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* Department of Pathobiology, School of Public Health and Community Medicine, University of Washington, Seattle, WA 98195;
Microbial Pathogens Program, Seattle Biomedical Research Institute, Seattle, WA 98109; and
Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655
We have previously shown that C3 binding to serum-resistant nontypeable Haemophilus influenzae (NTHi) strain R2866 is slower than C3 binding to a serum-sensitive strain. Ab-dependent classical pathway activation is required for complement-dependent killing of NTHi. To further characterize the mechanism(s) of serum resistance of R2866, we compared binding of complement component C4b to R2866 with a serum-sensitive variant, R3392. We show that C4b binding to R2866 relative to R3392 was delayed, suggesting regulation of the classical pathway of complement. Increased C4b deposition on R3392 was independent of the amount and subclass of Ab binding, suggesting that an impediment to C4b binding existed on R2866. Immunoblotting and mass spectrometry indicated that lipooligosaccharide and outer membrane proteins P2 and P5 were targets for C4b. P2 and P5 sequences and expression levels were similar in both strains. Insertional inactivation of the phase-variable lipooligosaccharide biosynthesis gene lgtC in R2866 augmented C4b deposition to levels seen with R3392 and rendered the bacteria sensitive to serum and whole blood. These results suggest a direct role of lgtC expression in the inhibition of C4b deposition and consequent serum resistance of R2866. Alteration of surface glycans of NTHi may be a critical event in determining the ability of a strain to evade host defenses and cause disseminated infection.
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1 This work was supported by National Institutes of Health Grants AI44002 and AI054544.
2 Address correspondence and reprint requests to Dr. Arnold L. Smith, Microbial Pathogens Program, Seattle Biomedical Research Institute, 307 Westlake Avenue N, Suite 500, Seattle, WA 98109-5219. E-mail address: arnold.smith{at}sbri.org
3 Abbreviations used in this paper: NTHi, nontypeable H. influenzae; CP, classical pathway; LOS, lipooligosaccharide; NHS, normal human serum; sBHI, supplemented brain-heart infusion broth; HINHS, heat-inactivated NHS; ORF, open reading frame; KDO, 2-keto-3-deoxyoctulosonic acid; PEA, phosphoethanolamine; ChoP, phosphorylcholine; Hib, H. influenzae type B.
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