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Vol. 49, No. 3, 2006
Issue release date: January 2006
Intervirology 2006;49:173–184
(DOI:10.1159/000089378)

Serological Assays for the Detection of Human Andes Hantavirus Infections Based on Its Yeast-Expressed Nucleocapsid Protein

Schmidt J.a · Meisel H.a · Capria S.G.b · Petraityte R.c · Lundkvist Å.d · Hjelle B.e, f · Vial P.A.g · Padula P.b · Krüger D.H.a · Ulrich R.a, h
aInstitute of Virology, Charité School of Medicine, Berlin, Germany; bDepartamento de Virología, Instituto Nacional de Enfermedades Infecciosas, A.N.L.I.S. ‘Dr. Carlos G. Malbrán’, Buenos Aires, Argentina; cInstitute of Biotechnology, Vilnius, Lithuania; dSwedish Institute for Infectious Disease Control and Tumorbiology Center, Karolinska Institute, Stockholm, Sweden; eDepartment of Pathology and Infectious Diseases and Inflammation Program, University of New Mexico Health Sciences Center, fTriCore Reference Laboratory, Albuquerque, N. Mex., USA; gClínica Alemana School of Medicine, Institute of Science, Universidad del Desarrollo, Santiago, Chile; hFriedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Institute of Epidemiology, Wusterhausen, Germany
email Corresponding Author

Abstract

Background: The objective of the study was to develop and evaluate IgM and IgG ELISAs and an IgG Western blot test for the serological detection of human infections with Andes virus (ANDV), the major cause of hantavirus cardiopulmonary syndrome (HCPS) in South America. Methods: The entire nucleocapsid (N) protein-encoding sequence of ANDV (strain AH-1) was cloned and expressed in the yeast Saccharomyces cerevisiae. The polyhistidine-tagged recombinant N (rN) protein of ANDV was purified by nickel-chelation chromatography and characterized by its reactivity with different N-specific monoclonal antibodies. To detect an antibody response directed against ANDV in humans, indirect IgM and IgG ELISAs and an IgG Western blot test based on ANDV rN antigen were developed. The evaluation of the tests was performed using a negative serum panel and 63 blinded sera from Argentina and Chile, containing acute-phase and convalescent sera from HCPS patients. Results: The specificities and sensitivities for the IgM and IgG ELISAs were demonstrated to be very high. The IgG ELISA data were confirmed by the IgG Western blot assay based on the same rN antigen. Almost all anti-ANDV-positive sera reacted to higher endpoint titers with N protein of ANDV than with those of Sin Nombre, Laguna Negra or Puumala virus. The cross-reactivity of anti-ANDV-N IgG-positive sera to rN proteins of other hantaviruses was found to be increased with time after the onset of HCPS. Conclusion: The high sensitivity of the novel assays should facilitate early diagnosis of ANDV infections and might contribute to a successful treatment of HCPS patients.


 goto top of outline Key Words

  • Hantavirus
  • Andes virus
  • ELISA
  • Hantavirus cardiopulmonary syndrome

 goto top of outline Abstract

Background: The objective of the study was to develop and evaluate IgM and IgG ELISAs and an IgG Western blot test for the serological detection of human infections with Andes virus (ANDV), the major cause of hantavirus cardiopulmonary syndrome (HCPS) in South America. Methods: The entire nucleocapsid (N) protein-encoding sequence of ANDV (strain AH-1) was cloned and expressed in the yeast Saccharomyces cerevisiae. The polyhistidine-tagged recombinant N (rN) protein of ANDV was purified by nickel-chelation chromatography and characterized by its reactivity with different N-specific monoclonal antibodies. To detect an antibody response directed against ANDV in humans, indirect IgM and IgG ELISAs and an IgG Western blot test based on ANDV rN antigen were developed. The evaluation of the tests was performed using a negative serum panel and 63 blinded sera from Argentina and Chile, containing acute-phase and convalescent sera from HCPS patients. Results: The specificities and sensitivities for the IgM and IgG ELISAs were demonstrated to be very high. The IgG ELISA data were confirmed by the IgG Western blot assay based on the same rN antigen. Almost all anti-ANDV-positive sera reacted to higher endpoint titers with N protein of ANDV than with those of Sin Nombre, Laguna Negra or Puumala virus. The cross-reactivity of anti-ANDV-N IgG-positive sera to rN proteins of other hantaviruses was found to be increased with time after the onset of HCPS. Conclusion: The high sensitivity of the novel assays should facilitate early diagnosis of ANDV infections and might contribute to a successful treatment of HCPS patients.

Copyright © 2006 S. Karger AG, Basel


 goto top of outline References
  1. Orellana C: Chilean research throws light on hantavirus transmission. Lancet Infect Dis 2003;3:8.
  2. Zeitz PS, Butler JC, Cheek JE, Samuel MC, Childs JE, Shands LA, Turner RE, Voorhees RE, Sarisky J, Rollin PE: A case-control study of hantavirus pulmonary syndrome during an outbreak in the southwestern United States. J Infect Dis 1995;171:864–870.
  3. Krüger DH, Ulrich R, Lundkvist Å: Hantavirus infections and their prevention. Microbes Infect 2001;3:1129–1144.
  4. Schmaljohn CS, Hjelle B: Hantaviruses: a global disease problem. Emerg Infect Dis 1997;3:95–104.
  5. Zavasky DM, Hjelle B, Peterson MC, Denton RW, Reimer L: Acute infection with Sin Nombre hantavirus without pulmonary edema. Clin Infect Dis 1999;29:664–666.
  6. Childs JE, Ksiazek TG, Spiropoulou CF, Krebs JW, Morzunov S, Maupin GO, Gage KL, Rollin PE, Sarisky J, Enscore RE: Serologic and genetic identification of Peromyscus maniculatus as the primary rodent reservoir for a new hantavirus in the southwestern United States. J Infect Dis 1994;169:1271–1280.
  7. CDC: Outbreak of acute illness – Southwestern United States. MMWR Morb Mortal Wkly Rep 1993;42:421–424.
  8. Nichol ST, Spiropoulou CF, Morzunov S, Rollin PE, Ksiazek TG, Feldmann H, Sanchez A, Childs J, Zaki S, Peters CJ: Genetic identification of a hantavirus associated with an outbreak of acute respiratory illness. Science 1993;262:914–917.
  9. Peters CJ, Khan AS: Hantavirus pulmonary syndrome: The new American hemorrhagic fever. Clin Infect Dis 2002;34:1224–1231.
  10. CDC: http://www.cdc.gov/ncidod/diseases/hanta/hps/ 2005.
  11. Nichol ST, Ksiazek TG, Rollin PE, Peters CJ: Hantavirus pulmonary syndrome and newly described hantaviruses in the United States;in Elliott RM (ed): The Bunyaviridae. New York, Plenum Press, 1996, pp 269–280.
  12. Levis S, Morzunov SP, Rowe JE, Enria D, Pini N, Calderon G, Sabattini M, St Jeor SC: Genetic diversity and epidemiology of hantaviruses in Argentina. J Infect Dis 1998;177:529–538.
  13. Johnson AM, Bowen MD, Ksiazek TG, Williams RJ, Bryan RT, Mills JN, Peters CJ, Nichol ST: Laguna Negra virus associated with HPS in western Paraguay and Bolivia. Virology 1997;238:115–127.
  14. Padula PJ, Colavecchia SB, Martinez VP, Gonzalez Della Valle MO, Edelstein A, Miguel SD, Russi J, Riquelme JM, Colucci N, Almiron M, Rabinovich RD: Genetic diversity, distribution, and serological features of hantavirus infection in five countries in South America. J Clin Microbiol 2000;38:323–330.
  15. Enria D, Padula P, Segura EL, Pini N, Edelstein A, Posse CR, Weissenbacher MC: Hantavirus pulmonary syndrome in Argentina: possibility of person to person transmission. Medicina 1996;56:709–711.
  16. Padula PJ, Edelstein A, Miguel SD, Lopez NM, Rossi CM, Rabinovich RD: Hantavirus pulmonary syndrome outbreak in Argentina: molecular evidence for person-to-person transmission of Andes virus. Virology 1998;241:323–330.
  17. Toro J, Vega JD, Khan AS, Mills JN, Padula P, Terry W, Yadon Z, Valderrama R, Ellis BA, Pavletic C, Cerda R, Zaki S, Shieh WJ, Meyer R, Tapia M, Mansilla C, Baro M, Vergara JA, Concha M, Calderon G, Enria D, Peters CJ, Ksiazek TG: An outbreak of hantavirus pulmonary syndrome, Chile, 1997. Emerg Infect Dis 1998;4:687–694.
  18. Wells RM, Sosa Estani S, Yadon ZE, Enria D, Padula P, Pini N, Mills JN, Peters CJ, Segura EL: An unusual hantavirus outbreak in southern Argentina: person-to-person transmission? Emerg Infect Dis 1997;3:171–174.
  19. Pinna DM, Martinez VP, Bellomo CM, Lopez C, Padula P: New epidemiologic and molecular evidence of person to person transmission of hantavirus Andes Sout (in Spanish). Medicina (B Aires) 2004;64:43–46.
  20. Hooper JW, Larsen T, Custer DM, Schmaljohn CS: A lethal disease model for hantavirus pulmonary syndrome. Virology 2001;289:6–14.
  21. Milazzo ML, Eyzaguirre EJ, Molina CP, Fulhorst CF: Maporal viral infection in the Syrian golden hamster: a model of hantavirus pulmonary syndrome. J Infect Dis 2002;186:1390–1395.
  22. Riquelme R, Riquelme M, Torres A, Rioseco ML, Vergara JA, Scholz L, Carriel A: Hantavirus pulmonary syndrome, Southern Chile. Emerg Infect Dis 2003;9:1438–1443.
  23. Groen J, Dalrymple J, Fisher-Hoch S, Jordans JG, Clement JP, Osterhaus AD: Serum antibodies to structural proteins of hantavirus arise at different times after infection. J Med Virol 1992;37:283–287.
  24. Brus Sjölander K, Golovljova I, Plyusnin A, Lundkvist Å: Diagnostic potential of Puumala virus nucleocapsid protein expressed in Drosophila melanogaster cells. J Clin Microbiol 2000;38:2324–2329.
  25. Feldmann H, Sanchez A, Morzunov S, Spiropoulou CF, Rollin PE, Ksiazek TG, Peters CJ, Nichol ST: Utilization of autopsy RNA for the synthesis of the nucleocapsid antigen of a newly recognized virus associated with hantavirus pulmonary syndrome. Virus Res 1993;30:351–367.
  26. Hjelle B, Jenison S, Torrez-Martinez N, Herring B, Quan S, Polito A, Pichuantes S, Yamada T, Morris C, Elgh F, Lee HW, Artsob H, Dinello R: Rapid and specific detection of Sin Nombre virus antibodies in patients with hantavirus pulmonary syndrome by a strip immunoblot assay suitable for field diagnosis. J Clin Microbiol 1997;35:600–608.
  27. Jenison S, Yamada T, Morris C, Anderson B, Torrez-Martinez N, Keller N, Hjelle B: Characterization of human antibody responses to Four Corners hantavirus infections among patients with hantavirus pulmonary syndrome. J Virol 1994;68:3000–3006.
  28. Kallio-Kokko H, Vapalahti O, Lundkvist Å, Vaheri A: Evaluation of Puumala virus IgG and IgM enzyme immunoassays based on recombinant baculovirus-expressed nucleocapsid protein for early nephropathia epidemica diagnosis. Clin Diagn Virol 1998;10:83–90.
  29. Padula PJ, Rossi CM, Della Valle MO, Martinez PV, Colavecchia SB, Edelstein A, Miguel SDL, Rabinovich RD, Segura EL: Development and evaluation of a solid-phase enzyme immunoassay based on Andes hantavirus recombinant nucleoprotein. J Med Microbiol 2000;49:149–155.
  30. Vapalahti O, Lundkvist Å, Kallio-Kokko H, Paukku K, Julkunen I, Lankinen H, Vaheri A: Antigenic properties and diagnostic potential of Puumala virus nucleocapsid protein expressed in insect cells. J Clin Microbiol 1996;34:119–125.
  31. Yamada T, Hjelle B, Lanzi R, Morris C, Anderson B, Jenison S: Antibody responses to Four Corners hantavirus infections in the deer mouse (Peromyscus maniculatus): identification of an immunodominant region of the viral nucleocapsid protein. J Virol 1995;69:1939–1943.
  32. Zöller L, Yang S, Gött P, Bautz EKF, Darai G: Use of recombinant nucleocapsid proteins of the Hantaan and Nephropathia epidemica serotypes of hantaviruses as immunodiagnostic antigens. J Med Virol 1993;39:200–207.
  33. Zöller LG, Yang S, Gött P, Bautz EKF, Darai G: A novel μ-capture enzyme-linked immunosorbent assay based on recombinant proteins for sensitive and specific diagnosis of hemorrhagic fever with renal syndrome. J Clin Microbiol 1993;31:1194–1199.
  34. Schmidt J, Meisel H, Hjelle B, Krüger DH, Ulrich R: Development and evaluation of serological assays for detection of human hantavirus infections caused by Sin Nombre virus. J Clin Virol 2005;33:247–253.
  35. Gött P, Zöller L, Darai G, Bautz EK: A major antigenic domain of hantaviruses is located on the aminoproximal site of the viral nucleocapsid protein. Virus Genes 1997;14:31–40.
  36. Murgue B, Domart Y, Coudrier D, Rollin PE, Darchis JP, Merrien D, Zeller HG: First reported case of imported hantavirus pulmonary syndrome in Europe. Emerg Infect Dis 2002;8:106–107.
  37. Lopez N, Padula P, Rossi C, Miguel S, Edelstein A, Ramirez E, Franze-Fernandez MT: Genetic characterization and phylogeny of Andes virus and variants from Argentina and Chile. Virus Res 1997;50:77–84.
  38. Dargeviciute A, Brus Sjölander K, Sasnauskas K, Krüger DH, Meisel H, Ulrich R, Lundkvist Å: Yeast-expressed Puumala hantavirus nucleocapsid protein induces protection in a bank vole model. Vaccine 2002;20:3523–3531.
  39. Razanskiene A, Schmidt J, Geldmacher A, Ritzi A, Niedrig M, Lundkvist Å, Krüger DH, Meisel H, Sasnauskas K, Ulrich R: High yields of stable and highly pure nucleocapsid proteins of different hantaviruses can be generated in the yeast Saccharomyces cerevisiae. J Biotechnol 2004;111:319–333.
  40. Schmidt J, Jandrig B, Klempa B, Yoshimatsu K, Arikawa J, Meisel H, Niedrig M, Pitra C, Krüger DH, Ulrich R: Nucleocapsid protein of cell culture-adapted Seoul virus strain 80-39: analysis of its encoding sequence, expression in yeast and immuno-reactivity. Virus Genes 2005;30:37–48.
  41. Rossi C, Ksiazek T: Enzyme-linked immunosorbent assay (ELISA); in Lee HW, Calisher C, Schmaljohn CS (eds): Manual of Hemorrhagic Fever with Renal Syndrome and Hantavirus Pulmonary Syndrome. Seoul, WHO Collaborating Center for Virus Reference and Research, 1999, pp 87–91.
  42. Johnson AM, Bowen MD, Ksiazek TG, Williams RJ, Bryan RT, Mills JN, Peters CJ, Nichol ST: Laguna Negra virus associated with HPS in western Paraguay and Bolivia. Virology 1997;238:115–127.
  43. Täger-Frey M, Vial PA, Castillo C, Godoy P, Hjelle B, Ferrés M: Hantavirus prevalence in the IX region of Chile. Emerg Infect Dis 2003;9:827–832.
  44. Hjelle B, Glass GE: Outbreak of hantavirus infection in the Four Corners region of the United States in the wake of the 1997–1998 El Nino-southern oscillation. J Infect Dis 2000;181:1569–1573.
  45. Yoshimatsu K, Arikawa J, Tamura M, Yoshida R, Lundkvist Å, Niklasson B, Kariwa H, Azuma I: Characterization of the nucleocapsid protein of Hantaan virus strain 76-118 using monoclonal antibodies. J Gen Virol 1996;77:695–704.
  46. Lundkvist Å, Fatouros A, Niklasson B: Antigenic variation of European haemorrhagic fever with renal syndrome virus strains characterized using bank vole monoclonal antibodies. J Gen Virol 1991;72:2097–2103.
  47. Lundkvist Å, Niklasson B: Bank vole monoclonal antibodies against Puumala virus envelope glycoproteins: identification of epitopes involved in neutralization. Arch Virol 1992;126:93–105.
  48. Brus Sjölander K, Elgh F, Kallio-Kokko H, Vapalahti O, Hägglund M, Palmcrantz V, Juto P, Vaheri A, Niklasson B, Lundkvist Å: Evaluation of serological methods for diagnosis of Puumala hantavirus infection (nephropathia epidemica). J Clin Microbiol 1997;35:3264–3268.
  49. Bohlmann MC, Morzunov SP, Meissner J, Taylor MB, Ishibashi K, Rowe J, Levis S, Enria D, St Jeor SC: Analysis of hantavirus genetic diversity in Argentina: S segment-derived phylogeny. J Virol 2002;76:3765–3773.
  50. Sjölander KB, Lundkvist Å: Dobrava virus infection: serological diagnosis and cross-reactions to other hantaviruses. J Virol Methods 1999;80:137–143.
  51. Elgh F, Linderholm M, Wadell G, Tarnvik A, Juto P: Development of humoral cross-reactivity to the nucleocapsid protein of heterologous hantaviruses in nephropathia epidemica. FEMS Immunol Med Microbiol 1998;22:309–315.
  52. Geldmacher A, Schmaler M, Krüger DH, Ulrich R: Yeast-expressed hantavirus Dobrava nucleocapsid protein induces a strong, long-lasting and highly cross-reactive immune response in mice. Viral Immunol 2004;17:115–122.
  53. Khaiboullina SF, St Jeor SC: Hantavirus immunology. Viral Immunol 2002;15:609–625.
  54. Dzagurova T, Tkachenko E, Slonova R, Ivanov L, Ivanidze E, Markeshin S, Dekonenko A, Niklasson B, Lundkvist Å: Antigenic relationships of hantavirus strains analysed by monoclonal antibodies. Arch Virol 1995;140:1763–1773.

 goto top of outline Author Contacts

Dr. Rainer Ulrich
Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health
Institute of Epidemiology, Seestrasse 55
DE–16868 Wusterhausen (Germany)
Tel. +49 33979 80 162, Fax +49 33979 80 222, E-Mail rainer.ulrich@wus.bfav.de


 goto top of outline Article Information

Received: January 20, 2005
Accepted after revision: June 8, 2005
Number of Print Pages : 12
Number of Figures : 3, Number of Tables : 3, Number of References : 54


 goto top of outline Publication Details

Intervirology (International Journal of Basic and Medical Virology)

Vol. 49, No. 3, Year 2006 (Cover Date: January 2006)

Journal Editor: Liebert, U.G. (Leipzig)
ISSN: 0300–5526 (print), 1423–0100 (Online)

For additional information: http://www.karger.com/INT


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Background: The objective of the study was to develop and evaluate IgM and IgG ELISAs and an IgG Western blot test for the serological detection of human infections with Andes virus (ANDV), the major cause of hantavirus cardiopulmonary syndrome (HCPS) in South America. Methods: The entire nucleocapsid (N) protein-encoding sequence of ANDV (strain AH-1) was cloned and expressed in the yeast Saccharomyces cerevisiae. The polyhistidine-tagged recombinant N (rN) protein of ANDV was purified by nickel-chelation chromatography and characterized by its reactivity with different N-specific monoclonal antibodies. To detect an antibody response directed against ANDV in humans, indirect IgM and IgG ELISAs and an IgG Western blot test based on ANDV rN antigen were developed. The evaluation of the tests was performed using a negative serum panel and 63 blinded sera from Argentina and Chile, containing acute-phase and convalescent sera from HCPS patients. Results: The specificities and sensitivities for the IgM and IgG ELISAs were demonstrated to be very high. The IgG ELISA data were confirmed by the IgG Western blot assay based on the same rN antigen. Almost all anti-ANDV-positive sera reacted to higher endpoint titers with N protein of ANDV than with those of Sin Nombre, Laguna Negra or Puumala virus. The cross-reactivity of anti-ANDV-N IgG-positive sera to rN proteins of other hantaviruses was found to be increased with time after the onset of HCPS. Conclusion: The high sensitivity of the novel assays should facilitate early diagnosis of ANDV infections and might contribute to a successful treatment of HCPS patients.



 goto top of outline Author Contacts

Dr. Rainer Ulrich
Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health
Institute of Epidemiology, Seestrasse 55
DE–16868 Wusterhausen (Germany)
Tel. +49 33979 80 162, Fax +49 33979 80 222, E-Mail rainer.ulrich@wus.bfav.de


 goto top of outline Article Information

Received: January 20, 2005
Accepted after revision: June 8, 2005
Number of Print Pages : 12
Number of Figures : 3, Number of Tables : 3, Number of References : 54


 goto top of outline Publication Details

Intervirology (International Journal of Basic and Medical Virology)

Vol. 49, No. 3, Year 2006 (Cover Date: January 2006)

Journal Editor: Liebert, U.G. (Leipzig)
ISSN: 0300–5526 (print), 1423–0100 (Online)

For additional information: http://www.karger.com/INT


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Orellana C: Chilean research throws light on hantavirus transmission. Lancet Infect Dis 2003;3:8.
  2. Zeitz PS, Butler JC, Cheek JE, Samuel MC, Childs JE, Shands LA, Turner RE, Voorhees RE, Sarisky J, Rollin PE: A case-control study of hantavirus pulmonary syndrome during an outbreak in the southwestern United States. J Infect Dis 1995;171:864–870.
  3. Krüger DH, Ulrich R, Lundkvist Å: Hantavirus infections and their prevention. Microbes Infect 2001;3:1129–1144.
  4. Schmaljohn CS, Hjelle B: Hantaviruses: a global disease problem. Emerg Infect Dis 1997;3:95–104.
  5. Zavasky DM, Hjelle B, Peterson MC, Denton RW, Reimer L: Acute infection with Sin Nombre hantavirus without pulmonary edema. Clin Infect Dis 1999;29:664–666.
  6. Childs JE, Ksiazek TG, Spiropoulou CF, Krebs JW, Morzunov S, Maupin GO, Gage KL, Rollin PE, Sarisky J, Enscore RE: Serologic and genetic identification of Peromyscus maniculatus as the primary rodent reservoir for a new hantavirus in the southwestern United States. J Infect Dis 1994;169:1271–1280.
  7. CDC: Outbreak of acute illness – Southwestern United States. MMWR Morb Mortal Wkly Rep 1993;42:421–424.
  8. Nichol ST, Spiropoulou CF, Morzunov S, Rollin PE, Ksiazek TG, Feldmann H, Sanchez A, Childs J, Zaki S, Peters CJ: Genetic identification of a hantavirus associated with an outbreak of acute respiratory illness. Science 1993;262:914–917.
  9. Peters CJ, Khan AS: Hantavirus pulmonary syndrome: The new American hemorrhagic fever. Clin Infect Dis 2002;34:1224–1231.
  10. CDC: http://www.cdc.gov/ncidod/diseases/hanta/hps/ 2005.
  11. Nichol ST, Ksiazek TG, Rollin PE, Peters CJ: Hantavirus pulmonary syndrome and newly described hantaviruses in the United States;in Elliott RM (ed): The Bunyaviridae. New York, Plenum Press, 1996, pp 269–280.
  12. Levis S, Morzunov SP, Rowe JE, Enria D, Pini N, Calderon G, Sabattini M, St Jeor SC: Genetic diversity and epidemiology of hantaviruses in Argentina. J Infect Dis 1998;177:529–538.
  13. Johnson AM, Bowen MD, Ksiazek TG, Williams RJ, Bryan RT, Mills JN, Peters CJ, Nichol ST: Laguna Negra virus associated with HPS in western Paraguay and Bolivia. Virology 1997;238:115–127.
  14. Padula PJ, Colavecchia SB, Martinez VP, Gonzalez Della Valle MO, Edelstein A, Miguel SD, Russi J, Riquelme JM, Colucci N, Almiron M, Rabinovich RD: Genetic diversity, distribution, and serological features of hantavirus infection in five countries in South America. J Clin Microbiol 2000;38:323–330.
  15. Enria D, Padula P, Segura EL, Pini N, Edelstein A, Posse CR, Weissenbacher MC: Hantavirus pulmonary syndrome in Argentina: possibility of person to person transmission. Medicina 1996;56:709–711.
  16. Padula PJ, Edelstein A, Miguel SD, Lopez NM, Rossi CM, Rabinovich RD: Hantavirus pulmonary syndrome outbreak in Argentina: molecular evidence for person-to-person transmission of Andes virus. Virology 1998;241:323–330.
  17. Toro J, Vega JD, Khan AS, Mills JN, Padula P, Terry W, Yadon Z, Valderrama R, Ellis BA, Pavletic C, Cerda R, Zaki S, Shieh WJ, Meyer R, Tapia M, Mansilla C, Baro M, Vergara JA, Concha M, Calderon G, Enria D, Peters CJ, Ksiazek TG: An outbreak of hantavirus pulmonary syndrome, Chile, 1997. Emerg Infect Dis 1998;4:687–694.
  18. Wells RM, Sosa Estani S, Yadon ZE, Enria D, Padula P, Pini N, Mills JN, Peters CJ, Segura EL: An unusual hantavirus outbreak in southern Argentina: person-to-person transmission? Emerg Infect Dis 1997;3:171–174.
  19. Pinna DM, Martinez VP, Bellomo CM, Lopez C, Padula P: New epidemiologic and molecular evidence of person to person transmission of hantavirus Andes Sout (in Spanish). Medicina (B Aires) 2004;64:43–46.
  20. Hooper JW, Larsen T, Custer DM, Schmaljohn CS: A lethal disease model for hantavirus pulmonary syndrome. Virology 2001;289:6–14.
  21. Milazzo ML, Eyzaguirre EJ, Molina CP, Fulhorst CF: Maporal viral infection in the Syrian golden hamster: a model of hantavirus pulmonary syndrome. J Infect Dis 2002;186:1390–1395.
  22. Riquelme R, Riquelme M, Torres A, Rioseco ML, Vergara JA, Scholz L, Carriel A: Hantavirus pulmonary syndrome, Southern Chile. Emerg Infect Dis 2003;9:1438–1443.
  23. Groen J, Dalrymple J, Fisher-Hoch S, Jordans JG, Clement JP, Osterhaus AD: Serum antibodies to structural proteins of hantavirus arise at different times after infection. J Med Virol 1992;37:283–287.
  24. Brus Sjölander K, Golovljova I, Plyusnin A, Lundkvist Å: Diagnostic potential of Puumala virus nucleocapsid protein expressed in Drosophila melanogaster cells. J Clin Microbiol 2000;38:2324–2329.
  25. Feldmann H, Sanchez A, Morzunov S, Spiropoulou CF, Rollin PE, Ksiazek TG, Peters CJ, Nichol ST: Utilization of autopsy RNA for the synthesis of the nucleocapsid antigen of a newly recognized virus associated with hantavirus pulmonary syndrome. Virus Res 1993;30:351–367.
  26. Hjelle B, Jenison S, Torrez-Martinez N, Herring B, Quan S, Polito A, Pichuantes S, Yamada T, Morris C, Elgh F, Lee HW, Artsob H, Dinello R: Rapid and specific detection of Sin Nombre virus antibodies in patients with hantavirus pulmonary syndrome by a strip immunoblot assay suitable for field diagnosis. J Clin Microbiol 1997;35:600–608.
  27. Jenison S, Yamada T, Morris C, Anderson B, Torrez-Martinez N, Keller N, Hjelle B: Characterization of human antibody responses to Four Corners hantavirus infections among patients with hantavirus pulmonary syndrome. J Virol 1994;68:3000–3006.
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