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.

[1]  G. Baranton,et al.  Leptospira fainei sp. nov., isolated from pigs in Australia. , 1998, International journal of systematic bacteriology.

[2]  R. Aebersold,et al.  Proteome-wide cellular protein concentrations of the human pathogen Leptospira interrogans , 2009, Nature.

[3]  G. Dettori,et al.  Epidemiological trend of human leptospirosis in Italy between 1994 and 1996 , 2004, European Journal of Epidemiology.

[4]  D. Ojcius,et al.  Inactivation of the fliY gene encoding a flagellar motor switch protein attenuates mobility and virulence of Leptospira interrogans strain Lai , 2009, BMC Microbiology.

[5]  R. Klempfner,et al.  The changing epidemiology of leptospirosis in Israel. , 2001, Emerging infectious diseases.

[6]  J. Timoney,et al.  Cloning and Molecular Characterization of an Immunogenic LigA Protein of Leptospira interrogans , 2002, Infection and Immunity.

[7]  Guo-Ping Zhao,et al.  Genome-wide transcriptional analysis of temperature shift in L. interrogans serovar lai strain 56601 , 2006, BMC Microbiology.

[8]  D. Hospenthal,et al.  Antimicrobial therapy of leptospirosis , 2006, Current opinion in infectious diseases.

[9]  R. Coppel,et al.  Genome reduction in Leptospira borgpetersenii reflects limited transmission potential , 2006, Proceedings of the National Academy of Sciences.

[10]  A. L. Nascimento,et al.  A Newly Identified Leptospiral Adhesin Mediates Attachment to Laminin , 2006, Infection and Immunity.

[11]  S. F. Goldstein,et al.  Genetics of motility and chemotaxis of a fascinating group of bacteria: the spirochetes. , 2002, Annual review of genetics.

[12]  R. Zuerner,et al.  Response of Leptospira interrogans to Physiologic Osmolarity: Relevance in Signaling the Environment-to-Host Transition , 2007, Infection and Immunity.

[13]  W. Degrave,et al.  Comparative Genomics of Two Leptospira interrogans Serovars Reveals Novel Insights into Physiology and Pathogenesis , 2004, Journal of bacteriology.

[14]  Guo-Ping Zhao,et al.  Cytotoxic activity and probable apoptotic effect of Sph2, a sphigomyelinase hemolysin from Leptospira interrogans strain Lai. , 2008, BMB reports.

[15]  R. Gómez,et al.  Evaluation of the Expression and Protective Potential of Leptospiral Sphingomyelinases , 2010, Current Microbiology.

[16]  I. Saint-Girons,et al.  Inactivation of the Spirochete recA Gene Results in a Mutant with Low Viability and Irregular Nucleoid Morphology , 2002, Journal of bacteriology.

[17]  I. Saint Girons,et al.  Construction and complementation of the first auxotrophic mutant in the spirochaete Leptospira meyeri. , 2003, Microbiology.

[18]  G. Pappas,et al.  The globalization of leptospirosis: worldwide incidence trends. , 2008, International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases.

[19]  E. Wagar,et al.  Leptospiral Outer Membrane Proteins OmpL1 and LipL41 Exhibit Synergistic Immunoprotection , 1999, Infection and Immunity.

[20]  M. Willig,et al.  Leptospirosis: a zoonotic disease of global importance. , 2003, The Lancet. Infectious diseases.

[21]  M. Fishbein,et al.  Lethal Infection of C3H/HeJ and C3H/SCID Mice with an Isolate of Leptospira interrogans Serovar Copenhageni , 2005, Infection and Immunity.

[22]  Yung-Fu Chang,et al.  Immunoprotection of Recombinant Leptospiral Immunoglobulin-Like Protein A against Leptospira interrogans Serovar Pomona Infection , 2006, Infection and Immunity.

[23]  P. Ho,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 , 2008, Infection and Immunity.

[24]  Haruo Watanabe,et al.  Molecular cloning and characterization of a novel leptospiral lipoprotein with OmpA domain. , 2003, FEMS microbiology letters.

[25]  A. L. Nascimento,et al.  A newly identified protein of Leptospira interrogans mediates binding to laminin. , 2009, Journal of medical microbiology.

[26]  A. Ko,et al.  Leptospira: the dawn of the molecular genetics era for an emerging zoonotic pathogen , 2009, Nature Reviews Microbiology.

[27]  I. Saint Girons,et al.  Isolation and Characterization of FecA- and FeoB-Mediated Iron Acquisition Systems of the Spirochete Leptospira biflexa by Random Insertional Mutagenesis , 2005, Journal of bacteriology.

[28]  R. Marchevsky,et al.  Experimental leptospirosis in marmoset monkeys (Callithrix jacchus): a new model for studies of severe pulmonary leptospirosis. , 2005, The American journal of tropical medicine and hygiene.

[29]  C. Médigue,et al.  Genome Sequence of the Saprophyte Leptospira biflexa Provides Insights into the Evolution of Leptospira and the Pathogenesis of Leptospirosis , 2008, PloS one.

[30]  K. Wannemuehler,et al.  Outbreak of leptospirosis among Adventure Race participants in Florida, 2005. , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[31]  W. Gaastra,et al.  Characterization of three putative Serpulina hyodysenteriae hemolysins. , 1994, Microbial pathogenesis.

[32]  J. Potts,et al.  The molecular basis of fibronectin‐mediated bacterial adherence to host cells , 2004, Molecular microbiology.

[33]  M. Chignard,et al.  Differential TLR Recognition of Leptospiral Lipid A and Lipopolysaccharide in Murine and Human Cells1 , 2005, The Journal of Immunology.

[34]  D. Haake Hamster Model of Leptospirosis , 2006, Current protocols in microbiology.

[35]  R. Gómez,et al.  Whole-genome analysis of Leptospira interrogans to identify potential vaccine candidates against leptospirosis. , 2005, FEMS microbiology letters.

[36]  S. Faine Virulence in leptospira. II. The growth in vivo of virulent Leptospira icterohaemorrhagiae. , 1957, British journal of experimental pathology.

[37]  Y. Sánchez,et al.  Osmolarity, a Key Environmental Signal Controlling Expression of Leptospiral Proteins LigA and LigB and the Extracellular Release of LigA , 2005, Infection and Immunity.

[38]  A. Steigerwalt,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. , 1999, International journal of systematic bacteriology.

[39]  A. Steigerwalt,et al.  Leptospira broomii sp. nov., isolated from humans with leptospirosis. , 2006, International journal of systematic and evolutionary microbiology.

[40]  I. Saint Girons,et al.  First evidence for gene replacement in Leptospira spp. Inactivation of L. biflexa flaB results in non‐motile mutants deficient in endoflagella , 2001, Molecular microbiology.

[41]  I. Perry The causes of diabetes: a non-geneocentric view , 1996, The Lancet.

[42]  A. Ko,et al.  The OmpA-Like Protein Loa22 Is Essential for Leptospiral Virulence , 2007, PLoS pathogens.

[43]  R. Gómez,et al.  Leptospiral TlyC is an extracellular matrix‐binding protein and does not present hemolysin activity , 2009, FEBS letters.

[44]  J. Timoney,et al.  Molecular Characterization of Thermoinduced Immunogenic Proteins Q1p42 and Hsp15 of Leptospira interrogans , 2001, Infection and Immunity.

[45]  L. Nicholson,et al.  A novel fibronectin type III module binding motif identified on C-terminus of Leptospira immunoglobulin-like protein, LigB. , 2009, Biochemical and biophysical research communications.

[46]  D. Haake,et al.  A Comprehensive Approach to Identification of Surface-Exposed, Outer Membrane-Spanning Proteins of Leptospira interrogans , 2009, PloS one.

[47]  M. Höök,et al.  MSCRAMM-mediated adherence of microorganisms to host tissues. , 1994, Annual review of microbiology.

[48]  R. Marchevsky,et al.  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. , 1998, Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie.

[49]  R. Zuerner,et al.  The Leptospiral Major Outer Membrane Protein LipL32 Is a Lipoprotein Expressed during Mammalian Infection , 2000, Infection and Immunity.

[50]  P. Zipfel,et al.  Leptospiral Endostatin-Like Protein A Is a Bacterial Cell Surface Receptor for Human Plasminogen , 2010, Infection and Immunity.

[51]  S Faine,et al.  A monoclonal antibody reacting with a determinant on leptospiral lipopolysaccharide protects guinea pigs against leptospirosis. , 1986, Journal of medical microbiology.

[52]  M. Reis,et al.  Pathogenic Leptospira species express surface‐exposed proteins belonging to the bacterial immunoglobulin superfamily , 2003, Molecular microbiology.

[53]  J. Whitelegge,et al.  Characterization of the Outer Membrane Proteome of Leptospira interrogans Expressed during Acute Lethal Infection , 2006, Infection and Immunity.

[54]  T. Kirkland,et al.  Toll-Like Receptor 4 Protects against Lethal Leptospira interrogans Serovar Icterohaemorrhagiae Infection and Contributes to In Vivo Control of Leptospiral Burden , 2006, Infection and Immunity.

[55]  M. Picardeau Conjugative Transfer between Escherichia coli and Leptospira spp. as a New Genetic Tool , 2007, Applied and Environmental Microbiology.

[56]  S. Egan,et al.  LipL32 Is an Extracellular Matrix-Interacting Protein of Leptospira spp. and Pseudoalteromonas tunicata , 2008, Infection and Immunity.

[57]  P. Bjorkman,et al.  Crystal structure of invasin: a bacterial integrin-binding protein. , 1999, Science.

[58]  S. Cordwell,et al.  Comparative Transcriptional and Translational Analysis of Leptospiral Outer Membrane Protein Expression in Response to Temperature , 2009, PLoS neglected tropical diseases.

[59]  M. Reis,et al.  The terminal portion of leptospiral immunoglobulin-like protein LigA confers protective immunity against lethal infection in the hamster model of leptospirosis. , 2007, Vaccine.

[60]  M. Prevost,et al.  Biofilm formation by saprophytic and pathogenic leptospires. , 2008, Microbiology.

[61]  A. Shriram,et al.  Leptospirosis: an emerging global public health problem , 2008, Journal of Biosciences.

[62]  M. Reis,et al.  Characterization of virulence of Leptospira isolates in a hamster model. , 2008, Vaccine.

[63]  N. Ahmed,et al.  Annals of Clinical Microbiology and , 2005 .

[64]  D. Ojcius,et al.  Replication or death: distinct fates of pathogenic Leptospira strain Lai within macrophages of human or mouse origin , 2010, Innate immunity.

[65]  M. Reis,et al.  Urban epidemic of severe leptospirosis in Brazil , 1999, The Lancet.

[66]  J. Sejvar,et al.  Leptospirosis in “Eco-Challenge” Athletes, Malaysian Borneo, 2000 , 2003, Emerging infectious diseases.

[67]  I. Saint Girons,et al.  Random Insertional Mutagenesis of Leptospira interrogans, the Agent of Leptospirosis, Using a mariner Transposon , 2005, Journal of bacteriology.

[68]  A. Danchin,et al.  Unique physiological and pathogenic features of Leptospira interrogans revealed by whole-genome sequencing , 2003, Nature.

[69]  P. Cumberland,et al.  Persistence of anti-leptospiral IgM, IgG and agglutinating antibodies in patients presenting with acute febrile illness in Barbados 1979–1989 , 2004, European Journal of Epidemiology.

[70]  D. Born,et al.  Mycobacterium marinum Infection of Adult Zebrafish Causes Caseating Granulomatous Tuberculosis and Is Moderated by Adaptive Immunity , 2006, Infection and Immunity.

[71]  C. Heuer,et al.  Sero-prevalence of leptospirosis in workers at a New Zealand slaughterhouse. , 2009, The New Zealand medical journal.

[72]  G. Baranton,et al.  Identification of a 36-kDa fibronectin-binding protein expressed by a virulent variant of Leptospira interrogans serovar icterohaemorrhagiae. , 2000, FEMS microbiology letters.

[73]  R. Goldstein,et al.  The Flagellar Cytoskeleton of the Spirochetes , 2006, Journal of Molecular Microbiology and Biotechnology.

[74]  N. Suttorp,et al.  A Severe Case of Leptospirosis Acquired During an Iron Man Contest , 2001, European Journal of Clinical Microbiology and Infectious Diseases.

[75]  M. Suchard,et al.  Leptospira interrogans Endostatin-Like Outer Membrane Proteins Bind Host Fibronectin, Laminin and Regulators of Complement , 2007, PloS one.

[76]  A. Aderem,et al.  Leptospiral lipopolysaccharide activates cells through a TLR2-dependent mechanism , 2001, Nature Immunology.

[77]  M. Sadkowska-Todys,et al.  Resurgence of field fever in a temperate country: an epidemic of leptospirosis among seasonal strawberry harvesters in Germany in 2007. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[78]  M. J. Kim,et al.  Identification and partial characterization of a novel hemolysin from Leptospira interrogans serovar lai. , 2000, Gene.

[79]  G. Trueba,et al.  Cell aggregation: a mechanism of pathogenic Leptospira to survive in fresh water. , 2004, International microbiology : the official journal of the Spanish Society for Microbiology.

[80]  B. Adler,et al.  Leptospira and Leptospirosis , 2001, Current Topics in Microbiology and Immunology.

[81]  G. V. van Eys,et al.  Presence of putative sphingomyelinase genes among members of the family Leptospiraceae , 1992, Infection and immunity.

[82]  J. McCurry Philippines struggles to recover from typhoons , 2009, The Lancet.

[83]  L. Nicholson,et al.  Repeated Domains of Leptospira Immunoglobulin-like Proteins Interact with Elastin and Tropoelastin* , 2009, The Journal of Biological Chemistry.

[84]  S. Yoshida,et al.  Leptospirosis in the Asia Pacific region , 2009, BMC infectious diseases.

[85]  B. Adler,et al.  The Role of Macrophages in the Protection of Mice Against Leptospirosis: In Vitro and In Vivo Studies , 1982, Pathology.

[86]  I. Saint Girons,et al.  Leptospira spp. possess a complete haem biosynthetic pathway and are able to use exogenous haem sources , 2003, Molecular microbiology.

[87]  M. Reis,et al.  Morphological alterations in the kidney of rats with natural and experimental Leptospira infection. , 2007, Journal of comparative pathology.

[88]  C. Woods,et al.  Outbreak of leptospirosis among triathlon participants and community residents in Springfield, Illinois, 1998. , 2002, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[89]  P. Glaser,et al.  The LE1 Bacteriophage Replicates as a Plasmid within Leptospira biflexa: Construction of an L. biflexa-Escherichia coli Shuttle Vector , 2000, Journal of bacteriology.

[90]  R. Raman,et al.  Calcium Binds to Leptospiral Immunoglobulin-like Protein, LigB, and Modulates Fibronectin Binding* , 2008, Journal of Biological Chemistry.

[91]  F. Merien,et al.  Quantitative PCR Assay To Evaluate Ampicillin, Ofloxacin, and Doxycycline for Treatment of Experimental Leptospirosis , 2002, Antimicrobial Agents and Chemotherapy.

[92]  Yung-Fu Chang,et al.  The C-terminal variable domain of LigB from Leptospira mediates binding to fibronectin , 2008, Journal of veterinary science.

[93]  J. Pfeifer,et al.  Streptococcus-Zebrafish Model of Bacterial Pathogenesis , 2002, Infection and Immunity.

[94]  Yuh-Ju Sun,et al.  Calcium Binds to LipL32, a Lipoprotein from Pathogenic Leptospira, and Modulates Fibronectin Binding* , 2009, The Journal of Biological Chemistry.

[95]  S. Park,et al.  Cytotoxic Activities of Leptospira interrogans Hemolysin SphH as a Pore-Forming Protein on Mammalian Cells , 2002, Infection and Immunity.

[96]  A. Ko,et al.  Genome-Wide Transposon Mutagenesis in Pathogenic Leptospira Species , 2008, Infection and Immunity.

[97]  D. Dean,et al.  Overview of the epidemiology, microbiology, and pathogenesis of Leptospira spp. in humans. , 2000, Microbes and infection.

[98]  J. Timoney,et al.  Host-Inducible Immunogenic Sphingomyelinase-Like Protein, Lk73.5, of Leptospira interrogans , 2004, Infection and Immunity.

[99]  Yung-Fu Chang,et al.  Immunogenicity and protective efficacy of recombinant Leptospira immunoglobulin-like protein B (rLigB) in a hamster challenge model. , 2009, Microbes and infection.

[100]  M. Picardeau,et al.  Genetic Manipulation of Leptospira biflexa , 2007, Current protocols in microbiology.

[101]  P. Zipfel,et al.  LfhA, a Novel Factor H-Binding Protein of Leptospira interrogans , 2006, Infection and Immunity.

[102]  Yung-Fu Chang,et al.  A domain of the Leptospira LigB contributes to high affinity binding of fibronectin. , 2007, Biochemical and biophysical research communications.

[103]  Yung-Fu Chang,et al.  Leptospirosis: pathogenesis, immunity, and diagnosis , 2007, Current opinion in infectious diseases.

[104]  D. Powell,et al.  Effects of Temperature on Gene Expression Patterns in Leptospira interrogans Serovar Lai as Assessed by Whole-Genome Microarrays , 2006, Infection and Immunity.

[105]  M. Reis,et al.  Targeted Mutagenesis in Pathogenic Leptospira Species: Disruption of the LigB Gene Does Not Affect Virulence in Animal Models of Leptospirosis , 2008, Infection and Immunity.

[106]  R. Pfuetzner,et al.  Crystal structure of enteropathogenic Escherichia coli intimin–receptor complex , 2000, Nature.

[107]  D. Alt,et al.  Use of a monovalent leptospiral vaccine to prevent renal colonization and urinary shedding in cattle exposed to Leptospira borgpetersenii serovar hardjo. , 2001, American journal of veterinary research.

[108]  Lisa M. D'Souza,et al.  Genome sequence of the Brown Norway rat yields insights into mammalian evolution , 2004, Nature.

[109]  David A. Haake,et al.  Leptospira interrogans Stably Infects Zebrafish Embryos, Altering Phagocyte Behavior and Homing to Specific Tissues , 2009, PLoS neglected tropical diseases.

[110]  M. Reis,et al.  Rattus norvegicus as a model for persistent renal colonization by pathogenic Leptospira interrogans. , 2008, Acta tropica.

[111]  D. Haake Spirochaetal lipoproteins and pathogenesis. , 2000, Microbiology.

[112]  G. Baranton,et al.  First isolation of bacteriophages for a spirochaete: potential genetic tools for Leptospira. , 1990, Research in microbiology.

[113]  C. Werts,et al.  TLR4- and TLR2-Mediated B Cell Responses Control the Clearance of the Bacterial Pathogen, Leptospira interrogans1 , 2009, The Journal of Immunology.

[114]  Melissa M. Kelley,et al.  Physiological Osmotic Induction of Leptospira interrogans Adhesion: LigA and LigB Bind Extracellular Matrix Proteins and Fibrinogen , 2007, Infection and Immunity.

[115]  J. Nally,et al.  Proteomic Analysis of Leptospira interrogans Shed in Urine of Chronically Infected Hosts , 2008, Infection and Immunity.

[116]  R. Bey,et al.  Copurification of Leptospira interrogans serovar pomona hemolysin and sphingomyelinase C , 1986, Infection and immunity.

[117]  Haruo Watanabe,et al.  Leptospiral immunoglobulin-like proteins elicit protective immunity. , 2004, Vaccine.

[118]  J. Nováková,et al.  Leptospira interrogans Binds to Human Cell Surface Receptors Including Proteoglycans , 2009, Infection and Immunity.

[119]  A. Ko,et al.  Major Surface Protein LipL32 Is Not Required for Either Acute or Chronic Infection with Leptospira interrogans , 2008, Infection and Immunity.

[120]  F. Vernel-Pauillac,et al.  Differential Cytokine Gene Expression According to Outcome in a Hamster Model of Leptospirosis , 2010, PLoS neglected tropical diseases.

[121]  B. Adler,et al.  Host immunological mechanisms in the resistance of mice to leptospiral infections , 1977, Infection and immunity.

[122]  R. Zuerner,et al.  Global Proteome Analysis of Leptospira interrogans , 2009, Journal of proteome research.

[123]  M. Fishbein,et al.  Alveolar septal deposition of immunoglobulin and complement parallels pulmonary hemorrhage in a guinea pig model of severe pulmonary leptospirosis. , 2004, The American journal of pathology.

[124]  A. L. Nascimento,et al.  Lsa63, a newly identified surface protein of Leptospira interrogans binds laminin and collagen IV. , 2010, The Journal of infection.

[125]  T. de Brito,et al.  Lsa21, a novel leptospiral protein binding adhesive matrix molecules and present during human infection , 2008, BMC Microbiology.