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Journal of Virology, January 2007, p. 991-999, Vol. 81, No. 2
0022-538X/07/$08.00+0     doi:10.1128/JVI.01783-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

C5 Modulates Airway Hyperreactivity and Pulmonary Eosinophilia during Enhanced Respiratory Syncytial Virus Disease by Decreasing C3a Receptor Expression{triangledown}

Guillermina A. Melendi,1,2,3,{dagger} Scott J. Hoffman,2,3,{dagger} Ruth A. Karron,2,4 Pablo M. Irusta,1,9 Federico R. Laham,1,2 Alison Humbles,6 Brian Schofield,5 Chien-Hsiung Pan,3 Richard Rabold,5 Bhagvanji Thumar,4 Adeep Thumar,3 Norma P. Gerard,6 Wayne Mitzner,5 Scott R. Barnum,7 Craig Gerard,6 Steven R. Kleeberger,8 and Fernando P. Polack1,2,3,4*

INFANT Fundacion, Buenos Aires, Argentina,1 Department of Pediatrics, School of Medicine,2 Departments of Molecular Microbiology and Immunology,3 International Health,4 Environmental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland,5 Department of Pediatrics, Harvard Medical School, Cambridge, Massachusetts,6 Department of Microbiology, University of Alabama, Birmingham, Alabama,7 Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle, North Carolina,8 Department of Human Science, Georgetown University, Washington, D.C.9

Received 17 August 2006/ Accepted 17 October 2006

Enhanced respiratory syncytial virus disease, a serious pulmonary disorder that affected recipients of an inactivated vaccine against respiratory syncytial virus in the 1960s, has delayed the development of vaccines against the virus. The enhanced disease was characterized by immune complex-mediated airway hyperreactivity and a severe pneumonia associated with pulmonary eosinophilia. In this paper, we show that complement factors contribute to enhanced-disease phenotypes. Mice with a targeted disruption of complement component C5 affected by the enhanced disease displayed enhanced airway reactivity, lung eosinophilia, and mucus production compared to wild-type mice and C5-deficient mice reconstituted with C5. C3aR expression in bronchial epithelial and smooth muscle cells in the lungs of C5-deficient mice was enhanced compared to that in wild-type and reconstituted rodents. Treatment of C5-deficient mice with a C3aR antagonist significantly attenuated airway reactivity, eosinophilia, and mucus production. These results indicate that C5 plays a crucial role in modulating the enhanced-disease phenotype, by affecting expression of C3aR in the lungs. These findings reveal a novel autoregulatory mechanism for the complement cascade that affects the innate and adaptive immune responses.

* Corresponding author. Mailing address: Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, E5202, Baltimore, MD 21205. Phone: (443) 287-6407. Fax: (410) 955-0105. E-mail: fpolack{at}jhsph.edu.

{triangledown} Published ahead of print on 1 November 2006.

{dagger} Both authors contributed equally to this work.

Journal of Virology, January 2007, p. 991-999, Vol. 81, No. 2
0022-538X/07/$08.00+0     doi:10.1128/JVI.01783-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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