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Infection and Immunity, January 2007, p. 325-333, Vol. 75, No. 1
0019-9567/07/$08.00+0     doi:10.1128/IAI.01054-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Role of Complement in Defense of the Middle Ear Revealed by Restoring the Virulence of Nontypeable Haemophilus influenzae siaB Mutants{triangledown}

Marisol A. Figueira,1* Sanjay Ram,2 Richard Goldstein,1 Derek W. Hood,3 E. Richard Moxon,3 and Stephen I. Pelton1

Section of Pediatric Infectious Diseases, Boston Medical Center, Boston, Massachusetts 02118,1 Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605,2 University of Oxford, Department of Pediatrics, Molecular Infectious Diseases Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom3

Received 5 July 2006/ Returned for modification 23 August 2006/ Accepted 26 October 2006

Nontypeable (NT) Haemophilus influenzae is an important cause of otitis media in children. We have shown previously that NT H. influenzae mutants defective in their ability to sialylate lipopolysaccharide (LPS), called siaB mutants, show attenuated virulence in a chinchilla model of experimental otitis media (EOM). We show that complement is a key arm of host innate immunity against NT H. influenzae-induced EOM. Depleting complement in chinchillas by use of cobra venom factor (CoVF) rendered two otherwise avirulent siaB mutants fully virulent and able to cause EOM with severity similar to that of wild-type strains. Clearance of infection caused by siaB mutants in CoVF-treated animals coincided with reappearance of C3. Wild-type strains were more resistant to direct complement-mediated killing than their siaB mutants. The serum-resistant strain bound less C3 and C4 than the serum-sensitive strain. Neither NT H. influenzae strain tested bound factor H (alternative complement pathway regulator). Selective activation of the alternative pathway resulted in more C3 binding to siaB mutants. LPS sialylation had a more profound impact on the amount of alternative-pathway-mediated C3 binding (~5-fold decrease in fluorescence) when LPS was the main C3 target, as occurred on the more serum-resistant strain. In contrast, only an ~1.5-fold decrease in fluorescence intensity of C3 binding was seen with the serum-sensitive strain, where surface proteins predominantly bound C3. Differences in binding sites for C3 and C4 may account for variations in serum resistance between NT H. influenzae strains, which in turn may impact their virulence. These data demonstrate a central role for complement in innate immune defenses against NT H. influenzae infections and specifically EOM.

* Corresponding author. Mailing address: Section of Pediatric Infectious Diseases, Maxwell Finland Laboratory for Infectious Diseases, Room 508, 774 Albany Street, Boston Medical Center, Boston, MA 02118. Phone: (617) 414-4328. Fax: (617) 414-5230. E-mail: maf6559{at}bu.edu.

{triangledown} Published ahead of print on 6 November 2006.

Editor: J. N. Weiser

Infection and Immunity, January 2007, p. 325-333, Vol. 75, No. 1
0019-9567/07/$08.00+0     doi:10.1128/IAI.01054-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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