptospirosis. PLoS Pathog. 12, e1005943 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Wilson, M. R. et al. Actionable diagnosis of neuroleptospirosis by next-generation sequencing. N. Engl. J. Med. 370, 2408–2417 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Ratet, G. et al. Live imaging of bioluminescent Leptospira interrogans in mice reveals renal colonization as a stealth escape from the blood defenses and antibiotics. PLoS Negl. Trop. Dis. 8, e3359 (2014). The paper is the first to use live imaging to track the dissemination of leptospires in mice.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Pappas, C. J., Benaroudj, N. & Picardeau, M. A replicative plasmid vector allows efficient complementation of pathogenic Leptospira strains. Appl. Environ. Microbiol. 81, 3176–3781 (2015). This paper describes the first replicative plasmid for pathogenic strains of Leptospira.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Pappas, C. J. & Picardeau, M. Control of gene expression in Leptospira spp. by transcription activator-like effectors (TALEs) demonstrates a potential role for LigA and LigB in virulence in L. interrogans. Appl. Environ. Microbiol. 81, 7888–7892 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Lourdault, K., Matsunaga, J. & Haake, D. A. High-throughput parallel sequencing to measure fitness of Leptospira interrogans transposon insertion mutants during acute infection. PLoS Negl. Trop. Dis. 10, e0005117 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Picardeau, M. in The Prokaryotes (ed. Rosenberg, E.) 711–729 (Springer-Verlag Berlin, 2014).

    Google Scholar 

  108. Bharti, A. R. et al. Leptospirosis: a zoonotic disease of global importance. Lancet Infect. Dis. 3, 757–771 (2003). Together with reference 109, this comprehensive reviewprovides broad coverage of our knowledge of leptospirosis.

    Article  PubMed  Google Scholar 

  109. Levett, P. N. Leptospirosis. Clin. Microbiol. Rev. 14, 296–326 (2001).

    Article  CAS  PubMed  Google Scholar 

  110. De la Peña-Moctezuma, A., Bulach, D. M., Kalambaheti, T. & Adler, B. Comparative analysis of the LPS biosynthetic loci of the genetic subtypes of serovar Hardjo: Leptospira interrogans subtype Hardjoprajitno and Leptospira borgpetersenii subtype Hardjobovis. FEMS Microbiol. Lett. 177, 319–326 (1999).

    Article  PubMed  Google Scholar 

  111. Llanes, A., Restrepo, C. M. & Rajeev, S. Whole genome sequencing allows better understanding of the evolutionary history of Leptospira interrogans serovar Hardjo. PLoS ONE 11, e0159387 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Galloway, R. L. & Levett, P. N. Evaluation of a modified pulsed-field gel electrophoresis approach for the identification of Leptospira serovars. Am. J. Trop. Med. Hyg. 78, 628–632 (2008).

    Article  CAS  PubMed  Google Scholar 

  113. Herrmann, J. L., Bellenger, E., Perolat, P., Baranton, G. & Saint Girons, I. Pulsed-field gel electrophoresis of NotI digests of leptospiral DNA: a new rapid method of serovar identification. J. Clin. Microbiol. 30, 1696–1702 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Schmid, G. P. et al. Newly recognized Leptospira species (“Leptospira inadai” serovar lyme) isolated from human skin. J. Clin. Microbiol. 24, 484–486 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Matthias, M. A. et al. Human leptospirosis caused by a new, antigenically unique Leptospira associated with a Rattus species reservoir in the peruvian Amazon. PLoS Negl. Trop. Dis. 2, e213 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Paster, B. J. et al. Phylogenetic analysis of the spirochetes. J. Bacteriol. 173, 6101–6109 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Yasuda, P. H. et al. Deoxyribonucleic acid relatedness between serogroups and serovars in the family Leptospiraceae with proposals for seven new Leptospira species. Int. J. Syst. Bacteriol. 37, 407–415 (1987).

    Article  Google Scholar 

  118. Brenner, D. J. et al. Further determination of DNA relatedness between serogroups and serovars in the family Leptospiraceae with a proposal for Leptospira alexanderi sp. nov. and four new Leptospira genomospecies. Int. J. Syst. Bacteriol. 49, 839–858 (1999).

    Article  CAS  PubMed  Google Scholar 

  119. Boonsilp, S. et al. A single multilocus sequence typing (MLST) scheme for seven pathogenic Leptospira species. PLoS Negl. Trop. Dis. 7, e1954 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Ahmed, N. et al. Multilocus sequence typing method for identification and genotypic classification of pathogenic Leptospira species. Ann. Clin. Microbiol. Antimicrob. 5, 28 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Rettinger, A. et al. Leptospira spp. strain identification by MALDI TOF MS is an equivalent tool to 16S rRNA gene sequencing and multi locus sequence typing (MLST). BMC Microbiol. 12, 185 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Richter, M. & Rosselló-Móra, R. Shifting the genomic gold standard for the prokaryotic species definition. Proc. Natl Acad. Sci. USA 106, 19126–19131 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Bourhy, P., Collet, L., Brisse, S. & Picardeau, M. Leptospira mayottensis sp. nov., a pathogenic Leptospira species isolated from humans. Int. J. Syst. Evol. Microbiol. 64, 4061–4067 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Ristow, P. et al. The OmpA-like protein Loa22 is essential for leptospiral virulence. PLoS Pathog. 3, e97 (2007). The identification of the first virulence determinant, according to Koch's molecular postulates.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Murray, G. L. et al. The major surface protein LipL32 is not required for either acute or chronic infection with Leptospira interrogans. Infect. Immun. 77, 952–958 (2009).

    Article  CAS  PubMed  Google Scholar 

  126. Murray, G. L. et al. Leptospira interrogans requires heme oxygenase for disease pathogenesis. Microbes Infect. 11, 311–314 (2009).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The author would like to thank members of the Biology of Spirochetes Unit, L. Isaac, R. Gomez, C. Toma and V. Pelicic for their crucial advice during the preparation of this manuscript and J. Guglielmini for the phylogenomic analysis of the Leptospira genus. This Review was supported by the Institut Pasteur, Paris, France.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mathieu Picardeau.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

PowerPoint slides

Glossary

Zoonosis

An infectious disease in animals that can be transmitted to humans.

Weil's disease

A severe form of leptospirosis, the symptoms of which include jaundice and acute kidney injury; these symptoms were first described by Weil in 1886.

Cross-agglutinin absorption test

(CAAT). The standard serological method for determining a Leptospira serovar by comparing the agglutinating antigens of an unknown isolate with those of known reference strains.

MreB filaments

Cytoskeletal filaments that are formed of actin-like MreB proteins, which influence cell shape.

Haematogenous

A term that pertains to anything transported by the blood.

Moonlighting functions

A term that is used to describe a protein that can carry out multiple, and often unrelated, biological functions.

Plasmin

A key enzyme in fibrinolysis and homeostasis that can degrade components of the extracellular matrix (ECM).

Fibrin clots

Clots that are formed of fibrin in the final step of blood coagulation; thrombin converts soluble fibrinogen into long, insoluble strands of fibrin.

Lytic membrane attack complex

A complex that is formed on the bacterial cell surface by complement activation, which leads to cell lysis.

Neutrophil extracellular traps

DNA that is expelled, mainly by neutrophils, in response to infection.

Lipid A

A structural component of lipopolysaccharides (LPS) that is also known as endotoxin.

Neuroleptospirosis

Leptospiral meningitis; leptospires can be recovered from the cerebrospinal fluid (CSF) of patients who have disease.

Koch's molecular postulates

A series of conditions that must be met to establish that a gene is a virulence factor. For example, the gene must be present in strains that are associated with disease but not in those that are not, and mutation of the gene must decrease or abolish bacterial virulence, but complementation with a functional gene must restore it.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Picardeau, M. Virulence of the zoonotic agent of leptospirosis: still terra incognita?. Nat Rev Microbiol 15, 297–307 (2017). https://doi.org/10.1038/nrmicro.2017.5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro.2017.5

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing