title: Immune evasion of Moraxella catarrhalis involves ubiquitous surface protein A-dependent C3d binding.
abstract: The complement system plays an important role in eliminating invading pathogens. Activation of complement results in C3b deposition (opsonization), phagocytosis, anaphylatoxin (C3a, C5a) release, and consequently cell lysis. Moraxella catarrhalis is a human respiratory pathogen commonly found in children with otitis media and in adults with chronic obstructive pulmonary disease. The species has evolved multiple complement evasion strategies, which among others involves the ubiquitous surface protein (Usp) family consisting of UspA1, A2, and A2 hybrid. In the present study, we found that the ability of M. catarrhalis to bind C3 correlated with UspA expression and that C3 binding contributed to serum resistance in a large number of clinical isolates. Recombinantly expressed UspA1 and A2 inhibit both the alternative and classical pathways, C3b deposition, and C3a generation when bound to the C3 molecule. We also revealed that the M. catarrhalis UspA-binding domain on C3b was located to C3d and that the major bacterial C3d-binding domains were within UspA1(299-452) and UspA2(165-318). The interaction with C3 was not species specific since UspA-expressing M. catarrhalis also bound mouse C3 that resulted in inhibition of the alternative pathway of mouse complement. Taken together, the binding of C3 to UspAs is an efficient strategy of Moraxella to block the activation of complement and to inhibit C3a-mediated inflammation.
authors.affiliation: Department of Laboratory Medicine Malmö, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Teresia
authors.initials: T
authors.lastname: Hallström
authors.forename: Therése
authors.initials: T
authors.lastname: Nordström
authors.forename: Thuan Tong
authors.initials: TT
authors.lastname: Tan
authors.forename: Taras
authors.initials: T
authors.lastname: Manolov
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
authors.forename: David E
authors.initials: DE
authors.lastname: Isenman
authors.forename: Peter F
authors.initials: PF
authors.lastname: Zipfel
authors.forename: Anna M
authors.initials: AM
authors.lastname: Blom
authors.forename: Kristian
authors.initials: K
authors.lastname: Riesbeck
mesh_terms: D000328:Adult; D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism / Q000502:physiology*; D000954:Antigens, Surface / Q000378:metabolism / Q000502:physiology*; D001425:Bacterial Outer Membrane Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D002648:Child; D003167:Complement Activation / Q000276:immunology; D015926:Complement C3a / Q000037:antagonists & inhibitors / Q000502:physiology; D015933:Complement C3d / Q000378:metabolism*; D003169:Complement Inactivator Proteins / Q000502:physiology; D003170:Complement Pathway, Alternative / Q000276:immunology; D006801:Humans; D057131:Immune Evasion / Q000276:immunology*; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D001936:Moraxella catarrhalis / Q000276:immunology* / Q000302:isolation & purification / Q000472:pathogenicity; D045828:Moraxellaceae Infections / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D011485:Protein Binding / Q000276:immunology; D011817:Rabbits; D012756:Sheep
chemical_list: D000942:Antigens, Bacterial; D000954:Antigens, Surface; D001425:Bacterial Outer Membrane Proteins; D003169:Complement Inactivator Proteins; C089675:UspA protein, Moraxella catarrhalis; D015926:Complement C3a; D015933:Complement C3d