title: Haemophilus influenzae Type f Hijacks Vitronectin Using Protein H To Resist Host Innate Immunity and Adhere to Pulmonary Epithelial Cells.
abstract: The incidence of invasive Haemophilus influenzae type b (Hib) disease has significantly decreased since the introduction of an efficient vaccine against Hib. However, in contrast to Hib, infections caused by H. influenzae serotype f (Hif) are emerging. We recently did a whole genome sequencing of an invasive Hif isolate, and reported that Hif interacts with factor H by expressing protein H (PH). In this study, upon screening with various human complement regulators, we revealed that PH is also a receptor for vitronectin (Vn), an abundant plasma protein that regulates the terminal pathway of the human complement system in addition to being a component of the extracellular matrix. Bacterial Vn binding was significantly reduced when the lph gene encoding PH was deleted in an invasive Hif isolate. The dissociation constant (KD) of the interaction between recombinant PH and Vn was 2.2 μM, as revealed by Biolayer interferometry. We found that PH has different regions for simultaneous interaction with both Vn and factor H, and that it recognized the C-terminal part of Vn (aa 352-362). Importantly, PH-dependent Vn binding resulted in better survival of the wild-type Hif or PH-expressing Escherichia coli when exposed to human serum. Finally, we observed that PH mediated an increased bacterial adherence to alveolar epithelial cells in the presence of Vn. In conclusion, our study reveals that PH most likely plays an important role in Hif pathogenesis by increasing serum resistance and adhesion to the airways.
authors.affiliation: Clinical Microbiology, Department of Translational Medicine, Lund University, SE-205 02 Malmö, Sweden;
authors.forename: Tamim
authors.identifier: http://orcid.org/0000-0001-6954-5293
authors.initials: T
authors.lastname: Al-Jubair
authors.affiliation: Clinical Microbiology, Department of Translational Medicine, Lund University, SE-205 02 Malmö, Sweden;
authors.forename: Oindrilla
authors.initials: O
authors.lastname: Mukherjee
authors.affiliation: Clinical Microbiology, Department of Translational Medicine, Lund University, SE-205 02 Malmö, Sweden;
authors.forename: Sharon
authors.identifier: http://orcid.org/0000-0002-3531-091X
authors.initials: S
authors.lastname: Oosterhuis
authors.affiliation: Clinical Microbiology, Department of Translational Medicine, Lund University, SE-205 02 Malmö, Sweden;
authors.forename: Birendra
authors.identifier: http://orcid.org/0000-0002-7246-1442
authors.initials: B
authors.lastname: Singh
authors.affiliation: Clinical Microbiology, Department of Translational Medicine, Lund University, SE-205 02 Malmö, Sweden;
authors.forename: Yu-Ching
authors.identifier: http://orcid.org/0000-0003-3398-6294
authors.initials: YC
authors.lastname: Su
authors.affiliation: Clinical Microbiology, Department of Translational Medicine, Lund University, SE-205 02 Malmö, Sweden;
authors.forename: Christophe
authors.initials: C
authors.lastname: Fleury
authors.affiliation: Protein Chemistry, Department of Translational Medicine, Lund University, SE-205 02 Malmö, Sweden; and.
authors.forename: Anna M
authors.identifier: http://orcid.org/0000-0002-1348-1734
authors.initials: AM
authors.lastname: Blom
authors.affiliation: Department of Biochemistry and Structural Biology, Lund University, SE-221 00 Lund, Sweden.
authors.forename: Susanna
authors.identifier: http://orcid.org/0000-0002-9435-8243
authors.initials: S
authors.lastname: Törnroth-Horsefield
authors.affiliation: Clinical Microbiology, Department of Translational Medicine, Lund University, SE-205 02 Malmö, Sweden; kristian.riesbeck@med.lu.se.
authors.forename: Kristian
authors.initials: K
authors.lastname: Riesbeck
mesh_terms: D001422:Bacterial Adhesion; D001770:Blood Bactericidal Activity; D017242:Complement Factor H / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology* / Q000382:microbiology; D057809:HEK293 Cells; D006192:Haemophilus Infections / Q000276:immunology / Q000382:microbiology*; D006193:Haemophilus influenzae / Q000472:pathogenicity*; D006801:Humans; D057131:Immune Evasion; D007113:Immunity, Innate; D011650:Pulmonary Alveoli / Q000473:pathology*; D019096:Vitronectin / Q000378:metabolism*
chemical_list: D019096:Vitronectin; D017242:Complement Factor H