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Published in: Respiratory Research 1/2010

Open Access 01-12-2010 | Research

Respiratory Syncytial Virus (RSV) RNA loads in peripheral blood correlates with disease severity in mice

Authors: Juan Pablo Torres, Ana M Gomez, Shama Khokhar, Vijay G Bhoj, Claudia Tagliabue, Michael L Chang, Peter A Kiener, Paula A Revell, Octavio Ramilo, Asuncion Mejias

Published in: Respiratory Research | Issue 1/2010

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Abstract

Background

Respiratory Syncytial Virus (RSV) infection is usually restricted to the respiratory epithelium. Few studies have documented the presence of RSV in the systemic circulation, however there is no consistent information whether virus detection in the blood correlates with disease severity.

Methods

Balb/c mice were inoculated with live RSV, heat-inactivated RSV or medium. A subset of RSV-infected mice was treated with anti-RSV antibody 72 h post-inoculation. RSV RNA loads were measured by PCR in peripheral blood from day 1-21 post-inoculation and were correlated with upper and lower respiratory tract viral loads, the systemic cytokine response, lung inflammation and pulmonary function. Immunohistochemical staining was used to define the localization of RSV antigens in the respiratory tract and peripheral blood.

Results

RSV RNA loads were detected in peripheral blood from day 1 to 14 post-inoculation, peaked on day 5 and significantly correlated with nasal and lung RSV loads, airway obstruction, and blood CCL2 and CXCL1 expression. Treatment with anti-RSV antibody reduced blood RSV RNA loads and improved airway obstruction. Immunostaining identified RSV antigens in alveolar macrophages and peripheral blood monocytes.

Conclusions

RSV RNA was detected in peripheral blood upon infection with live RSV, followed a time-course parallel to viral loads assessed in the respiratory tract and was significantly correlated with RSV-induced airway disease.
Literature
1.
go back to reference Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ: Bronchiolitis-associated hospitalizations among US children, 1980–1996. Jama 1999, 282:1440–1446.CrossRefPubMed Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ: Bronchiolitis-associated hospitalizations among US children, 1980–1996. Jama 1999, 282:1440–1446.CrossRefPubMed
2.
3.
go back to reference Mejias A, Chavez-Bueno S, Ramilo O: Respiratory syncytial virus pneumonia: mechanisms of inflammation and prolonged airway hyperresponsiveness. Curr Opin Infect Dis 2005, 18:199–204.CrossRefPubMed Mejias A, Chavez-Bueno S, Ramilo O: Respiratory syncytial virus pneumonia: mechanisms of inflammation and prolonged airway hyperresponsiveness. Curr Opin Infect Dis 2005, 18:199–204.CrossRefPubMed
4.
go back to reference Tripp RA, Oshansky C, Alvarez R: Cytokines and respiratory syncytial virus infection. Proc Am Thorac Soc 2005, 2:147–149.CrossRefPubMed Tripp RA, Oshansky C, Alvarez R: Cytokines and respiratory syncytial virus infection. Proc Am Thorac Soc 2005, 2:147–149.CrossRefPubMed
5.
go back to reference Sheeran P, Jafri H, Carubelli C, Saavedra J, Johnson C, Krisher K, Sanchez PJ, Ramilo O: Elevated cytokine concentrations in the nasopharyngeal and tracheal secretions of children with respiratory syncytial virus disease. Pediatr Infect Dis J 1999, 18:115–122.CrossRefPubMed Sheeran P, Jafri H, Carubelli C, Saavedra J, Johnson C, Krisher K, Sanchez PJ, Ramilo O: Elevated cytokine concentrations in the nasopharyngeal and tracheal secretions of children with respiratory syncytial virus disease. Pediatr Infect Dis J 1999, 18:115–122.CrossRefPubMed
6.
go back to reference Bennett BL, Garofalo RP, Cron SG, Hosakote YM, Atmar RL, Macias CG, Piedra PA: Immunopathogenesis of respiratory syncytial virus bronchiolitis. J Infect Dis 2007, 195:1532–1540.CrossRefPubMed Bennett BL, Garofalo RP, Cron SG, Hosakote YM, Atmar RL, Macias CG, Piedra PA: Immunopathogenesis of respiratory syncytial virus bronchiolitis. J Infect Dis 2007, 195:1532–1540.CrossRefPubMed
8.
go back to reference O'Donnell DR, McGarvey MJ, Tully JM, Balfour-Lynn IM, Openshaw PJ: Respiratory syncytial virus RNA in cells from the peripheral blood during acute infection. J Pediatr 1998, 133:272–274.CrossRefPubMed O'Donnell DR, McGarvey MJ, Tully JM, Balfour-Lynn IM, Openshaw PJ: Respiratory syncytial virus RNA in cells from the peripheral blood during acute infection. J Pediatr 1998, 133:272–274.CrossRefPubMed
9.
go back to reference Yui I, Hoshi A, Shigeta Y, Takami T, Nakayama T: Detection of human respiratory syncytial virus sequences in peripheral blood mononuclear cells. J Med Virol 2003, 70:481–489.CrossRefPubMed Yui I, Hoshi A, Shigeta Y, Takami T, Nakayama T: Detection of human respiratory syncytial virus sequences in peripheral blood mononuclear cells. J Med Virol 2003, 70:481–489.CrossRefPubMed
10.
go back to reference Rohwedder A, Keminer O, Forster J, Schneider K, Schneider E, Werchau H: Detection of respiratory syncytial virus RNA in blood of neonates by polymerase chain reaction. J Med Virol 1998, 54:320–327.CrossRefPubMed Rohwedder A, Keminer O, Forster J, Schneider K, Schneider E, Werchau H: Detection of respiratory syncytial virus RNA in blood of neonates by polymerase chain reaction. J Med Virol 1998, 54:320–327.CrossRefPubMed
11.
go back to reference Campbell APCJ, Kuypers J, Englund JA, Wald A, Guthrie KA, Corey L, Boeckh M: Respiratory Virus Pneumonia after Hematopoietic Cell Transplantation (HCT): Associations between Viral Load in Bronchoalveolar Lavage Samples, Viral RNA Detection in Serum Samples, and Clinical Outcomes of HCT. J Infect Dis 2010:1404–1412. Campbell APCJ, Kuypers J, Englund JA, Wald A, Guthrie KA, Corey L, Boeckh M: Respiratory Virus Pneumonia after Hematopoietic Cell Transplantation (HCT): Associations between Viral Load in Bronchoalveolar Lavage Samples, Viral RNA Detection in Serum Samples, and Clinical Outcomes of HCT. J Infect Dis 2010:1404–1412.
12.
go back to reference Burress CSEB, Barik S: An Infant with Respiratory Syncytial Virus Bronchiolitis, Viremia and Hepatitis. J Investig Med 2008, 56:405. Burress CSEB, Barik S: An Infant with Respiratory Syncytial Virus Bronchiolitis, Viremia and Hepatitis. J Investig Med 2008, 56:405.
13.
go back to reference Grant PR, Garson JA, Tedder RS, Chan PK, Tam JS, Sung JJ: Detection of SARS coronavirus in plasma by real-time RT-PCR. N Engl J Med 2003, 349:2468–2469.CrossRefPubMed Grant PR, Garson JA, Tedder RS, Chan PK, Tam JS, Sung JJ: Detection of SARS coronavirus in plasma by real-time RT-PCR. N Engl J Med 2003, 349:2468–2469.CrossRefPubMed
14.
go back to reference Xatzipsalti M, Kyrana S, Tsolia M, Psarras S, Bossios A, Laza-Stanca V, Johnston SL, Papadopoulos NG: Rhinovirus viremia in children with respiratory infections. Am J Respir Crit Care Med 2005, 172:1037–1040.CrossRefPubMed Xatzipsalti M, Kyrana S, Tsolia M, Psarras S, Bossios A, Laza-Stanca V, Johnston SL, Papadopoulos NG: Rhinovirus viremia in children with respiratory infections. Am J Respir Crit Care Med 2005, 172:1037–1040.CrossRefPubMed
15.
go back to reference Poliakova TG, Ketiladze ES, Zhilina NN, Stakhanova VM: [Viremia in influenza A2 (Hong Kong)]. Vopr Virusol 1970, 15:724–728.PubMed Poliakova TG, Ketiladze ES, Zhilina NN, Stakhanova VM: [Viremia in influenza A2 (Hong Kong)]. Vopr Virusol 1970, 15:724–728.PubMed
16.
go back to reference Tsuruoka H, Xu H, Kuroda K, Hayashi K, Yasui O, Yamada A, Ishizaki T, Yamada Y, Watanabe T, Hosaka Y: Detection of influenza virus RNA in peripheral blood mononuclear cells of influenza patients. Jpn J Med Sci Biol 1997, 50:27–34.CrossRefPubMed Tsuruoka H, Xu H, Kuroda K, Hayashi K, Yasui O, Yamada A, Ishizaki T, Yamada Y, Watanabe T, Hosaka Y: Detection of influenza virus RNA in peripheral blood mononuclear cells of influenza patients. Jpn J Med Sci Biol 1997, 50:27–34.CrossRefPubMed
17.
go back to reference de Jong MD, Simmons CP, Thanh TT, Hien VM, Smith GJ, Chau TN, Hoang DM, Chau NV, Khanh TH, Dong VC, Qui PT, Cam BV, Ha do Q, Guan Y, Peiris JS, Chinh NT, Hien TT, Farrar J: Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med 2006, 12:1203–1207.CrossRefPubMedPubMedCentral de Jong MD, Simmons CP, Thanh TT, Hien VM, Smith GJ, Chau TN, Hoang DM, Chau NV, Khanh TH, Dong VC, Qui PT, Cam BV, Ha do Q, Guan Y, Peiris JS, Chinh NT, Hien TT, Farrar J: Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med 2006, 12:1203–1207.CrossRefPubMedPubMedCentral
18.
go back to reference Mejias A, Chavez-Bueno S, Rios AM, Saavedra-Lozano J, Fonseca Aten M, Hatfield J, Kapur P, Gomez AM, Jafri HS, Ramilo O: Anti-respiratory syncytial virus (RSV) neutralizing antibody decreases lung inflammation, airway obstruction, and airway hyperresponsiveness in a murine RSV model. Antimicrob Agents Chemother 2004, 48:1811–1822.CrossRefPubMedPubMedCentral Mejias A, Chavez-Bueno S, Rios AM, Saavedra-Lozano J, Fonseca Aten M, Hatfield J, Kapur P, Gomez AM, Jafri HS, Ramilo O: Anti-respiratory syncytial virus (RSV) neutralizing antibody decreases lung inflammation, airway obstruction, and airway hyperresponsiveness in a murine RSV model. Antimicrob Agents Chemother 2004, 48:1811–1822.CrossRefPubMedPubMedCentral
19.
go back to reference Jafri HS, Chavez-Bueno S, Mejias A, Gomez AM, Rios AM, Nassi SS, Yusuf M, Kapur P, Hardy RD, Hatfield J, Rogers BB, Krisher K, Ramilo O: Respiratory syncytial virus induces pneumonia, cytokine response, airway obstruction, and chronic inflammatory infiltrates associated with long-term airway hyperresponsiveness in mice. J Infect Dis 2004, 189:1856–1865.CrossRefPubMed Jafri HS, Chavez-Bueno S, Mejias A, Gomez AM, Rios AM, Nassi SS, Yusuf M, Kapur P, Hardy RD, Hatfield J, Rogers BB, Krisher K, Ramilo O: Respiratory syncytial virus induces pneumonia, cytokine response, airway obstruction, and chronic inflammatory infiltrates associated with long-term airway hyperresponsiveness in mice. J Infect Dis 2004, 189:1856–1865.CrossRefPubMed
20.
go back to reference Chavez-Bueno S, Mejias A, Gomez AM, Olsen KD, Rios AM, Fonseca-Aten M, Ramilo O, Jafri HS: Respiratory syncytial virus-induced acute and chronic airway disease is independent of genetic background: an experimental murine model. Virol J 2005, 2:46.CrossRefPubMedPubMedCentral Chavez-Bueno S, Mejias A, Gomez AM, Olsen KD, Rios AM, Fonseca-Aten M, Ramilo O, Jafri HS: Respiratory syncytial virus-induced acute and chronic airway disease is independent of genetic background: an experimental murine model. Virol J 2005, 2:46.CrossRefPubMedPubMedCentral
21.
go back to reference Estripeaut D, Torres JP, Somers CS, Tagliabue C, Khokhar S, Bhoj VG, Grube SM, Wozniakowski A, Gomez AM, Ramilo O, Jafti HS, Mejias A: Respiratory syncytial virus persistence in the lungs correlates with airway hyperreactivity in the mouse model. J Infect Dis 2008, 198:1435–1443.CrossRefPubMedPubMedCentral Estripeaut D, Torres JP, Somers CS, Tagliabue C, Khokhar S, Bhoj VG, Grube SM, Wozniakowski A, Gomez AM, Ramilo O, Jafti HS, Mejias A: Respiratory syncytial virus persistence in the lungs correlates with airway hyperreactivity in the mouse model. J Infect Dis 2008, 198:1435–1443.CrossRefPubMedPubMedCentral
22.
go back to reference Mejias A, Chavez-Bueno S, Rios AM, Aten MF, Raynor B, Peromingo E, Soni P, Olsen KD, Kiener PA, Gomez AM, et al.: Comparative effects of two neutralizing anti-respiratory syncytial virus (RSV) monoclonal antibodies in the RSV murine model: time versus potency. Antimicrob Agents Chemother 2005, 49:4700–4707.CrossRefPubMedPubMedCentral Mejias A, Chavez-Bueno S, Rios AM, Aten MF, Raynor B, Peromingo E, Soni P, Olsen KD, Kiener PA, Gomez AM, et al.: Comparative effects of two neutralizing anti-respiratory syncytial virus (RSV) monoclonal antibodies in the RSV murine model: time versus potency. Antimicrob Agents Chemother 2005, 49:4700–4707.CrossRefPubMedPubMedCentral
23.
go back to reference Wubbel L, Jafri HS, Olsen K, Shelton S, Barton Rogers B, Gambill G, Patel P, Keyser E, Cassell G, McCracken GH: Mycoplasma pneumoniae pneumonia in a mouse model. J Infect Dis 1998, 178:1526–1529.CrossRefPubMed Wubbel L, Jafri HS, Olsen K, Shelton S, Barton Rogers B, Gambill G, Patel P, Keyser E, Cassell G, McCracken GH: Mycoplasma pneumoniae pneumonia in a mouse model. J Infect Dis 1998, 178:1526–1529.CrossRefPubMed
24.
go back to reference Mejias A, Chavez-Bueno S, Raynor MB, Connolly J, Kiener PA, Jafri HS, Ramilo O: Motavizumab, A Neutralizing Anti-Respiratory Syncytial Virus (RSV) Monoclonal Antibody Significantly Modifies The Local And Systemic Cytokine Responses Induced By RSV In The Mouse Model. Virol J 2007, 4:109.CrossRefPubMedPubMedCentral Mejias A, Chavez-Bueno S, Raynor MB, Connolly J, Kiener PA, Jafri HS, Ramilo O: Motavizumab, A Neutralizing Anti-Respiratory Syncytial Virus (RSV) Monoclonal Antibody Significantly Modifies The Local And Systemic Cytokine Responses Induced By RSV In The Mouse Model. Virol J 2007, 4:109.CrossRefPubMedPubMedCentral
25.
go back to reference Fonseca-Aten M, Rios AM, Mejias A, Chavez-Bueno S, Katz K, Gomez AM, McCracken GH Jr, Hardy RD: Mycoplasma pneumoniae induces host-dependent pulmonary inflammation and airway obstruction in mice. Am J Respir Cell Mol Biol 2005, 32:201–210.CrossRefPubMed Fonseca-Aten M, Rios AM, Mejias A, Chavez-Bueno S, Katz K, Gomez AM, McCracken GH Jr, Hardy RD: Mycoplasma pneumoniae induces host-dependent pulmonary inflammation and airway obstruction in mice. Am J Respir Cell Mol Biol 2005, 32:201–210.CrossRefPubMed
26.
go back to reference Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001, 25:402–408.CrossRefPubMed Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001, 25:402–408.CrossRefPubMed
27.
go back to reference Bont L, Heijnen CJ, Kavelaars A, van Aalderen WM, Brus F, Draaisma JT, Geelen SM, van Vught HJ, Kimpen JL: Peripheral blood cytokine responses and disease severity in respiratory syncytial virus bronchiolitis. Eur Respir J 1999, 14:144–149.CrossRefPubMed Bont L, Heijnen CJ, Kavelaars A, van Aalderen WM, Brus F, Draaisma JT, Geelen SM, van Vught HJ, Kimpen JL: Peripheral blood cytokine responses and disease severity in respiratory syncytial virus bronchiolitis. Eur Respir J 1999, 14:144–149.CrossRefPubMed
28.
go back to reference Gill MALK, Kwon T, Muñiz L, Mejías A, Connolly J, Roy L, Banchereau J, and Ramilo O: Differential recruitment of dendritic cells and monocytes to respiratory mucosal sites in children with influenza and respiratory syncytial virus infections. J Infect Dis 2008, 198:1667–1776.CrossRefPubMedPubMedCentral Gill MALK, Kwon T, Muñiz L, Mejías A, Connolly J, Roy L, Banchereau J, and Ramilo O: Differential recruitment of dendritic cells and monocytes to respiratory mucosal sites in children with influenza and respiratory syncytial virus infections. J Infect Dis 2008, 198:1667–1776.CrossRefPubMedPubMedCentral
29.
go back to reference Garofalo RP, Patti J, Hintz KA, Hill V, Ogra PL, Welliver RC: Macrophage inflammatory protein-1alpha (not T helper type 2 cytokines) is associated with severe forms of respiratory syncytial virus bronchiolitis. J Infect Dis 2001, 184:393–399.CrossRefPubMed Garofalo RP, Patti J, Hintz KA, Hill V, Ogra PL, Welliver RC: Macrophage inflammatory protein-1alpha (not T helper type 2 cytokines) is associated with severe forms of respiratory syncytial virus bronchiolitis. J Infect Dis 2001, 184:393–399.CrossRefPubMed
30.
go back to reference Esolen LM, Ward BJ, Moench TR, Griffin DE: Infection of monocytes during measles. J Infect Dis 1993, 168:47–52.CrossRefPubMed Esolen LM, Ward BJ, Moench TR, Griffin DE: Infection of monocytes during measles. J Infect Dis 1993, 168:47–52.CrossRefPubMed
31.
go back to reference Mori I, Komatsu T, Takeuchi K, Nakakuki K, Sudo M, Kimura Y: Parainfluenza virus type 1 infects olfactory neurons and establishes long-term persistence in the nerve tissue. J Gen Virol 1995,76(Pt 5):1251–1254.CrossRefPubMed Mori I, Komatsu T, Takeuchi K, Nakakuki K, Sudo M, Kimura Y: Parainfluenza virus type 1 infects olfactory neurons and establishes long-term persistence in the nerve tissue. J Gen Virol 1995,76(Pt 5):1251–1254.CrossRefPubMed
32.
go back to reference Domurat F, Roberts NJ Jr, Walsh EE, Dagan R: Respiratory syncytial virus infection of human mononuclear leukocytes in vitro and in vivo. J Infect Dis 1985, 152:895–902.CrossRefPubMed Domurat F, Roberts NJ Jr, Walsh EE, Dagan R: Respiratory syncytial virus infection of human mononuclear leukocytes in vitro and in vivo. J Infect Dis 1985, 152:895–902.CrossRefPubMed
33.
go back to reference Valentova V, Psikal I, Kovarcik K: Demonstration of bovine respiratory syncytial virus RNA in peripheral blood leukocytes of naturally infected cattle. Acta Virol 2003, 47:33–36.PubMed Valentova V, Psikal I, Kovarcik K: Demonstration of bovine respiratory syncytial virus RNA in peripheral blood leukocytes of naturally infected cattle. Acta Virol 2003, 47:33–36.PubMed
34.
go back to reference Mejias A, Chavez-Bueno S, Raynor MB, Connolly J, Kiener PA, Jafri HS, Ramilo O: Motavizumab, a neutralizing anti-Respiratory Syncytial Virus (Rsv) monoclonal antibody significantly modifies the local and systemic cytokine responses induced by Rsv in the mouse model. Virol J 2007, 4:109.CrossRefPubMedPubMedCentral Mejias A, Chavez-Bueno S, Raynor MB, Connolly J, Kiener PA, Jafri HS, Ramilo O: Motavizumab, a neutralizing anti-Respiratory Syncytial Virus (Rsv) monoclonal antibody significantly modifies the local and systemic cytokine responses induced by Rsv in the mouse model. Virol J 2007, 4:109.CrossRefPubMedPubMedCentral
Metadata
Title
Respiratory Syncytial Virus (RSV) RNA loads in peripheral blood correlates with disease severity in mice
Authors
Juan Pablo Torres
Ana M Gomez
Shama Khokhar
Vijay G Bhoj
Claudia Tagliabue
Michael L Chang
Peter A Kiener
Paula A Revell
Octavio Ramilo
Asuncion Mejias
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2010
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/1465-9921-11-125

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