title: Complement Factor H Serum Levels Determine Resistance to Pneumococcal Invasive Disease.
abstract: Streptococcus pneumoniae is a major cause of life-threatening infections. Complement activation plays a vital role in opsonophagocytic killing of pneumococci in blood. Initial complement activation via the classical and lectin pathways is amplified through the alternative pathway amplification loop. Alternative pathway activity is inhibited by complement factor H (FH). Our study demonstrates the functional consequences of the variability in human serum FH levels on host defense. Using an in vivo mouse model combined with human in vitro assays, we show that the level of serum FH correlates with the efficacy of opsonophagocytic killing of pneumococci. In summary, we found that FH levels determine a delicate balance of alternative pathway activity, thus affecting the resistance to invasive pneumococcal disease. Our results suggest that variation in FH expression levels, naturally occurring in the human population, plays a thus far unrecognized role in the resistance to invasive pneumococcal disease.
authors.affiliation: Laboratory of Pediatric Infectious Diseases.
authors.forename: Erika
authors.initials: E
authors.lastname: van der Maten
authors.affiliation: Division of Pediatric Nephrology.
authors.forename: Dineke
authors.initials: D
authors.lastname: Westra
authors.affiliation: Laboratory of Pediatric Infectious Diseases.
authors.forename: Saskia
authors.initials: S
authors.lastname: van Selm
authors.affiliation: Laboratory of Pediatric Infectious Diseases.
authors.forename: Jeroen D
authors.initials: JD
authors.lastname: Langereis
authors.affiliation: Laboratory of Pediatric Infectious Diseases.
authors.forename: Hester J
authors.initials: HJ
authors.lastname: Bootsma
authors.affiliation: Laboratory of Pediatric Infectious Diseases.
authors.forename: Fred J H
authors.initials: FJ
authors.lastname: van Opzeeland
authors.affiliation: Laboratory of Pediatric Infectious Diseases.
authors.forename: Ronald
authors.initials: R
authors.lastname: de Groot
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College, London, United Kingdom.
authors.forename: Marieta M
authors.initials: MM
authors.lastname: Ruseva
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College, London, United Kingdom.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Pickering
authors.affiliation: Division of Pediatric Nephrology.
authors.forename: Lambert P W J
authors.initials: LP
authors.lastname: van den Heuvel
authors.affiliation: Division of Pediatric Nephrology.
authors.forename: Nicole C A J
authors.initials: NC
authors.lastname: van de Kar
authors.affiliation: Laboratory of Pediatric Infectious Diseases.
authors.forename: Marien I
authors.initials: MI
authors.lastname: de Jonge
authors.affiliation: Laboratory of Pediatric Infectious Diseases Division of Pediatric Infectious Diseases and Immunology, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: van der Flier
mesh_terms: D000818:Animals; D003176:Complement C3 / Q000276:immunology; D017242:Complement Factor H / Q000276:immunology; D060467:Disease Resistance / Q000276:immunology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011008:Pneumococcal Infections / Q000276:immunology* / Q000517:prevention & control
chemical_list: C493495:CFH protein, human; D003176:Complement C3; D017242:Complement Factor H
keywords: C3 opsonization; Streptococcus pneumoniae; alternative pathway; complement system; factor H; invasive pneumococcal disease