Skip to main content
SpringerLink
Log in

Overview of Leptospirosis

  • Chapter
  • First Online:
Neglected Tropical Diseases - South Asia

Part of the book series: Neglected Tropical Diseases ((NTD))

  • 663 Accesses

Abstract

Leptospirosis has re-emerged as serious public health problem that is no longer limited to those who work and live in a rural setting [1]. The migration of poverty-stricken individuals to urban settings, together with climate change, has resulted in dramatic increases in the incidence of leptospirosis worldwide [2], particularly in tropical and subtropical developing countries [3, 4]. Leptospirosis is caused by pathogenic Leptospira spp. that have been characterized into >300 serovars [5]. Urban leptospirosis is mainly spread by rats that have proved difficult if not impossible to control. Rural leptospirosis is equally difficult to control due to the plethora of animal reservoirs and transmission between wild and domestic animal hosts. To further complicate matters, clinical diagnosis of leptospirosis is difficult as the symptoms are similar to febrile illnesses caused by dengue, Zika, chikungunya, hantavirus, as well as viral hepatitis and malaria. Laboratory diagnosis is carried out using the WHO-recommended microagglutination test (MAT), yet this is not widely available and is usually limited to reference laboratories [6]. The MAT requires two serum samples taken during the acute and convalescent phase of the disease so it has limited application to patient management. Alternative, commercially available, diagnostic tests are typically based on whole-cell antigens (inactivated leptospires), and sensitivity and specificity during the acute phase are highly variable (28–71%) [7, 8]. Therefore, there is an urgent need for new diagnostic tests that are faster and able to detect the disease at an early stage and that may be performed in areas having limited laboratory capacity, allowing for the rapid initiation of treatment of the patient. Inactivated vaccines, known as bacterins, are highly effective against the target serovar, but they are poorly cross-protective against other serovars and can cause severe side effects, and few countries around the world have approved their use as human vaccines [9]. Severe leptospirosis is life-threatening and can manifest as acute kidney injury (AKI), the classic manifestation of Weil’s disease, and more recently as leptospirosis pulmonary haemorrhage syndrome (LPHS) [10]. The aim of this chapter is to provide an overview of human leptospirosis and its causative agent, the pathogenic Leptospira spp.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Picardeau M. Virulence of the zoonotic agent of leptospirosis: still terra incognita? Nat Rev Microbiol. 2017;15(5):297–307.

    Article  CAS  PubMed  Google Scholar 

  2. Bharti AR, Nally JE, Ricaldi JN, Matthias MA, Diaz MM, Lovett MA, et al. Leptospirosis: a zoonotic disease of global importance. Lancet Infect Dis. 2003;3(12):757–71.

    Article  PubMed  Google Scholar 

  3. Costa F, Hagan JE, Calcagno J, Kane M, Torgerson P, Martinez-Silveira MS, et al. Global morbidity and mortality of leptospirosis: a systematic review. PLoS Negl Trop Dis. 2015;9(9):e0003898.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Torgerson PR, Hagan JE, Costa F, Calcagno J, Kane M, Martinez-Silveira MS, et al. Global burden of leptospirosis: estimated in terms of disability adjusted life years. PLoS Negl Trop Dis. 2015;9(10):e0004122.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Levett PN. Systematics of leptospiraceae. Curr Top Microbiol Immunol. 2015;387:11–20.

    CAS  PubMed  Google Scholar 

  6. WHO, ILS. Human leptospirosis: guidance for diagnosis, surveillance and control. Malta: World Health Organization; 2003.

    Google Scholar 

  7. McBride AJ, Athanazio DA, Reis MG, Ko AI. Leptospirosis. Curr Opin Infect Dis. 2005;18(5):376–86.

    Article  PubMed  Google Scholar 

  8. Picardeau M, Bertherat E, Jancloes M, Skouloudis AN, Durski K, Hartskeerl RA. Rapid tests for diagnosis of leptospirosis: current tools and emerging technologies. Diagn Microbiol Infect Dis. 2014;78(1):1–8.

    Article  PubMed  Google Scholar 

  9. Dellagostin OA, Grassmann AA, Rizzi C, Schuch RA, Jorge S, Oliveira TL, et al. Reverse vaccinology: an approach for identifying leptospiral vaccine candidates. Int J Mol Sci. 2017;18(1)

    Google Scholar 

  10. Croda J, Neto AN, Brasil RA, Pagliari C, Nicodemo AC, Duarte MI. Leptospirosis pulmonary haemorrhage syndrome is associated with linear deposition of immunoglobulin and complement on the alveolar surface. Clin Microbiol Infect. 2010;16(6):593–9.

    Article  CAS  PubMed  Google Scholar 

  11. Gideon - Global Infectious Disease and Epidemiology Online Network [Internet]. GIDEON Informatics, Inc. 2017 [cited 14/07/2017]. Available from: www.gideononline.com.

  12. Faruque LI, Zaman RU, Gurley ES, Massung RF, Alamgir AS, Galloway RL, et al. Prevalence and clinical presentation of Rickettsia, Coxiella, Leptospira, Bartonella and Chikungunya virus infections among hospital-based febrile patients from December 2008 to November 2009 in Bangladesh. BMC Infect Dis. 2017;17(1):141.

    Article  PubMed  PubMed Central  Google Scholar 

  13. LaRocque RC, Breiman RF, Ari MD, Morey RE, Janan FA, Hayes JM, et al. Leptospirosis during dengue outbreak, Bangladesh. Emerg Infect Dis. 2005;11(5):766–9.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Swoboda P, Fuehrer HP, Ley B, Starzengruber P, Ley-Thriemer K, Jung M, et al. Evidence of a major reservoir of non-malarial febrile diseases in malaria-endemic regions of Bangladesh. Am J Trop Med Hyg. 2014;90(2):377–82.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Victoriano AF, Smythe LD, Gloriani-Barzaga N, Cavinta LL, Kasai T, Limpakarnjanarat K, et al. Leptospirosis in the Asia Pacific region. BMC Infect Dis. 2009;9:147.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Pappas G, Papadimitriou P, Siozopoulou V, Christou L, Akritidis N. The globalization of leptospirosis: worldwide incidence trends. Int J Infect Dis. 2008;12(4):351–7.

    Article  PubMed  Google Scholar 

  17. Kamath R, Swain S, Pattanshetty S, Nair NS. Studying risk factors associated with human leptospirosis. J Glob Infect Dis. 2014;6(1):3–9.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Patil DY, Dahake RV, Chowdhary AS, Deshmukh RA. Clinico-epidemiological observations of human leptospirosis from Mumbai, India. J Infect Public Health. 2017;10(2):247–8.

    Article  PubMed  Google Scholar 

  19. Maskey M, Shastri JS, Saraswathi K, Surpam R, Vaidya N. Leptospirosis in Mumbai: post-deluge outbreak 2005. Indian J Med Microbiol. 2006;24(4):337–8.

    Article  CAS  PubMed  Google Scholar 

  20. DebMandal M, Mandal S, Pal NK. Serologic evidence of human leptospirosis in and around Kolkata, India: a clinico-epidemiological study. Asian Pac J Trop Med. 2011;4(12):1001–6.

    Article  PubMed  Google Scholar 

  21. Sethi S, Sharma N, Kakkar N, Taneja J, Chatterjee SS, Banga SS, et al. Increasing trends of leptospirosis in northern India: a clinico-epidemiological study. PLoS Negl Trop Dis. 2010;4(1):e579.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Shivakumar S, Shareek PS. Diagnosis of leptospirosis utilizing modified Faine’s criteria. J Assoc Phys India. 2004;52:678–9.

    CAS  Google Scholar 

  23. Kumar SS. Indian guidelines for the diagnosis and management of human leptospirosis. In: Muruganathan M, editor. Medicine Update. 23. Tamil Nadu, India; 2013.

    Google Scholar 

  24. Angnani R, Pathak AA, Mishra M. Prevalence of leptospirosis in various risk groups. Indian J Med Microbiol. 2003;21(4):271–3.

    CAS  PubMed  Google Scholar 

  25. Vijayachari P, Sugunan AP, Singh SS, Mathur PP. Leptospirosis among the self-supporting convicts of Andaman Island during the 1920s--the first report on pulmonary haemorrhage in leptospirosis? Indian J Med Res. 2015;142(1):11–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lall C, Kumar KV, Raj RV, Vedhagiri K, Vijayachari P. Prevalence and diversity of leptospires in different ecological niches of urban and rural areas of south Andaman Island. Microbes Environ JSME. 2016;31(1):79–82.

    Article  Google Scholar 

  27. Sharma S, Vijayachari P, Sugunan AP, Natarajaseenivasan K, Sehgal SC. Seroprevalence of leptospirosis among high-risk population of Andaman Islands, India. Am J Trop Med Hyg. 2006;74(2):278–83.

    PubMed  Google Scholar 

  28. Dahal KP, Sharma S, Sherchand JB, Upadhyay BP, Bhatta DR. Detection of anti-Leptospira IgM antibody in serum samples of suspected patients visiting National Public Health Laboratory, Teku, Kathmandu. Int J Microbiol. 2016;2016:7286918.

    Google Scholar 

  29. Gautam M, Adhikary RP, Koirala P. Investigating the zoonotic risk of human leptospirosis among febrile patients in Nepal. Bhutan: South Asia Regional One Health Symposium; 2013.

    Google Scholar 

  30. Kandel N, Thakur GD, Andjaparidze A. Leptospirosis in Nepal. J Nepal Med Assoc. 2012;52(187):151–3.

    CAS  Google Scholar 

  31. Verma AK, Kumar A, Dhama K, Deb R, Rahal A. Mahima, et al. Leptospirosis-persistence of a dilemma: an overview with particular emphasis on trends and recent advances in vaccines and vaccination strategies. Pak J Biol Sci. 2012;15(20):954–63.

    Article  PubMed  Google Scholar 

  32. Ahmed IP. Serological studies on leptospirosis in Pakistan. J Pak Med Assoc. 1987;37(9):233–6.

    CAS  PubMed  Google Scholar 

  33. Saleem MH, Khan MS, Durrani AZ, Hassan A, Ijaz M, Ali MM. Leptospirosis: an emerging zoonosis in Pakistan. Pak J Zool. 2013;45(4):909–12.

    Google Scholar 

  34. Agampodi S, Peacock SJ, Thevanesam V. The potential emergence of leptospirosis in Sri Lanka. Lancet Infect Dis. 2009;9(9):524–6.

    Article  PubMed  Google Scholar 

  35. Bandara KK, Weerasekera M, Gunasekara CP, Ranasinghe N, Marasinghe C, Fernando N. Molecular characterisation and disease severity of leptospirosis in Sri Lanka. Mem Inst Oswaldo Cruz. 2015;110(4):485–91.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Agampodi SB, Dahanayaka NJ, Bandaranayaka AK, Perera M, Priyankara S, Weerawansa P, et al. Regional differences of leptospirosis in Sri Lanka: observations from a flood-associated outbreak in 2011. PLoS Negl Trop Dis. 2014;8(1):e2626.

    Google Scholar 

  37. Agampodi SB, Peacock SJ, Thevanesam V, Nugegoda DB, Smythe L, Thaipadungpanit J, et al. Leptospirosis outbreak in Sri Lanka in 2008: lessons for assessing the global burden of disease. Am J Trop Med Hyg. 2011;85(3):471–8.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Denipitiya DT, Chandrasekharan NV, Abeyewickreme W, Hartskeerl RA, Hapugoda MD. Identification of cattle, buffaloes and rodents as reservoir animals of Leptospira in the District of Gampaha, Sri Lanka. BMC Res Notes. 2017;10(1):134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Amarasekera J, Agampodi S, Kodituwakku M. Risk factors and reservoir species for leptospirosis in Sri Lanka. South Asia Regional One Health Symposium, Bhutan; 2013.

    Google Scholar 

  40. Brenner DJ, Kaufmann AF, Sulzer KR, Steigerwalt AG, Rogers FC, Weyant RS. 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. 1999;49(Pt 2):839–58.

    Article  CAS  PubMed  Google Scholar 

  41. Smythe L, Adler B, Hartskeerl RA, Galloway RL, Turenne CY, Levett PN, et al. Classification of Leptospira genomospecies 1, 3, 4 and 5 as Leptospira alstonii sp. nov., Leptospira vanthielii sp. nov., Leptospira terpstrae sp. nov. and Leptospira yanagawae sp. nov., respectively. Int J Syst Evol Microbiol. 2013;63(Pt 5):1859–62.

    Google Scholar 

  42. Yasuda PH, Steigerwalt AG, Sulzer KR, Kaufmann AF, Rogers F, Brenner DJ. Deoxyribonucleic acid relatedness between serogroups and serovars in the family Leptospiraceae with proposals for seven new Leptospira species. Int J Syst Evol Microbiol. 1987;37(4):407–15.

    Google Scholar 

  43. Faine S, Stallman ND. Amended descriptions of the genus Leptospira Noguchi 1917 and the species L. interrogans (Stimson 1907) Wenyon 1926 and L. biflexa (Wolbach and Binger 1914) Noguchi 1918. Int J Syst Evol Microbiol. 1982;32(4):461–3.

    Google Scholar 

  44. Ramadass P, Jarvis BD, Corner RJ, Penny D, Marshall RB. Genetic characterization of pathogenic Leptospira species by DNA hybridization. Int J Syst Bacteriol. 1992;42(2):215–9.

    Google Scholar 

  45. Slack AT, Khairani-Bejo S, Symonds ML, Dohnt MF, Galloway RL, Steigerwalt AG, et al. Leptospira kmetyi sp. nov., isolated from an environmental source in Malaysia. Int J Syst Evol Microbiol. 2009;59(Pt 4):705–8.

    Article  CAS  PubMed  Google Scholar 

  46. Bourhy P, Collet L, Brisse S, Picardeau M. Leptospira mayottensis sp. nov., a pathogenic species of the genus Leptospira isolated from humans. Int J Syst Evol Microbiol. 2014;64(Pt 12):4061–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Levett PN, Morey RE, Galloway RL, Steigerwalt AG. Leptospira broomii sp. nov., isolated from humans with leptospirosis. Int J Syst Evol Microbiol. 2006;56(Pt 3):671–3.

    Article  CAS  PubMed  Google Scholar 

  48. Perolat P, Chappel RJ, Adler B, Baranton G, Bulach DM, Billinghurst ML, et al. Leptospira fainei sp. nov., isolated from pigs in Australia. Int J Syst Bacteriol. 1998;48(Pt 3):851–8.

    Article  CAS  PubMed  Google Scholar 

  49. Matthias MA, Ricaldi JN, Cespedes M, Diaz MM, Galloway RL, Saito M, 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. 2008;2(4):e213.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Slack AT, Kalambaheti T, Symonds ML, Dohnt MF, Galloway RL, Steigerwalt AG, et al. Leptospira wolffii sp. nov., isolated from a human with suspected leptospirosis in Thailand. Int J Syst Evol Microbiol. 2008;58(Pt 10):2305–8.

    Article  CAS  PubMed  Google Scholar 

  51. Saito M, Villanueva SY, Kawamura Y, Iida K, Tomida J, Kanemaru T, et al. Leptospira idonii sp. nov., isolated from environmental water. Int J Syst Evol Microbiol. 2013;63(Pt 7):2457–62.

    Article  CAS  PubMed  Google Scholar 

  52. Adler B. Leptospira and Leptospirosis. In: Adler B, editor. Berlin: Springer; 2015.

    Google Scholar 

  53. Cameron CE. Leptospiral structure, physiology, and metabolism. Curr Top Microbiol Immunol. 2015;387:21–41.

    CAS  PubMed  Google Scholar 

  54. Grassmann AA, Kremer FS, Dos Santos JC, Souza JD, Pinto LDS, McBride AJA. Discovery of novel Leptospirosis vaccine candidates using reverse and structural vaccinology. Front Immunol. 2017;8:463.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Haake DA, Zuckert WR. The leptospiral outer membrane. Curr Top Microbiol Immunol. 2015;387:187–221.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Zeng L, Zhang Y, Zhu Y, Yin H, Zhuang X, Zhu W, et al. Extracellular proteome analysis of Leptospira interrogans serovar Lai. Omics. 2013;17(10):527–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Amamura TA, Fraga TR, Vasconcellos SA, Barbosa AS, Isaac L. Pathogenic Leptospira secreted proteases target the membrane attack complex: a potential role for thermolysin in complement inhibition. Front Microbiol. 2017;8:958.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Eshghi A, Pappalardo E, Hester S, Thomas B, Pretre G, Picardeau M. Pathogenic Leptospira interrogans exoproteins are primarily involved in heterotrophic processes. Infect Immun. 2015;83(8):3061–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zuerner RL. Laboratory maintenance of pathogenic Leptospira. Curr Protoc Microbiol. 2005;Chap 12:Unit 12E.1.

    Google Scholar 

  60. Fouts DE, Matthias MA, Adhikarla H, Adler B, Amorim-Santos L, Berg DE, et al. What makes a bacterial species pathogenic?: comparative genomic analysis of the genus Leptospira. PLoS Negl Trop Dis. 2016;10(2):e0004403.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Johnson RC, Harris VG. Differentiation of pathogenic and saprophytic letospires. I. Growth at low temperatures. J Bacteriol. 1967;94(1):27–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Haake DA. Hamster model of leptospirosis. Curr Protoc Microbiol. 2006;Chap 12:Unit 12E 2.

    Google Scholar 

  63. Nascimento AL, Ko AI, Martins EA, Monteiro-Vitorello CB, Ho PL, Haake DA, et al. Comparative genomics of two Leptospira interrogans serovars reveals novel insights into physiology and pathogenesis. J Bacteriol. 2004;186(7):2164–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Wang Y, Zhuang X, Zhong Y, Zhang C, Zhang Y, Zeng L, et al. Distribution of plasmids in distinct Leptospira pathogenic species. PLoS Negl Trop Dis. 2015;9(11):e0004220.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Zhukova A, Fernandes LG, Hugon P, Pappas CJ, Sismeiro O, Coppee JY, et al. Genome-wide transcriptional start site mapping and sRNA identification in the pathogen Leptospira interrogans. Front Cell Infect Microbiol. 2017;7:10.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Caimano MJ, Sivasankaran SK, Allard A, Hurley D, Hokamp K, Grassmann AA, et al. A model system for studying the transcriptomic and physiological changes associated with mammalian host-adaptation by Leptospira interrogans serovar Copenhageni. PLoS Pathog. 2014;10(3):e1004004.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Lo M, Bulach DM, Powell DR, Haake DA, Matsunaga J, Paustian ML, et al. Effects of temperature on gene expression patterns in Leptospira interrogans serovar Lai as assessed by whole-genome microarrays. Infect Immun. 2006;74(10):5848–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Xue F, Dong H, Wu J, Wu Z, Hu W, Sun A, et al. Transcriptional responses of Leptospira interrogans to host innate immunity: significant changes in metabolism, oxygen tolerance, and outer membrane. PLoS Negl Trop Dis. 2010;4(10):e857.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Qin JH, Sheng YY, Zhang ZM, Shi YZ, He P, Hu BY, et al. Genome-wide transcriptional analysis of temperature shift in L. interrogans serovar lai strain 56601. BMC Microbiol. 2006;6:51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Lo M, Cordwell SJ, Bulach DM, Adler B. Comparative transcriptional and translational analysis of leptospiral outer membrane protein expression in response to temperature. PLoS Negl Trop Dis. 2009;3(12):e560.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Malmstrom J, Beck M, Schmidt A, Lange V, Deutsch EW, Aebersold R. Proteome-wide cellular protein concentrations of the human pathogen Leptospira interrogans. Nature. 2009;460(7256):762–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Nally JE, Timoney JF, Stevenson B. Temperature-regulated protein synthesis by Leptospira interrogans. Infect Immun. 2001;69(1):400–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Eshghi A, Cullen PA, Cowen L, Zuerner RL, Cameron CE. Global proteome analysis of Leptospira interrogans. J Proteome Res. 2009;8(10):4564–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Matsunaga J, Sanchez Y, Xu X, Haake DA. Osmolarity, a key environmental signal controlling expression of leptospiral proteins LigA and LigB and the extracellular release of LigA. Infect Immun. 2005;73(1):70–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Matsunaga J, Schlax PJ, Haake DA. Role for cis-acting RNA sequences in the temperature-dependent expression of the multiadhesive lig proteins in Leptospira interrogans. J Bacteriol. 2013;195(22):5092–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Eshghi A, Pinne M, Haake DA, Zuerner RL, Frank A, Cameron CE. Methylation and in vivo expression of the surface-exposed Leptospira interrogans outer-membrane protein OmpL32. Microbiology. 2012;158(Pt 3):622–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Cao XJ, Dai J, Xu H, Nie S, Chang X, Hu BY, et al. High-coverage proteome analysis reveals the first insight of protein modification systems in the pathogenic spirochete Leptospira interrogans. Cell Res. 2010;20(2):197–210.

    Article  CAS  PubMed  Google Scholar 

  78. Ricaldi JN, Matthias MA, Vinetz JM, Lewis AL. Expression of sialic acids and other nonulosonic acids in Leptospira. BMC Microbiol. 2012;12:161.

    Article  CAS  PubMed  Google Scholar 

  79. Trueba G, Zapata S, Madrid K, Cullen P, Haake D. Cell aggregation: a mechanism of pathogenic Leptospira to survive in fresh water. Int Microbiol. 2004;7(1):35–40.

    PubMed  Google Scholar 

  80. Andre-Fontaine G, Aviat F, Thorin C. Waterborne Leptospirosis: survival and preservation of the virulence of pathogenic Leptospira spp. in fresh water. Curr Microbiol. 2015;71(1):136–42.

    Article  CAS  PubMed  Google Scholar 

  81. Mwachui MA, Crump L, Hartskeerl R, Zinsstag J, Hattendorf J. Environmental and behavioural determinants of Leptospirosis transmission: a systematic review. PLoS Negl Trop Dis. 2015;9(9):e0003843.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Haake DA, Levett PN. Leptospirosis in humans. Curr Top Microbiol Immunol. 2015;387:65–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Segura ER, Ganoza CA, Campos K, Ricaldi JN, Torres S, Silva H, et al. Clinical spectrum of pulmonary involvement in leptospirosis in a region of endemicity, with quantification of leptospiral burden. Clin Infect Dis. 2005;40(3):343–51.

    Article  PubMed  PubMed Central  Google Scholar 

  84. 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. 2001;204(2):317–21.

    Article  CAS  PubMed  Google Scholar 

  85. Fernandes LG, Siqueira GH, Teixeira AR, Silva LP, Figueredo JM, Cosate MR, et al. Leptospira spp.: novel insights into host-pathogen interactions. Vet Immunol Immunopathol. 2016;176:50–7.

    Article  CAS  PubMed  Google Scholar 

  86. 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. 2005;187(9):3255–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Murray GL, Srikram A, Hoke DE, Wunder EA Jr, Henry R, Lo M, et al. Major surface protein LipL32 is not required for either acute or chronic infection with Leptospira interrogans. Infect Immun. 2009;77(3):952–958.

    Google Scholar 

  88. Croda J, Figueira CP, Wunder EA, Jr., Santos CS, Reis MG, Ko AI, et al. Targeted mutagenesis in pathogenic Leptospira species: disruption of the LigB gene does not affect virulence in animal models of leptospirosis. Infect Immun. 2008;76(12):5826–5833.

    Google Scholar 

  89. Zhang L, Zhang C, Ojcius DM, Sun D, Zhao J, Lin X, 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. 2012;83(5):1006–23.

    Article  CAS  PubMed  Google Scholar 

  90. Kassegne K, Hu W, Ojcius DM, Sun D, Ge Y, Zhao J, et al. Identification of collagenase as a critical virulence factor for invasiveness and transmission of pathogenic Leptospira species. J Infect Dis. 2014;209(7):1105–15.

    Article  CAS  PubMed  Google Scholar 

  91. Liao S, Sun A, Ojcius DM, Wu S, Zhao J, Yan J. Inactivation of the fliY gene encoding a flagellar motor switch protein attenuates mobility and virulence of Leptospira interrogans strain Lai. BMC Microbiol. 2009;9:253.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Ristow P, Bourhy P, da Cruz McBride FW, Figueira CP, Huerre M, Ave P, et al. The OmpA-like protein Loa22 is essential for leptospiral virulence. PLoS Pathog. 2007;3(7):e97.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Murray GL, Srikram A, Henry R, Hartskeerl RA, Sermswan RW, Adler B. Mutations affecting Leptospira interrogans lipopolysaccharide attenuate virulence. Mol Microbiol. 2010;78(3):701–9.

    Article  CAS  PubMed  Google Scholar 

  94. Lambert A, Picardeau M, Haake DA, Sermswan RW, Srikram A, Adler B, 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. 2012;80(6):2019–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Fontana C, Lambert A, Benaroudj N, Gasparini D, Gorgette O, Cachet N, et al. Analysis of a spontaneous non-motile and avirulent mutant shows that FliM is required for full endoflagella assembly in Leptospira interrogans. PLoS One. 2016;11(4):e0152916.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Wunder EA, Jr., Figueira CP, Benaroudj N, Hu B, Tong BA, Trajtenberg F, et al. A novel flagellar sheath protein, FcpA, determines filament coiling, translational motility and virulence for the Leptospira spirochete. Mol Microbiol. 2016;101(3):457-470.

    Google Scholar 

  97. Murray GL, Srikram A, Henry R, Puapairoj A, Sermswan RW, Adler B. Leptospira interrogans requires heme oxygenase for disease pathogenesis. Microbes Infect. 2009;11(2):311–4.

    Article  CAS  PubMed  Google Scholar 

  98. Lourdault K, Cerqueira GM, Wunder EA, Jr., Picardeau M. Inactivation of clpB in the pathogen Leptospira interrogans reduces virulence and resistance to stress conditions. Infect Immun. 2011;79(9):3711-3717.

    Google Scholar 

  99. King AM, Pretre G, Bartpho T, Sermswan RW, Toma C, Suzuki T, et al. High-temperature protein G is an essential virulence factor of Leptospira interrogans. Infect Immun. 2014;82(3):1123–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Zhang K, Murray GL, Seemann T, Srikram A, Bartpho T, Sermswan RW, et al. Leptospiral LruA is required for virulence and modulates an interaction with mammalian apolipoprotein AI. Infect Immun. 2013;81(10):3872–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Eshghi A, Lourdault K, Murray GL, Bartpho T, Sermswan RW, Picardeau M, et al. Leptospira interrogans catalase is required for resistance to H2O2 and for virulence. Infect Immun. 2012;80(11):3892–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. King AM, Bartpho T, Sermswan RW, Bulach DM, Eshghi A, Picardeau M, et al. Leptospiral outer membrane protein LipL41 is not essential for acute leptospirosis but requires a small chaperone protein, lep, for stable expression. Infect Immun. 2013;81(8):2768–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Murray GL. The molecular basis of leptospiral pathogenesis. Curr Top Microbiol Immunol. 2015;387:139–85.

    CAS  PubMed  Google Scholar 

  104. Xue F, Zhao X, Yang Y, Zhao J, Yang Y, Cao Y, et al. Responses of murine and human macrophages to leptospiral infection: a study using comparative array analysis. PLoS Negl Trop Dis. 2013;7(10):e2477.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Toma C, Murray GL, Nohara T, Mizuyama M, Koizumi N, Adler B, et al. Leptospiral outer membrane protein LMB216 is involved in enhancement of phagocytic uptake by macrophages. Cell Microbiol. 2014;16(9):1366–77.

    Article  CAS  PubMed  Google Scholar 

  106. Scharrig E, Carestia A, Ferrer MF, Cedola M, Pretre G, Drut R, et al. Neutrophil extracellular traps are involved in the innate immune response to infection with Leptospira. PLoS Negl Trop Dis. 2015;9(7):e0003927.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Chassin C, Picardeau M, Goujon JM, Bourhy P, Quellard N, Darche S, et al. TLR4- and TLR2-mediated B cell responses control the clearance of the bacterial pathogen, Leptospira interrogans. J Immunol. 2009;

    Google Scholar 

  108. Viriyakosol S, Matthias MA, Swancutt MA, Kirkland TN, Vinetz JM. Toll-like receptor 4 protects against lethal Leptospira interrogans serovar icterohaemorrhagiae infection and contributes to in vivo control of leptospiral burden. Infect Immun. 2006;74(2):887–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Castiblanco-Valencia MM, Fraga TR, Breda LC, Vasconcellos SA, Figueira CP, Picardeau 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. 2016;173:61–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Fraga TR, Courrol Ddos S, Castiblanco-Valencia MM, Hirata IY, Vasconcellos SA, Juliano L, et al. Immune evasion by pathogenic Leptospira strains: the secretion of proteases that directly cleave complement proteins. J Infect Dis. 2014;209(6):876–86.

    Article  CAS  PubMed  Google Scholar 

  111. Kyriakidis I, Samara P, Papa A. Serum TNF-alpha, sTNFR1, IL-6, IL-8 and IL-10 levels in Weil’s syndrome. Cytokine. 2011;

    Google Scholar 

  112. Reis EA, Hagan JE, Ribeiro GS, Teixeira-Carvalho A, Martins-Filho OA, Montgomery RR, et al. Cytokine response signatures in disease progression and development of severe clinical outcomes for leptospirosis. PLoS Negl Trop Dis. 2013;7(9):e2457.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Mikulski M, Boisier P, Lacassin F, Soupe-Gilbert ME, Mauron C, Bruyere-Ostells L, et al. Severity markers in severe leptospirosis: a cohort study. Eur J Clin Microbiol Infect Dis. 2015;34(4):687–95.

    Article  CAS  PubMed  Google Scholar 

  114. Adler B, Faine S. Susceptibility of mice treated with cyclophosphamide to lethal infection with Leptospira interrogans Serovar pomona. Infect Immun. 1976;14(3):703–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Lessa-Aquino C, Lindow JC, Randall A, Wunder E, Pablo J, Nakajima R, et al. Distinct antibody responses of patients with mild and severe leptospirosis determined by whole proteome microarray analysis. PLoS Negl Trop Dis. 2017;11(1):e0005349.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Adler B, Faine S. Host immunological mechanisms in the resistance of mice to leptospiral infections. Infect Immun. 1977;17(1):67–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Jost BH, Adler B, Vinh T, Faine S. A monoclonal antibody reacting with a determinant on leptospiral lipopolysaccharide protects guinea pigs against leptospirosis. J Med Microbiol. 1986;22(3):269–75.

    Article  CAS  PubMed  Google Scholar 

  118. Jost BH, Adler B, Faine S. Experimental immunisation of hamsters with lipopolysaccharide antigens of Leptospira interrogans. J Med Microbiol. 1989;29(2):115–20.

    Article  CAS  PubMed  Google Scholar 

  119. Sonrier C, Branger C, Michel V, Ruvoen-Clouet N, Ganiere JP, Andre-Fontaine G. Evidence of cross-protection within Leptospira interrogans in an experimental model. Vaccine. 2000;19(1):86–94.

    Article  CAS  PubMed  Google Scholar 

  120. Srikram A, Zhang K, Bartpho T, Lo M, Hoke DE, Sermswan RW, et al. Cross-protective immunity against leptospirosis elicited by a live, attenuated lipopolysaccharide mutant. J Infect Dis. 2011;203(6):870–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. WHO. Leptospirosis: an emerging public health problem. Wkly Epidemiol Rec. 2011;86(6):45–50.

    Google Scholar 

  122. Yang CW, Hung CC, Wu MS, Tian YC, Chang CT, Pan MJ, et al. Toll-like receptor 2 mediates early inflammation by leptospiral outer membrane proteins in proximal tubule cells. Kidney Int. 2006;69(5):815–22.

    Article  CAS  PubMed  Google Scholar 

  123. Visith S, Kearkiat P. Nephropathy in leptospirosis. J Postgrad Med. 2005;51(3):184–8.

    CAS  PubMed  Google Scholar 

  124. Seguro AC, Andrade L. Pathophysiology of leptospirosis. Shock. 2013;39(Suppl 1):17–23.

    Article  CAS  PubMed  Google Scholar 

  125. Daher Ede F, Zanetta DM, Abdulkader RC. Pattern of renal function recovery after leptospirosis acute renal failure. Nephron Clin Pract. 2004;98(1):c8–14.

    Article  PubMed  Google Scholar 

  126. Dolhnikoff M, Mauad T, Bethlem EP, Carvalho CR. Pathology and pathophysiology of pulmonary manifestations in leptospirosis. Braz J Infect Dis. 2007;11(1):142–8.

    Article  PubMed  Google Scholar 

  127. Gulati S, Gulati A. Pulmonary manifestations of leptospirosis. Lung India. 2012;29(4):347–53.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Gouveia EL, Metcalfe J, de Carvalho AL, Aires TS, Villasboas-Bisneto JC, Queirroz A, et al. Leptospirosis-associated severe pulmonary hemorrhagic syndrome, Salvador, Brazil. Emerg Infect Dis. 2008;14(3):505–8.

    Article  PubMed  PubMed Central  Google Scholar 

  129. De Brito T, Aiello VD, da Silva LF, Goncalves da Silva AM, Ferreira da Silva WL, Castelli JB, et al. Human hemorrhagic pulmonary leptospirosis: pathological findings and pathophysiological correlations. PLoS One. 2013;8(8):e71743.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Panicker JN, Mammachan R, Jayakumar RV. Primary neuroleptospirosis. Postgrad Med J. 2001;77(911):589–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Puca E, Majko J, Puca E, Qyra E, Gega A, Pipero P. Acute encephalitis as initial presentation of leptospirosis. J Infect Dev Ctries. 2017;11(4):361–3.

    Article  PubMed  Google Scholar 

  132. Shah K, Amonkar GP, Kamat RN, Deshpande JR. Cardiac findings in leptospirosis. J Clin Pathol. 2010;63(2):119–23.

    Article  PubMed  Google Scholar 

  133. Shukla D, Rathinam SR, Cunningham ET Jr. Leptospiral uveitis in the developing world. Int Ophthalmol Clin. 2010;50(2):113–24.

    Article  PubMed  Google Scholar 

  134. De Silva NL, Niloofa M, Fernando N, Karunanayake L, Rodrigo C, De Silva HJ, et al. Changes in full blood count parameters in leptospirosis: a prospective study. Int Arch Med. 2014;7:31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Miyahara S, Saito M, Kanemaru T, Villanueva SY, Gloriani NG, Yoshida SI. Destruction of the hepatocyte junction by intercellular invasion of Leptospira causes jaundice in a hamster model of Weil’s disease. Int J Exp Pathol. 2014;95(4):271–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Andrade L, Rodrigues AC Jr, Sanches TR, Souza RB, Seguro AC. Leptospirosis leads to dysregulation of sodium transporters in the kidney and lung. Am J Physiol Renal Physiol. 2007;292(2):F586–92.

    Article  CAS  PubMed  Google Scholar 

  137. Goris M, Leeflang M, Boer K, Goeijenbier M, van Gorp E, Wagenaar J, et al. Establishment of valid laboratory case definition for human leptospirosis. J Bacteriol Parasitol. 2011;3(2).

    Google Scholar 

  138. Ahmed A, Engelberts MF, Boer KR, Ahmed N, Hartskeerl RA. Development and validation of a real-time PCR for detection of pathogenic leptospira species in clinical materials. PLoS One. 2009;4(9):e7093.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Desvars A, Gigan J, Hoarau G, Gerardin P, Favier F, Michault A. Short report: Seroprevalence of human leptospirosis in Reunion Island (Indian Ocean) assessed by microscopic agglutination test on paper disc-absorbed whole blood. Am J Trop Med Hyg. 2011;85(6):1097–9.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Bourhy P, Bremont S, Zinini F, Giry C, Picardeau M. Comparison of real-time PCR assays for detection of pathogenic Leptospira spp. in blood and identification of variations in target sequences. J Clin Microbiol. 2011;49(6):2154–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Denipitiya DT, Chandrasekharan NV, Abeyewickreme W, Hartskeerl CM, Hartskeerl RA, Jiffrey AM, et al. Application of a real time polymerase chain reaction (PCR) assay for the early diagnosis of human leptospirosis in Sri Lanka. Biologicals. 2016;

    Google Scholar 

  142. Stoddard RA. Detection of pathogenic Leptospira spp. through real-time PCR (qPCR) targeting the LipL32 gene. Methods Mol Biol. 2013;943:257–66.

    Article  CAS  PubMed  Google Scholar 

  143. Agampodi SB, Moreno AC, Vinetz JM, Matthias MA. Utility and limitations of direct multi-locus sequence typing on qPCR-positive blood to determine infecting Leptospira strain. Am J Trop Med Hyg. 2013;88(1):184–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Ahmed SA, Sandai DA, Musa S, Hoe CH, Riadzi M, Lau KL, et al. Rapid diagnosis of leptospirosis by multiplex PCR. Malay J Med Sci. 2012;19(3):9–16.

    Google Scholar 

  145. Pelaez Sanchez RG, Quintero JAL, Pereira MM, Agudelo-Florez P. High-resolution melting curve analysis of the 16S ribosomal gene to detect and identify pathogenic and saprophytic Leptospira species in Colombian isolates. Am J Trop Med Hyg. 2017;96(5):1031–8.

    Article  PubMed  Google Scholar 

  146. Naze F, Desvars A, Picardeau M, Bourhy P, Michault A. Use of a new high resolution melting method for genotyping pathogenic Leptospira spp. PLoS One. 2015;10(7):e0127430.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Tulsiani SM, Craig SB, Graham GC, Cobbold RC, Dohnt MF, Burns MA, et al. High-resolution melt-curve analysis of random amplified polymorphic DNA (RAPD-HRM) for the characterisation of pathogenic leptospires: intra-serovar divergence, inter-serovar convergence, and evidence of attenuation in Leptospira reference collections. Ann Trop Med Parasitol. 2010;104(5):427–37.

    Article  CAS  PubMed  Google Scholar 

  148. Sengupta M, Prabhakar AK, Satyendra S, Thambu D, Abraham OC, Balaji V, et al. Utility of Loop-mediated isothermal amplification assay, polymerase chain reaction, and ELISA for diagnosis of Leptospirosis in South Indian patients. J Glob Infect Dis. 2017;9(1):3–7.

    Article  PubMed  PubMed Central  Google Scholar 

  149. Lin X, Chen Y, Lu Y, Yan J. Application of a loop-mediated isothermal amplification method for the detection of pathogenic Leptospira. Diagn Microbiol Infect Dis. 2009;63(3):237–42.

    Article  CAS  PubMed  Google Scholar 

  150. Sonthayanon P, Chierakul W, Wuthiekanun V, Thaipadungpanit J, Kalambaheti T, Boonsilp S, et al. Accuracy of loop-mediated isothermal amplification for diagnosis of human leptospirosis in Thailand. Am J Trop Med Hyg. 2011;84(4):614–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Chandy S, Kirubanandhan L, Hemavathy P, Khadeeja AM, Kurian SJ, Venkataraman K, et al. Serovar prevalence of Leptospira in semirural India and the development of an IgM-based indirect ELISA. J Infect Dev Ctries. 2017;11(3):234–41.

    Article  PubMed  Google Scholar 

  152. Niloofa R, Fernando N, de Silva NL, Karunanayake L, Wickramasinghe H, Dikmadugoda N, et al. Diagnosis of Leptospirosis: comparison between microscopic agglutination test, IgM-ELISA and IgM rapid immunochromatography test. PLoS One. 2015;10(6):e0129236.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Vedhagiri K, Velineni S, Timoney JF, Shanmughapriya S, Vijayachari P, Narayanan R, et al. Detection of LipL32-specific IgM by ELISA in sera of patients with a clinical diagnosis of leptospirosis. Pathog Glob Health. 2013;107(3):130–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Natarajaseenivasan K, Vijayachari P, Sharma S, Sugunan AP, Selvin J, Sehgal SC. Serodiagnosis of severe leptospirosis: evaluation of ELISA based on the recombinant OmpL1 or LipL41 antigens of Leptospira interrogans serovar autumnalis. Ann Trop Med Parasitol. 2008;102(8):699–708.

    Article  CAS  PubMed  Google Scholar 

  155. Suputtamongkol Y, Pongtavornpinyo W, Lubell Y, Suttinont C, Hoontrakul S, Phimda K, et al. Strategies for diagnosis and treatment of suspected leptospirosis: a cost-benefit analysis. PLoS Negl Trop Dis. 2010;4(2):e610.

    Article  PubMed  PubMed Central  Google Scholar 

  156. Goarant C, Bourhy P, D’Ortenzio E, Dartevelle S, Mauron C, Soupe-Gilbert ME, et al. Sensitivity and specificity of a new vertical flow rapid diagnostic test for the serodiagnosis of human leptospirosis. PLoS Negl Trop Dis. 2013;7(6):e2289.

    Article  PubMed  PubMed Central  Google Scholar 

  157. Bryceson AD. Clinical pathology of the Jarisch-Herxheimer reaction. J Infect Dis. 1976;133(6):696–704.

    Article  CAS  PubMed  Google Scholar 

  158. Guerrier G, D’Ortenzio E. The Jarisch-Herxheimer reaction in leptospirosis: a systematic review. PLoS One. 2013;8(3):e59266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Vaughan C, Cronin CC, Walsh EK, Whelton M. The Jarisch-Herxheimer reaction in leptospirosis. Postgrad Med J. 1994;70(820):118–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Fekade D, Knox K, Hussein K, Melka A, Lalloo DG, Coxon RE, et al. Prevention of Jarisch-Herxheimer reactions by treatment with antibodies against tumor necrosis factor alpha. N Engl J Med. 1996;335(5):311–5.

    Article  CAS  PubMed  Google Scholar 

  161. Schulze MH, Raschel H, Langen HJ, Stich A, Tappe D. Severe Leptospira interrogans serovar Icterohaemorrhagiae infection with hepato-renal-pulmonary involvement treated with corticosteroids. Clin Case Rep. 2014;2(5):191–6.

    Article  PubMed  PubMed Central  Google Scholar 

  162. Abdulkader RC, Seguro AC, Malheiro PS, Burdmann EA, Marcondes M. Peculiar electrolytic and hormonal abnormalities in acute renal failure due to leptospirosis. Am J Trop Med Hyg. 1996;54(1):1–6.

    Article  CAS  PubMed  Google Scholar 

  163. Seguro AC, Lomar AV, Rocha AS. Acute renal failure of leptospirosis: nonoliguric and hypokalemic forms. Nephron. 1990;55(2):146–51.

    Article  CAS  PubMed  Google Scholar 

  164. Andrade L, de Francesco DE, Seguro AC. Leptospiral nephropathy. Semin Nephrol. 2008;28(4):383–94.

    Article  CAS  PubMed  Google Scholar 

  165. Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi-Filho G, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med. 1998;338(6):347–54.

    Article  CAS  PubMed  Google Scholar 

  166. Costa F, Wunder EA Jr, De Oliveira D, Bisht V, Rodrigues G, Reis MG, et al. Patterns in Leptospira shedding in Norway rats (Rattus norvegicus) from Brazilian slum communities at high risk of disease transmission. PLoS Negl Trop Dis. 2015;9(6):e0003819.

    Article  PubMed  PubMed Central  Google Scholar 

  167. Martins G, Lilenbaum W. Control of bovine leptospirosis: aspects for consideration in a tropical environment. Res Vet Sci. 2017;112:156–60.

    Article  CAS  PubMed  Google Scholar 

  168. Costa F, Ribeiro GS, Felzemburgh RD, Santos N, Reis RB, Santos AC, et al. Influence of household rat infestation on Leptospira transmission in the urban slum environment. PLoS Negl Trop Dis. 2014;8(12):e3338.

    Article  PubMed  PubMed Central  Google Scholar 

  169. Reis RB, Ribeiro GS, Felzemburgh RD, Santana FS, Mohr S, Melendez AX, et al. Impact of environment and social gradient on Leptospira infection in urban slums. PLoS Negl Trop Dis. 2008;2(4):e228.

    Article  PubMed  PubMed Central  Google Scholar 

  170. Felzemburgh RD, Ribeiro GS, Costa F, Reis RB, Hagan JE, Melendez AX, et al. Prospective study of leptospirosis transmission in an urban slum community: role of poor environment in repeated exposures to the Leptospira agent. PLoS Negl Trop Dis. 2014;8(5):e2927.

    Article  PubMed  PubMed Central  Google Scholar 

  171. Hartskeerl RA, Collares-Pereira M, Ellis WA. Emergence, control and re-emerging leptospirosis: dynamics of infection in the changing world. Clin Microbiol Infect. 2011;17(4):494–501.

    Article  CAS  PubMed  Google Scholar 

  172. Faine SB, Adler B, Bolin C, Perolat P. Leptospira and leptospirosis. 2nd ed. MediSci: Melbourne; 1999.

    Google Scholar 

  173. Sehgal SC, Sugunan AP, Murhekar MV, Sharma S, Vijayachari P. Randomized controlled trial of doxycycline prophylaxis against leptospirosis in an endemic area. Int J Antimicrob Agents. 2000;13(4):249–55.

    Article  CAS  PubMed  Google Scholar 

  174. Takafuji ET, Kirkpatrick JW, Miller RN, Karwacki JJ, Kelley PW, Gray MR, et al. An efficacy trial of doxycycline chemoprophylaxis against leptospirosis. N Engl J Med. 1984;310(8):497–500.

    Article  CAS  PubMed  Google Scholar 

  175. Schneider MC, Velasco-Hernandez J, Min KD, Leonel DG, Baca-Carrasco D, Gompper ME, et al. The use of chemoprophylaxis after floods to reduce the occurrence and impact of leptospirosis outbreaks. Int J Environ Res Public Health. 2017;14(6).

    Google Scholar 

  176. Adler B. Vaccines against leptospirosis. Curr Top Microbiol Immunol. 2015;387:251–72.

    CAS  PubMed  Google Scholar 

  177. Ido Y, Hoki R, Ito H, Wani H. The prophylaxis of Weil’s disease (Spirochaetosis Icterohaemorrhagica). J Exp Med. 1916;24(5):471–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Chen T. Development and present status of a leptospiral vaccine and the technology of vaccine production in China. Nihon Saikingaku Zasshi. 1985;40(4):755–62.

    Article  CAS  PubMed  Google Scholar 

  179. Martinez Sanchez R, Perez Sierra A, Baro Suarez M, Alvarez AM, Menendez Hernandez J, Diaz Gonzalez M, et al. Evaluation of the effectiveness of a new vaccine against human leptospirosis in groups at risk. Rev Panam Salud Publica. 2000;8(6):385–92.

    Article  CAS  PubMed  Google Scholar 

  180. Yanagihara Y, Villanueva SY, Yoshida S, Okamoto Y, Masuzawa T. Current status of leptospirosis in Japan and Philippines. Comp Immunol Microbiol Infect Dis. 2007;30(5-6):399–413.

    Article  PubMed  Google Scholar 

  181. Rodriguez-Gonzalez I, Fillonneau C, Blanchet B, Suard I, Catilina P, Andre-Fontaine G. Efficacy of Spirolept vaccine against human leptospirosis as estimated by passive protection of laboratory rodents. Med Mal Infect. 2004;34(5):196–200.

    Article  CAS  PubMed  Google Scholar 

  182. Laurichesse H, Gourdon F, Smits HL, Abdoe TH, Estavoyer JM, Rebika H, et al. Safety and immunogenicity of subcutaneous or intramuscular administration of a monovalent inactivated vaccine against Leptospira interrogans serogroup Icterohaemorrhagiae in healthy volunteers. Clin Microbiol Infect. 2007;13(4):395–403.

    Article  CAS  PubMed  Google Scholar 

  183. Ikoev VN, Gorbunov MA, Vachaev BF, Yagovkin EA, Kondratenko VF, Ananyina YV, et al. Evaluation of the reactogenicity and immunogenic activity of a new concentrated inactivated leptospirosis vaccine. Zhurnal Mikrobiologii Epidemiologii i Immunobiologii. 1999;4:39–43.

    Google Scholar 

  184. Yan Y, Chen Y, Liou W, Ding J, Chen J, Zhang J, et al. An evaluation of the serological and epidemiological effects of the outer envelope vaccine to Leptospira. J Chin Med Assoc. 2003;66(4):224–30.

    PubMed  Google Scholar 

  185. Mailloux M, Lambert R, Chenu M. Human vaccination against leptospirosis icterohaemorrhagiae. Med Hyg (Geneve). 1983;41:1025–30.

    Google Scholar 

  186. Wani H. The prophylaxis of Spirochaetosis icterohaemorrhagica Inada (Weil’s disease) by vaccination. Z Immunitatsforsch. 1933;79:1–26.

    Google Scholar 

  187. da Cunha CE, Felix SR, Neto AC, Campello-Felix A, Kremer FS, Monte LG, et al. Infection with Leptospira kirschneri Serovar Mozdok: first report from the Southern Hemisphere. Am J Trop Med Hyg. 2016;94(3):519–21.

    Article  PubMed  PubMed Central  Google Scholar 

  188. Shenberg E, Torten M. A new leptospiral vaccine for use in man. I. Development of a vaccine from Leptospira grown on a chemically defined medium. J Infect Dis. 1973;128(5):642–6.

    Article  CAS  PubMed  Google Scholar 

  189. Haake DA, Mazel MK, McCoy AM, Milward F, Chao G, Matsunaga J, et al. Leptospiral outer membrane proteins OmpL1 and LipL41 exhibit synergistic immunoprotection. Infect Immun. 1999;67(12):6572–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Dellagostin OA, Grassmann AA, Hartwig DD, Felix SR, da Silva EF, McBride AJ. Recombinant vaccines against leptospirosis. Hum Vaccin. 2011;7(11):1215–24.

    Article  CAS  PubMed  Google Scholar 

  191. Grassmann AA, Souza JD, McBride AJ. A universal vaccine against leptospirosis: are we going in the right direction? Front Immunol. 2017;8:256.

    PubMed  PubMed Central  Google Scholar 

  192. Haake DA, Chao G, Zuerner RL, Barnett JK, Barnett D, Mazel M, et al. The leptospiral major outer membrane protein LipL32 is a lipoprotein expressed during mammalian infection. Infect Immun. 2000;68(4):2276–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Haake DA, Suchard MA, Kelley MM, Dundoo M, Alt DP, Zuerner RL. Molecular evolution and mosaicism of leptospiral outer membrane proteins involves horizontal DNA transfer. J Bacteriol. 2004;186(9):2818–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Branger C, Chatrenet B, Gauvrit A, Aviat F, Aubert A, Bach JM, et al. Protection against Leptospira interrogans sensu lato challenge by DNA immunization with the gene encoding hemolysin-associated protein 1. Infect Immun. 2005;73(7):4062–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Lucas DS, Cullen PA, Lo M, Srikram A, Sermswan RW, Adler B. Recombinant LipL32 and LigA from Leptospira are unable to stimulate protective immunity against leptospirosis in the hamster model. Vaccine. 2011;29(18):3413–8.

    Article  PubMed  CAS  Google Scholar 

  196. Grassmann AA, Felix SR, dos Santos CX, Amaral MG, Seixas Neto AC, Fagundes MQ, et al. Protection against lethal leptospirosis after vaccination with LipL32 coupled or coadministered with the B subunit of Escherichia coli heat-labile enterotoxin. Clin Vaccine Immunol. 2012;19(5):740–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Habarta A, Abreu PA, Olivera N, Hauk P, Cedola MT, Ferrer MF, et al. Increased immunogenicity to LipL32 of Leptospira interrogans when expressed as a fusion protein with the cholera toxin B subunit. Curr Microbiol. 2011;62(2):526–31.

    Article  CAS  PubMed  Google Scholar 

  198. Seixas FK, da Silva EF, Hartwig DD, Cerqueira GM, Amaral M, Fagundes MQ, et al. Recombinant Mycobacterium bovis BCG expressing the LipL32 antigen of Leptospira interrogans protects hamsters from challenge. Vaccine. 2007;26(1):88–95.

    Article  CAS  PubMed  Google Scholar 

  199. Branger C, Sonrier C, Chatrenet B, Klonjkowski B, Ruvoen-Clouet N, Aubert A, et al. Identification of the hemolysis-associated protein 1 as a cross-protective immunogen of Leptospira interrogans by adenovirus-mediated vaccination. Infect Immun. 2001;69(11):6831–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Pinne M, Haake DA. LipL32 is a subsurface lipoprotein of Leptospira interrogans: presentation of new data and reevaluation of previous studies. PLoS One. 2013;8(1):e51025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Guerreiro H, Croda J, Flannery B, Mazel M, Matsunaga J, Galvao RM, et al. Leptospiral proteins recognized during the humoral immune response to leptospirosis in humans. Infect Immun. 2001;69(8):4958–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Adler B, Lo M, Seemann T, Murray GL. Pathogenesis of leptospirosis: the influence of genomics. Vet Microbiol. 2011;153(1–2):73–81.

    Article  CAS  PubMed  Google Scholar 

  203. Matsunaga J, Barocchi MA, Croda J, Young TA, Sanchez Y, Siqueira I, et al. Pathogenic Leptospira species express surface-exposed proteins belonging to the bacterial immunoglobulin superfamily. Mol Microbiol. 2003;49(4):929–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Cerqueira GM, McBride AJ, Picardeau M, Ribeiro SG, Moreira AN, Morel V, et al. Distribution of the leptospiral immunoglobulin-like (lig) genes in pathogenic Leptospira species and application of ligB to typing leptospiral isolates. J Med Microbiol. 2009;58(Pt 9):1173–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. McBride AJ, Cerqueira GM, Suchard MA, Moreira AN, Zuerner RL, Reis MG, et al. Genetic diversity of the Leptospiral immunoglobulin-like (Lig) genes in pathogenic Leptospira spp. Infect Genet Evol. 2009;9(2):196–205.

    Article  CAS  PubMed  Google Scholar 

  206. Choy HA, Kelley MM, Chen TL, Moller AK, Matsunaga J, Haake DA. Physiological osmotic induction of Leptospira interrogans adhesion: LigA and LigB bind extracellular matrix proteins and fibrinogen. Infect Immun. 2007;75(5):2441–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Choy HA, Kelley MM, Croda J, Matsunaga J, Babbitt JT, Ko AI, et al. The multifunctional LigB adhesin binds homeostatic proteins with potential roles in cutaneous infection by pathogenic Leptospira interrogans. PLoS One. 2011;6(2):e16879.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Hsieh CL, Chang E, Tseng A, Ptak C, Wu LC, Su CL, et al. Leptospira immunoglobulin-like protein B (LigB) binds to both the C-terminal 23 amino acids of fibrinogen alphaC domain and Factor XIII: insight into the mechanism of LigB-mediated blockage of fibrinogen alpha chain cross-linking. PLoS Negl Trop Dis. 2016;10(9):e0004974.

    Article  PubMed  PubMed Central  Google Scholar 

  209. Choy HA. Multiple activities of LigB potentiate virulence of Leptospira interrogans: inhibition of alternative and classical pathways of complement. PLoS One. 2012;7(7):e41566.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Hartwig DD, Bacelo KL, Oliveira PD, Oliveira TL, Seixas FK, Amaral MG, et al. Mannosylated LigANI produced in Pichia pastoris protects hamsters against leptospirosis. Curr Microbiol. 2014;68(4):524–30.

    Article  CAS  PubMed  Google Scholar 

  211. Coutinho ML, Choy HA, Kelley MM, Matsunaga J, Babbitt JT, Lewis MS, et al. A LigA three-domain region protects hamsters from lethal infection by Leptospira interrogans. PLoS Negl Trop Dis. 2011;5(12):e1422.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Silva EF, Medeiros MA, McBride AJ, Matsunaga J, Esteves GS, Ramos JG, et al. The terminal portion of leptospiral immunoglobulin-like protein LigA confers protective immunity against lethal infection in the hamster model of leptospirosis. Vaccine. 2007;25(33):6277–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Conrad NL, Cruz McBride FW, Souza JD, Silveira MM, Felix S, Mendonca KS, et al. LigB subunit vaccine confers sterile immunity against challenge in the hamster model of leptospirosis. PLoS Negl Trop Dis. 2017;11(3):e0005441.

    Article  PubMed  PubMed Central  Google Scholar 

  214. Cao Y, Faisal SM, Yan W, Chang YC, McDonough SP, Zhang N, et al. Evaluation of novel fusion proteins derived from extracellular matrix binding domains of LigB as vaccine candidates against leptospirosis in a hamster model. Vaccine. 2011;29(43):7379–86.

    Article  CAS  PubMed  Google Scholar 

  215. Yan W, Faisal SM, McDonough SP, Divers TJ, Barr SC, Chang CF, et al. Immunogenicity and protective efficacy of recombinant Leptospira immunoglobulin-like protein B (rLigB) in a hamster challenge model. Microbes Infect. 2009;11(2):230–7.

    Article  CAS  PubMed  Google Scholar 

  216. Yan W, Faisal SM, McDonough SP, Chang CF, Pan MJ, Akey B, et al. Identification and characterization of OmpA-like proteins as novel vaccine candidates for leptospirosis. Vaccine. 2010;28(11):2277–83.

    Article  CAS  PubMed  Google Scholar 

  217. Umthong S, Buaklin A, Jacquet A, Sangjun N, Kerdkaew R, Patarakul K, et al. Immunogenicity of a DNA and recombinant protein vaccine combining LipL32 and Loa22 for leptospirosis using chitosan as a delivery system. J Microbiol Biotechnol. 2015;25(4):526–36.

    Article  CAS  PubMed  Google Scholar 

  218. Garcon N, Chomez P, Van Mechelen M. GlaxoSmithKline adjuvant systems in vaccines: concepts, achievements and perspectives. Expert Rev Vaccines. 2007;6(5):723–39.

    Article  CAS  PubMed  Google Scholar 

  219. Faisal SM, Yan W, McDonough SP, Mohammed HO, Divers TJ, Chang YF. Immune response and prophylactic efficacy of smegmosomes in a hamster model of leptospirosis. Vaccine. 2009;27(44):6129–36.

    Article  CAS  PubMed  Google Scholar 

  220. Faisal SM, Yan W, McDonough SP, Chang YF. Leptospira immunoglobulin-like protein A variable region (LigAvar) incorporated in liposomes and PLGA microspheres produces a robust immune response correlating to protective immunity. Vaccine. 2009;27(3):378–87.

    Article  CAS  PubMed  Google Scholar 

  221. Faisal SM, Yan W, McDonough SP, Chang CF, Pan MJ, Chang YF. Leptosome-entrapped leptospiral antigens conferred significant higher levels of protection than those entrapped with PC-liposomes in a hamster model. Vaccine. 2009;27(47):6537–45.

    Article  CAS  PubMed  Google Scholar 

  222. Oliveira TL, Bacelo KL, Schuch RA, Seixas FK, Collares T, Rodrigues OE, et al. Immune response in hamsters immunised with a recombinant fragment of LigA from Leptospira interrogans, associated with carrier molecules. Mem Inst Oswaldo Cruz. 2016:0.

    Google Scholar 

  223. Bacelo KL, Hartwig DD, Seixas FK, Schuch R, Moreira Ada S, Amaral M, et al. Xanthan gum as an adjuvant in a subunit vaccine preparation against leptospirosis. BioMed Res Int. 2014;2014:636491.

    Article  PubMed  PubMed Central  Google Scholar 

  224. Monaris D, Sbrogio-Almeida ME, Dib CC, Canhamero TA, Souza GO, Vasconcellos SA, et al. Protective immunity and reduced renal colonization induced by vaccines containing recombinant Leptospira interrogans outer membrane proteins and flagellin adjuvant. Clin Vaccine Immunol. 2015;22(8):965–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Rappuoli R. Reverse vaccinology, a genome-based approach to vaccine development. Vaccine. 2001;19(17-19):2688–91.

    Article  CAS  PubMed  Google Scholar 

  226. Kremer FS, Eslabao MR, Jorge S, Oliveira NR, Labonde J, Santos MN, et al. Draft genome of the Leptospira interrogans strains, Acegua, RCA, Prea, and Capivara, obtained from wildlife maintenance hosts and infected domestic animals. Mem Inst Oswaldo Cruz. 2016;111(4):280–3.

    Article  PubMed  PubMed Central  Google Scholar 

  227. Dormitzer PR, Grandi G, Rappuoli R. Structural vaccinology starts to deliver. Nat Rev Microbiol. 2012;10(12):807–13.

    Article  CAS  PubMed  Google Scholar 

  228. Umamaheswari A, Pradhan D, Hemanthkumar M. Computer aided subunit vaccine design against pathogenic Leptospira serovars. Interdiscip Sci. 2012;4(1):38–45.

    Article  CAS  PubMed  Google Scholar 

  229. Zeng L, Wang D, Hu N, Zhu Q, Chen K, Dong K, et al. A novel pan-genome reverse vaccinology approach employing a negative-selection strategy for screening surface-exposed antigens against leptospirosis. Front Microbiol. 2017;8:396.

    PubMed  PubMed Central  Google Scholar 

  230. Blumerman SL, Herzig CT, Wang F, Coussens PM, Baldwin CL. Comparison of gene expression by co-cultured WC1+ gammadelta and CD4+ alphabeta T cells exhibiting a recall response to bacterial antigen. Mol Immunol. 2007;44(8):2023–35.

    Article  CAS  PubMed  Google Scholar 

  231. Hsu H, Chen C, Nenninger A, Holz L, Baldwin CL, Telfer JC. WC1 is a hybrid gammadelta TCR coreceptor and pattern recognition receptor for pathogenic bacteria. J Immunol. 2015;194(5):2280–8.

    Article  CAS  PubMed  Google Scholar 

  232. Baldwin CL, Telfer JC. The bovine model for elucidating the role of gammadelta T cells in controlling infectious diseases of importance to cattle and humans. Mol Immunol. 2015;66(1):35–47.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Biotechnology Unit, Technological Development Centre, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil

    André Alex Grassmann, Carlos Eduardo Pouey da Cunha & Everton Burlamarque Bettin

  2. Núcleo de Biotecnologia, Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Capão de Leão, Brasil

    Alan John Alexander McBride

Authors
  1. André Alex Grassmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carlos Eduardo Pouey da Cunha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Everton Burlamarque Bettin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alan John Alexander McBride
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alan John Alexander McBride .

Editor information

Editors and Affiliations

  1. Faculty of Medicine, Molecular Biology Unit, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India

    Sunit K. Singh

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Grassmann, A.A., da Cunha, C.E.P., Bettin, E.B., McBride, A.J.A. (2017). Overview of Leptospirosis. In: Singh, S. (eds) Neglected Tropical Diseases - South Asia. Neglected Tropical Diseases. Springer, Cham. https://doi.org/10.1007/978-3-319-68493-2_8

Download citation

Publish with us

Policies and ethics

Search

Navigation