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.
Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to the full article PDF.
USD 39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Faine, S., Adler, B., Bolin, C. & Perolat, P. Leptospira and Leptospirosis (MedScience, Melbourne, 1999).
Weil, A. Ueber eine eigenthümliche, mit Milztumor, Icterus und Nephritis einhergehende acute Infectionskrankheit. Dtsch. Arch. Klin. Med. 39, 209–232 (1886) (in German).
Inada, R., Ido, Y., Hoki, R., Kakeno, R. & Ito, H. The etiology, mode of infection and specific therapy of Weil's disease (Spirochaetosis icterohaemorrhagica). J. Exp. Med. 23, 377–403 (1916). A landmark paper that describes the discovery of Leptospira spp. as the aetiological agents of leptospirosis.
Levett, P. N. Leptospirosis. Clin. Microbiol. Rev. 14, 296–326 (2001). This comprehensive review provides wide coverage of our knowledge of leptospirosis.
Bharti, A. R. et al. Leptospirosis: a zoonotic disease of global importance. Lancet Infect. Dis. 3, 757–771 (2003). This review provides important complementary information to reference 4 and discusses the main issues facing the field of leptospirosis.
McBride, A. J., Athanazio, D. A., Reis, M. G. & Ko, A. I. Leptospirosis. Curr. Opin. Infect. Dis. 18, 376–386 (2005).
Ko, A. I., et al. Urban epidemic of severe leptospirosis in Brazil. Lancet 354, 820–825 (1999).
Riley, L. W., Ko, A. I., Unger, A. & Reis, M. G. Slum health: diseases of neglected populations. BMC Int. Health Hum. Rights 7, 2 (2007).
Reis, R. B. et al. Impact of environment and social gradient on Leptospira infection in urban slums. PLoS Negl. Trop. Dis. 2, e228 (2008).
WHO. Leptospirosis worldwide, 1999. Wkly Epidemiol. Rec. 74, 237–242 (1999).
Paster, B. J. et al. Phylogenetic analysis of the spirochetes. J. Bacteriol. 173, 6101–6109 (1991).
Li, C., Motaleb, M. A., Sal, M., Goldstein, S. F. & Charon, N. Gyrations, rotations, periplasmic flagella: the biology of spirochete motility. J. Mol. Microbiol. Biotechnol. 2, 345–354 (2000).
Ren, S. et al. Unique and physiological pathogenic features of Leptospira interrogans revealed by whole genome sequencing. Nature 422, 888–893 (2003). This article describes the first complete genome sequence of a leptospiralspecies.
Nascimento, A. L. et al. Comparative genomics of two Leptospira interrogans serovars reveals novel insights into physiology and pathogenesis. J. Bacteriol. 186, 2164–2172 (2004).
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 showed that the L. borgpetersenii genome is undergoing a process of reduction that seems to have impaired its ability to survive in the external environment and has caused it to rely on direct contact as its mode of transmission.
Picardeau, M. et al. Genome sequence of the saprophyte Leptospira biflexa provides insights into the evolution of Leptospira and the pathogenesis of leptospirosis. PLoS ONE 3, e1607 (2008). This paper describes the genome of the model bacterium L. biflexa and its comparison to the pathogenic L. interrogans and L. borgpetersenii.
Xue, F., Yan, J. & Picardeau, M. Evolution and pathogenesis of Leptospira spp.: lessons learned from the genomes. Microbes Infect. 11, 328–333 (2008).
Thiermann, A. B. The Norway rat as a selective chronic carrier of Leptospira icterohaemorrhagiae. J. Wildl. Dis. 17, 39–43 (1981).
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).
Ristow, P. et al. Biofilm formation by saprophytic and pathogenic leptospires. Microbiology 154, 1309–1317 (2008). References 19 and 20 describe key findings about the survival mechanisms of pathogenic Leptospira spp. outside the host.
Haake, D. A. & Lovett, M. A. Interjunctional invasion of endothelial cell monolayers. Methods Enzymol. 236, 447–463 (1994).
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).
Liu, Y., Zheng, W., Li, L., Mao, Y. & Yan, J. Pathogenesis of leptospirosis: interaction of Leptospira interrogans with in vitro cultured mammalian cells. Med. Microbiol. Immunol. 196, 233–239 (2007).
Thomas, D. D. & Higbie, L. M. In vitro association of leptospires with host cells. Infect. Immun. 58, 581–585 (1990).
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 found that leptospires rapidly translocate across polarized cell monolayers by invading host cells and transiently residing in the cytoplasmic compartment.
Faine, S. Virulence in Leptospira. I. Reactions of guinea-pigs to experimental infections with Leptospira Icterohaemorrhagiae. Br. J. Exp. Pathol. 38, 1–7 (1957).
Faine, S. Virulence in Leptospira. II. The growth in vivo of virulent Leptospira icterohaemorrhagiae. Br. J. Exp. Pathol. 38, 8–14 (1957).
Athanazio, D. A. et al. Rattus norvegicus as a model for persistent renal colonization by pathogenic Leptospira interrogans. Acta Trop. 105, 176–180 (2008).
Lourdault, K., Aviat, F. & Picardeau, M. The use of quantitative real-time PCR to study the dissemination of Leptospira interrogans in the guinea pig infection model of leptospirosis. J. Med. Microbiol. 58, 648–655 (2009).
Segura, E. R. et al. Clinical spectrum of pulmonary involvement in leptospirosis in a region of endemicity, with quantification of leptospiral burden. Clin. Infect. Dis. 40, 343–351 (2005).
Truccolo, J., Serais, O., Merien, F. & Perolat, P. Following the course of human leptospirosis: evidence of a critical threshold for the vital prognosis using a quantitative PCR assay. FEMS Microbiol. Lett. 204, 17–321 (2001).
Cinco, M. & Banfi, E. Activation of complement by leptospires and its bactericidal activity. Zentralbl. Bakteriol. Mikrobiol. Hyg. A 254, 261–265 (1983).
Johnson, R. C. & Muschel, L. H. Antileptospiral activity of serum. I. Normal and immune serum. J. Bacteriol. 91, 1403–1409 (1966).
Meri, T., Murgia, R., Stefanel, P., Meri, S. & Cinco, M. Regulation of complement activation at the C3-level by serum resistant leptospires. Microb. Pathog. 39, 139–147 (2005).
Verma, A. et al. LfhA, a novel factor H-binding protein of Leptospira interrogans. Infect. Immun. 74, 2659–2666 (2006). This study is the first report of a leptospiral complement factor H-binding protein that potentially contributes to both Leptospira spp.resistance to complement-mediated killing and the evasion of the immune response as the pathogen disseminates in the bloodstream.
Stevenson, B. et al. Leptospira interrogans endostatin-like outer membrane proteins bind host fibronectin, laminin and regulators of complement. PLoS ONE 2, e1188 (2007).
Verma, A. et al. LruA and LruB antibodies in sera of humans with leptospiral uveitis. Clin. Vaccine Immunol. 15, 1019–1023 (2008).
Barbosa, A. S. et al. Immune evasion of Leptospira species by acquisition of human complement regulator C4BP. Infect. Immun. 77, 1137–1143 (2009).
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). This interesting study suggests that differential expression of LPS O antigen influences the ability of the pathogen to cause an acute lethal infection versus chronic renal carriage.
Sterling, C. R. & Thiermann, A. B. Urban rats as chronic carriers of leptospirosis: an ultrastructural investigation. Vet. Pathol. 18, 628–637 (1981).
Monahan, A. M., Callanan, J. J. & Nally, J. E. Proteomic analysis of Leptospira interrogans shed in urine of chronically infected hosts. Infect. Immun. 76, 4952–4958 (2008).
Ganoza, C. A. et al. Determining risk for severe leptospirosis by molecular analysis of environmental surface waters for pathogenic Leptospira. PLoS Med. 3, e308 (2006). This investigation found that an outbreak of severe leptospirosis was associated with exposure to high concentrations of pathogenic leptospires in environmental surface waters. The work was pioneering in that it developed new molecular tools to quantify leptospires in the environment.
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).
Thaipadungpanit, J. et al. A dominant clone of Leptospira interrogans associated with an outbreak of human leptospirosis in Thailand. PLoS Negl. Trop. Dis. 1, e56 (2007).
Slack, A., Symonds, M., Dohnt, M. & Smythe, L. An improved multiple-locus variable number of tandem repeats analysis for Leptospira interrogans serovar Australis: a comparison with fluorescent amplified fragment length polymorphism analysis and its use to redefine the molecular epidemiology of this serovar in Queensland, Australia. J. Med. Microbiol. 55, 1549–1557 (2006).
Zuerner, R. L. & Alt, D. P. Variable nucleotide tandem repeat analysis reveals a unique group of Leptospira interrogans serovar Pomona isolates associated with California sea lions. J. Clin. Microbiol. 47, 1202–1205 (2009).
Lingappa, J. et al. HLA-DQ6 and ingestion of contaminated water: possible gene-environment interaction in an outbreak of Leptospirosis. Genes Immun. 5, 311–314 (2004). This is the first report of a host genetic susceptibility factor for leptospirosis and also of a gene–environment interaction for an infectious disease.
Silva, E. F. et al. Characterization of virulence of Leptospira isolates in a hamster model. Vaccine 26, 3892–3896 (2008).
Nicodemo, A. C. et al. Lung lesions in human leptospirosis: microscopic, immunohistochemical, and ultrastructural features related to thrombocytopenia. Am. J. Trop. Med. Hyg. 56, 181–187 (1997).
De Brito, T., Böhm, G. M. & Yasuda, P. H. Vascular damage in acute experimental leptospirosis of the guinea-pig. J. Pathol. 128, 177–182 (1979).
Chierakul, W. et al. Activation of the coagulation cascade in patients with leptospirosis. Clin. Infect. Dis. 46, 254–260 (2008). This study found that activation of the coagulation cascade, including disseminated intravascular coagulation, is a prominent feature in leptospirosis.
Wagenaar, J. F. et al. What role do coagulation disorders play in the pathogenesis of leptospirosis? Trop. Med. Int. Health 12, 111–122 (2007).
Diament, D., Brunialti, M. K. C., Romero, E. C., Kallas, E. G. & Salomao, R. Peripheral blood mononuclear cell activation induced by Leptospira interrogans glycolipoprotein. Infect. Immun. 70, 1677–1683 (2002).
Klimpel, G. R., Matthias, M. A. & Vinetz, J. M. Leptospira interrogans activation of human peripheral blood mononuclear cells: preferential expansion of TCR γδ+ T cells vs TCR αβ+ T cells. J. Immunol. 171, 1447–1455 (2003).
Vernel-Pauillac, F. & Merien, F. Proinflammatory and immunomodulatory cytokine mRNA time course profiles in hamsters infected with a virulent variant of Leptospira interrogans. Infect. Immun. 74, 4172–4179 (2006).
de Fost, M., Hartskeerl, R. A., Groenendijk, M. R. & van der Poll, T. Interleukin 12 in part regulates gamma interferon release in human whole blood stimulated with Leptospira interrogans. Clin. Diagn. Lab. Immunol. 10, 332–335 (2003).
Tajiki, M. H. & Salomao, R. Association of plasma levels of tumor necrosis factor alpha with severity of disease and mortality among patients with leptospirosis. Clin. Infect. Dis. 23, 1177–1178 (1996).
Werts, C. et al. Leptospiral lipopolysaccharide activates cells through a TLR2-dependent mechanism. Nature Immunol. 2, 346–352 (2001).
Que-Gewirth, N. L. et al. A methylated phosphate group and four amide-linked acyl chains in Leptospira interrogans lipid A. The membrane anchor of an unusual lipopolysaccharide that activates TLR. J. Biol. Chem. 279, 25420–25429 (2004). References 58 and 59 show that Leptospira spp. possess an unusual LPS that uses TLR2 rather than TLR4 for signalling in human cells.
Yang, C. W. et al. Toll-like receptor 2 mediates early inflammation by leptospiral outer membrane proteins in proximal tubule cells. Kidney Int. 69, 815–822 (2006).
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).
Seguro, A. C., Lomar, A. V. & Rocha, A. S. Acute renal failure of leptospirosis: nonoliguric and hypokalemic forms. Nephron 55, 146–151 (1990).
Burth, P., Younes-Ibrahim, M., Santos, M. C., Castro- Faria Neto, H. C. & de Castro Faria, M. V. Role of nonesterified unsaturated fatty acids in the pathophysiological processes of leptospiral infection. J. Infect. Dis. 191, 51–57 (2005).
Wu, M. S., Yang, C. W., Pan, M. J., Chang, C. T. & Chen, Y. C. Reduced renal Na+–K+–Cl− co-transporter activity and inhibited NKCC2 mRNA expression by Leptospira shermani: from bed-side to bench. Nephrol. Dial. Transplant. 19, 2472–2479 (2004).
Andrade, L., Rodrigues, A. C. Jr, Sanches, T. R., Souza, R. B. & Seguro, A. C. Leptospirosis leads to dysregulation of sodium transporters in the kidney and lung. Am. J. Physiol. Renal Physiol. 292, F586–F592 (2007).
Isogai, E. et al. Apoptosis of lymphocytes in mice administered lipopolysaccharide from Leptospira interrogans. Zentralbl. Veterinarmed. B 45, 529–537 (1998).
Merien, F., Truccolo, J., Rougier, Y., Baranton, G. & Perolat, P. In vivo apoptosis of hepatocytes in guinea pigs infected with Leptospira interrogans serovar Icterohaemorrhagiae. FEMS Microbiol. Lett. 169, 95–102 (1998).
Rugman, F. P., Pinn, G., Palmer, M. F., Waite, M. & Hay, C. R. Anticardiolipin antibodies in leptospirosis. J. Clin. Pathol. 44, 517–519 (1991).
Nally, J. E. et al. Alveolar septal deposition of immunoglobulin and complement parallels pulmonary hemorrhage in a guinea pig model of severe pulmonary leptospirosis. Am. J. Pathol. 164, 1115–1127 (2004). This study raises the potential for the involvement of an autoimmune process in the development of this severe disease form.
Stamm, L. V., Parrish, E. A. & Gherardini, F. C. Cloning of the recA gene from a free-living leptospire and distribution of RecA-like protein among spirochetes. Appl. Environ. Microbiol. 57, 183–189 (1991).
Mitchison, M. et al. Identification and characterization of the dTDP-rhamnose biosynthesis and transfer genes of the lipopolysaccharide-related rfb locus in Leptospira interrogans serovar Copenhageni. J. Bacteriol. 179, 1262–1267 (1997).
Yelton, D. B. & Cohen, R. A. Analysis of cloned DNA from Leptospira biflexa serovar patoc which complements a deletion of the Escherichia coli trpE gene. J. Bacteriol. 165, 41–46 (1986).
Baril, C., Richaud, C., Fournie, E., Baranton, G. & Saint Girons, I. Cloning of dapD, aroD and asd of Leptospira interrogans serovar Icterohaemorrhagiae, and nucleotide sequence of the asd gene. J. Gen. Microbiol. 138, 47–53 (1992).
Saint Girons, I., Margarita, D., Amouriaux, P. & Baranton, G. First isolation of bacteriophages for a spirochaete: potential genetic tools for Leptospira. Res. Microbiol. 141, 1131–1138 (1990).
Bourhy, P. et al. A genomic island of the pathogen Leptospira interrogans serovar Lai can excise from its chromosome. Infect. Immun. 75, 677–683 (2007).
Saint Girons, I. et al. The LE1 bacteriophage replicates as a plasmid within Leptospira biflexa: construction of an L. biflexa-Escherichia coli shuttle vector. J. Bacteriol. 182, 5700–5705 (2000). The first study to show the successful introduction of DNA into Leptospira spp.
Bourhy, P., Louvel, H., Saint Girons, I. & Picardeau, M. Random insertional mutagenesis of Leptospira interrogans, the agent of leptospirosis, using a mariner transposon. J. Bacteriol. 187, 3255–3258 (2005). This paper describes the first evidence of gene transfer in pathogenic Leptospira spp. and the generation of the first mutants in these pathogens.
Picardeau, M. Conjugative transfer between Escherichia coli and Leptospira spp. as a new genetic tool. Appl. Environ. Microbiol. 74, 319–322 (2008).
Louvel, H. & Picardeau, M. Genetic manipulation of Leptospira biflexa. Curr. Protoc. Microbiol. 12, 12E.4 (2007).
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). The first and so far only description of targeted inactivation in pathogenic Leptospira spp.
Murray, G. L. et al. Genome-wide transposon mutagenesis in pathogenic Leptospira spp. Infect. Immun. 77, 810–816 (2009).
Louvel, H., Saint Girons, I. & Picardeau, M. Isolation and characterization of FecA- and FeoB- mediated iron acquisition systems of the spirochete Leptospira biflexa by random insertional mutagenesis. J. Bacteriol. 187, 3249–3254 (2005).
Louvel, H. et al. Comparative and functional genomic analyses of iron transport and regulation in Leptospira spp. J. Bacteriol. 188, 7893–7904 (2006).
Pereira, M. M., Andrade, J., Marchevsky, R. S. & Ribeiro dos Santos, R. Morphological characterization of lung and kidney lesions in C3H/HeJ mice infected with Leptospira interrogans serovar icterohaemorrhagiae: defect of CD4+ and CD8+ T-cells are prognosticators of the disease progression. Exp. Toxicol. Pathol. 50, 191–198 (1998).
Viriyakosol, S., Matthias, M. A., Swancutt, M. A., Kirkland, T. N. & Vinetz, J. M. Toll-like receptor 4 protects against lethal Leptospira interrogans serovar icterohaemorrhagiae infection and contributes to in vivo control of leptospiral burden. Infect. Immun. 74, 887–895 (2006). This article highlights the importance of TLR pathway activation in innate immunity against leptospirosis.
Koizumi, N. & Watanabe, H. Leptospiral immunoglobulin-like proteins elicit protective immunity. Vaccine 22, 1545–1552 (2004).
Minette, H. P. & Shaffer, M. F. Experimental leptospirosis in monkeys. Am. J. Trop. Med. Hyg. 17, 202–212 (1968).
Pereira, M. M. et al. Experimental leptospirosis in marmoset monkeys (Callithrix jacchus): a new model for studies of severe pulmonary leptospirosis. Am. J. Trop. Med. Hyg. 72, 13–20 (2005).
Ito, T. & Yanagawa, R. Leptospiral attachment to extracellular matrix of mouse fibroblast (L929) cells. Vet. Microbiol. 15, 89–96 (1987).
Merien, F., Truccolo, J., Baranton, G. & Perolat, P. Identification of a 36-kDa fibronectin-binding protein expressed by a virulent variant of Leptospira interrogans serovar icterohaemorrhagiae. FEMS Microbiol. Lett. 185, 17–22 (2000).
Atzingen, M. V. et al. Lsa21, a novel leptospiral protein binding adhesive matrix molecules and present during human infection. BMC Microbiol. 8, 70 (2008).
Hauk, P. et al. In LipL32, the major leptospiral lipoprotein, the C terminus is the primary immunogenic domain and mediates interaction with collagen IV and plasma fibronectin. Infect. Immun. 76, 2642–2650 (2008).
Hoke, D. E., Egan, S., Cullen, P. A. & Adler, B. LipL32 is an extracellular matrix-interacting protein of Leptospira spp. and Pseudoalteromonas tunicata. Infect. Immun. 76, 2063–2069 (2008).
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). The first study to determine that Lig proteins bind to extracellular matrix moieties.
Haake, D. A. et al. Changes in the surface of Leptospira interrogans serovar grippotyphosa during in vitro cultivation. Infect. Immun. 59, 1131–1140 (1991).
Setubal, J. C., Reis, M. G., Matsunaga, J. & Haake, D. A. Lipoprotein computational prediction in spirochaetal genomes. Microbiology 152, 113–121 (2006).
Viratyosin, W., Ingsriswang, S., Pacharawongsakda, E. & Palittapongarnpim, P. Genome-wide subcellular localization of putative outer membrane and extracellular proteins in Leptospira interrogans serovar Lai genome using bioinformatics approaches. BMC Genomics 9, 181 (2008).
Yang, H. L. et al. In silico and microarray-based genomic approaches to identifying potential vaccine candidates against Leptospira interrogans. BMC Genomics 7, 293 (2006).
Lee, S. H., Kim, S., Park, S. C. & Kim, M. J. Cytotoxic activities of Leptospira interrogans hemolysin SphH as a pore-forming protein on mammalian cells. Infect. Immun. 70, 315–322 (2002).
Cullen, P. A., Haake, D. A. & Adler, B. Outer membrane proteins of pathogenic spirochetes. FEMS Microbiol. Rev. 28, 291–318 (2004).
Haake, D. A. et al. Molecular cloning and sequence analysis of the gene encoding OmpL1, a transmembrane outer membrane protein of pathogenic Leptospira spp. J. Bacteriol. 175, 4225–4234 (1993).
Haake, D. A. et al. The leptospiral major outer membrane protein LipL32 is a lipoprotein expressed during mammalian infection. Infect. Immun. 68, 2276–2285 (2000).
Matsunaga, J. et al. Pathogenic Leptospira species express surface-exposed proteins belonging to the bacterial immunoglobulin superfamily. Mol. Microbiol. 49, 929–945 (2003).
Ristow, P. et al. The OmpA-like protein Loa22 is essential for leptospiral virulence. PLoS Pathog. 3, e97 (2007). The first identification of a virulence determinant according to Koch's molecular postulates.
Gamberini, M. et al. Whole-genome analysis of Leptospira interrogans to identify potential vaccine candidates against leptospirosis. FEMS Microbiol. Lett. 244, 305–313 (2005).
Nally, J. E., Whitelegge, J. P., Bassilian, S., Blanco, D. R. & Lovett, M. A. Characterization of the outer membrane proteome of Leptospira interrogans expressed during acute lethal infection. Infect. Immun. 75, 766–773 (2007).
Barbosa, A. S. et al. A newly identified leptospiral adhesin mediates attachment to laminin. Infect. Immun. 74, 6356–6364 (2006).
Lee, S. H. et al. Identification and partial characterization of a novel hemolysin from Leptospira interrogans serovar lai. Gene 254, 19–28 (2000). Together with reference 102, the first description of LipL32, the major surface-exposed protein of pathogens.
Cullen, P. A., Cordwell, S. J., Bulach, D. M., Haake, D. A. & Adler, B. Global analysis of outer membrane proteins from Leptospira interrogans serovar Lai. Infect. Immun. 70, 2311–2318 (2002).
Haake, D. A. et al. Molecular evolution and mosaicism of leptospiral outer membrane proteins involves horizontal DNA transfer. J. Bacteriol. 186, 2818–2828 (2004).
Vivian, J. P. et al. Crystal structure of LipL32, the most abundant surface protein of pathogenic Leptospira spp. J. Mol. Biol. 387, 1229–1238 (2009).
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).
Palaniappan, R. U. et al. Cloning and molecular characterization of an immunogenic LigA protein of Leptospira interrogans. Infect. Immun. 70, 5924–5930 (2002). This study and that in reference 103 identified LigA, LigB and LigC as members of the bacterial immunoglobulin-like superfamily of proteins.
Lin, Y. P. & Chang, Y. F. A domain of the Leptospira LigB contributes to high affinity binding of fibronectin. Biochem. Biophys. Res. Commun. 362, 443–448 (2007).
Lin, Y. P., Raman, R., Sharma, Y. & Chang, Y. F. Calcium binds to leptospiral immunoglobulin-like protein, LigB, and modulates fibronectin binding. J. Biol. Chem. 283, 25140–24149 (2008).
Matsunaga, J. et al. Response of Leptospira interrogans to physiologic osmolarity: relevance in signaling the environment-to-host transition. Infect. Immun. 75, 2864–2874 (2007). References 94 and 116 both found that physiological osmolarity is a key environmental signal for the differential regulation of leptospiral genes.
Srimanote, P. et al. Recombinant ligA for leptospirosis diagnosis and ligA among the Leptospira spp. clinical isolates. J. Microbiol. Methods 72, 73–81 (2008).
Croda, J. et al. Leptospira immunoglobulin-like proteins as a serodiagnostic marker for acute leptospirosis. J. Clin. Microbiol. 45, 1528–1534 (2007).
Ellis, W. A., Hovind-Hougen, K., Möller, S. & Birch-Andresen, A. Morphological changes upon subculturing of freshly isolated strains of Leptospira interrogans serovar hardjo. Zentralbl. Bakteriol. Mikrobiol. Hyg. A 255, 323–335 (1983).
Picardeau, M., Brenot, A. & Saint Girons, I. First evidence for gene replacement in Leptospira spp. Inactivation of L. biflexa flaB results in non-motile mutants deficient in endoflagella. Mol. Microbiol. 40, 189–199 (2001). The first report of targeted gene inactivation in Leptospira spp.; unlike that of the spirochaete B. burgdorferi , the cell body of the leptospiral flaB mutant remains helical.
Motaleb, M. A. et al. Borrelia burgdorferi periplasmic flagella have both skeletal and motility functions. Proc. Natl Acad. Sci. USA 97, 10899–10904 (2000).
Yuri, K. et al. Chemotaxis of leptospires to hemoglobin in relation to virulence. Infect. Immun. 61, 2270–2272 (1993).
Murray, G. L. et al. Leptospira interrogans requires heme oxygenase for disease pathogenesis. Microbes Infect. 11, 311–314 (2009).
Lo, M. et al. Effects of temperature on gene expression patterns in Leptospira interrogans serovar Lai as assessed by whole-genome microarrays. Infect. Immun. 74, 848–859 (2006).
Adler, B. & Faine, S. Host immunological mechanisms in the resistance of mice to leptospiral infections. Infect. Immun. 17, 67–72 (1977).
Adler, B. & Faine, S. The antibodies involved in the human immune response to leptospiral infection. J. Med. Microbiol. 11, 387–400 (1978).
Jost, B. H., Adler, B., Vinh, T. & Faine, S. A monoclonal antibody reacting with a determinant on leptospiral lipopolysaccharide protects guinea pigs against leptospirosis. J. Med. Microbiol. 22, 269–275 (1986).
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).
Naiman, B. M. et al. Evaluation of type 1 immune response in naive and vaccinated animals following challenge with Leptospira borgpetersenii serovar Hardjo: involvement of WC1+ γδ and CD4 T cells. Infect. Immun. 70, 6147–6157 (2002). This study raises the possibility that cell-mediated immune responses confer protection against leptospirosis in certain hosts, such as cows.
Brown, R. A. et al. Comparison of three different leptospiral vaccines for induction of a type 1 immune response to Leptospira borgpetersenii serovar Hardjo. Vaccine 21, 4448–4458 (2003).
Blumerman, S. L., Herzig, C. T. & Baldwin, C. L. WC1+ γδ T cell memory population is induced by killed bacterial vaccine. Eur. J. Immunol. 37, 1204–1216 (2007).
Ido, Y., Hoki, R., Ito, H. & Wani, H. The prophylaxis of Weil's disease (Spirochaetosis Icterohaemorrhagica). J. Exp. Med. 24, 471–483 (1916).
Koizumi, N. & Watanabe, H. Leptospirosis vaccines: past, present, and future. J. Postgrad. Med. 51, 210–214 (2005).
Gonzalez, A. et al. Immunogenicity and protective capacity of leptospiral whole-cell monovalent serogroup Ballum vaccines in hamsters. Rev. Argent. Microbiol. 37, 169–175 (2005).
Haake, D. A. et al. Leptospiral outer membrane proteins OmpL1 and LipL41 exhibit synergistic immunoprotection. Infect. Immun. 67, 6572–6582 (1999). The first evidence that immunization with a recombinant protein confers protection against experimental leptospirosis.
Branger, C. et al. Protection against Leptospira interrogans sensu lato challenge by DNA immunization with the gene encoding hemolysin-associated protein 1. Infect. Immun. 73, 4062–4069 (2005).
Seixas, F. K. et al. Recombinant Mycobacterium bovis BCG expressing the LipL32 antigen of Leptospira interrogans protects hamsters from challenge. Vaccine 26, 88–95 (2007).
Branger, C. et al. Identification of the hemolysis-associated protein 1 as a cross-protective immunogen of Leptospira interrogans by adenovirus-mediated vaccination. Infect. Immun. 69, 6831–6838 (2001).
Palaniappan, R. U. et al. Immunoprotection of recombinant leptospiral immunoglobulin-like protein A against Leptospira interrogans serovar Pomona infection. Infect. Immun. 74, 1745–1750 (2006). References 86 and 139 were the first to report that Lig proteins induce high-level immunoprotection against a lethal L. interrogans infection in experimental animals.
Silva, E. F. et al. The terminal portion of leptospiral immunoglobulin-like protein LigA confers protective immunity against lethal infection in the hamster model of leptospirosis. Vaccine 25, 6277–6286 (2007).
Yan, W. et al. Immunogenicity and protective efficacy of recombinant Leptospira immunoglobulin-like protein B (rLigB) in a hamster challenge model. Microbes Infect. 11, 230–237 (2009).
McBride, A. J. et al. Genetic diversity of the Leptospiral immunoglobulin-like (Lig) genes in pathogenic Leptospira spp. Infect. Genet. Evol. 9, 196–205 (2009).
Qin, J. H. et al. Identification of a novel prophage-like gene cluster actively expressed in both virulent and avirulent strains of Leptospira interrogans serovar Lai. Infect. Immun. 76, 2411–2419 (2008).
Salaün, L., Mérien, F., Gurianova, S., Baranton, G. & Picardeau, M. Application of multilocus variable-number tandem-repeat analysis for molecular typing of the agent of leptospirosis. J. Clin. Microbiol. 44, 3954–3962 (2006).
Ahmed, N. et al. Multilocus sequence typing method for identification and genotypic classification of pathogenic Leptospira species. Ann. Clin. Microbiol. Antimicrob. 5, 28 (2006).
Bourhy, P. et al. Complete nucleotide sequence of the LE1 prophage from the spirochete Leptospira biflexa and characterization of its replication and partition functions. J. Bacteriol. 187, 3931–3940 (2005).
Park, S. K. et al. Leptospirosis in Chonbuk Province of Korea in 1987: a study of 93 patients. Am. J. Trop. Med. Hyg. 41, 345–351 (1989).
Trevejo, R. T. et al. Epidemic leptospirosis associated with pulmonary hemorrhage — Nicaragua, 1995. J. Infect. Dis. 178, 1457–1463 (1998).
Panaphut, T., Domrongkitchaiporn, S. & Thinkamrop, B. Prognostic factors of death in leptospirosis: a prospective cohort study in Khon Kaen, Thailand. Int. J. Infect. Dis. 6, 52–59 (2002).
Marotto, P. C. F. et al. Acute lung injury in leptospirosis: clinical and laboratory features, outcome, and factors associated with mortality. Clin. Infect. Dis. 29, 1561–1563 (1999).
Gouveia, E. L. et al. Leptospirosis-associated severe pulmonary hemorrhagic syndrome, Salvador, Brazil. Emerg. Infect. Dis. 14, 505–508 (2008).
Yang, G. G. & Hsu, Y. H. Nitric oxide production and immunoglobulin deposition in leptospiral hemorrhagic respiratory failure. J. Formos. Med. Assoc. 104, 759–763 (2005).
Croda, J. et al. Leptospirosis pulmonary hemorrhage syndrome is associated with linear deposition of immunoglobulin and complement on the alveolar surface. Clin. Microbiol. Infect. (in the press).
Asuthkar, S., Velineni, S., Stadlmann, J., Altmann, F. & Sritharan, M. Expression and characterization of an iron-regulated hemin-binding protein, HbpA, from Leptospira interrogans serovar Lai. Infect. Immun. 75, 4582–4591 (2007).
Bos, M. P., Robert, V. & Tommassen, J. Biogenesis of the Gram-negative bacterial outer membrane. Annu. Rev. Microbiol. 61, 191–214 (2007).
Faisal, S. M. et al. Evaluation of protective immunity of Leptospira immunoglobulin like protein A (LigA) DNA vaccine against challenge in hamsters. Vaccine 26, 277–287 (2008).
Faisal, S. M., Yan, W., McDonough, S. P. & Chang, Y. F. Leptospira immunoglobulin-like protein A variable region (LigAvar) incorporated in liposomes and PLGA microspheres produces a robust immune response correlating to protective immunity. Vaccine 27, 378–387 (2009).
Acknowledgements
We thank C. Figueira, E. Wunder, E. Couture, M.-C. Prevost and P. Ristow for providing the figures of leptospires and their pathology. We also thank L. Riley, G. Baranton, I. Saint Girons, M. Reis and G. Ribeiro for their critical advice during the preparation of this manuscript. Some of the work described was supported by a cooperative agreement between Institut Pasteur and the Oswaldo Cruz Foundation, Brazilian National Research Council (grants 01.06.0298.00, 3773/2005 and 554788/2006, Instituto Nacional de Ciência e Tecnologia de Vacinas), by the Research Support Foundation for the State of Bahia (54663), by the National Institutes of Health (grants 2R01 AI052473 and 2D43 TW00919), by the Institut Pasteur and by Agence Nationale de la Recherche (n°05-JCJC-0105–01).
Author information
Authors and Affiliations
Corresponding author
Related links
Supplementary information
Supplementary information S1 (box) (download PDF )
Leptospirosis in animals (PDF 145 kb)
Glossary
- Zoonotic disease
-
An infectious disease of animals that can be transmitted to humans, whatever its transmission mode (vector borne, directly or indirectly through a product derived from the host animal), and that causes a disease syndrome in susceptible individuals.
- Enzootic
-
Pertaining to an infection that can be maintained in nature through continuous transmission among animal populations.
- Haematogenous
-
Pertaining to anything transported by the blood.
- Alternative pathway
-
The complement activation pathway that is stimulated by the spontaneous hydrolysis of the complement component C3 or the presence of microbial surface structures.
- Classical pathway
-
The complement activation pathway that is stimulated by the recognition of antigen–antibody complexes on foreign-cell surfaces by the hexameric complement component C1q.
- Human leukocyte antigen
-
Also known as the major histocompatibility complex, this is a key part of the human immune system.
- Jarisch-Herxheimer reaction
-
An inflammatory reaction (characterized by the sudden onset of fever, chills and, in some cases, hypotension) that is induced in certain cases by antimicrobial therapy and believed to be due to the rapid release of bacterial antigens.
- 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 the disease but not in those which are not, the mutation of the gene must reduce or abolish bacterial virulence and complementation of the mutant must restore it.
- T helper 1 cell
-
A type of activated Thelper cell that promotes responses associated with the production of a particular set of cytokines, including tumour necrosis factor and interferon-γ, the main function of which is to stimulate phagocytosis-mediated defences against pathogens.
Rights and permissions
About this article
Cite this article
Ko, A., Goarant, C. & Picardeau, M. Leptospira: the dawn of the molecular genetics era for an emerging zoonotic pathogen. Nat Rev Microbiol 7, 736–747 (2009). https://doi.org/10.1038/nrmicro2208
Issue date:
DOI: https://doi.org/10.1038/nrmicro2208
