Nontypeable Haemophilus influenzae P5 Binds Human C4b-Binding Protein, Promoting Serum Resistance

J Immunol. 2021 Sep 15;207(6):1566-1577. doi: 10.4049/jimmunol.2100105. Epub 2021 Aug 25.


Nontypeable Haemophilus influenzae (NTHi) is a Gram-negative human pathogen that causes infections mainly in the upper and lower respiratory tract. The bacterium is associated with bronchitis and exacerbations in patients suffering from chronic obstructive pulmonary disease and frequently causes acute otitis media in preschool children. We have previously demonstrated that the binding of C4b binding protein (C4BP) is important for NTHi complement evasion. In this study, we identified outer membrane protein 5 (P5) of NTHi as a novel ligand of C4BP. Importantly, we observed significantly lower C4BP binding and decreased serum resistance in P5-deficient NTHi mutants. Surface expression of recombinant P5 on Escherichia coli conferred C4BP binding and consequently increased serum resistance. Moreover, P5 expression was positively correlated with C4BP binding in a series of clinical isolates. We revealed higher levels of P5 surface expression and consequently more C4BP binding in isolates from the lower respiratory tract of chronic obstructive pulmonary disease patients and tonsil specimens compared with isolates from the upper respiratory tract and the bloodstream (invasive strains). Our results highlight P5 as an important protein for protecting NTHi against complement-mediated killing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Bacteremia / genetics
  • Bacteremia / immunology*
  • Bacterial Outer Membrane Proteins / genetics
  • Bacterial Outer Membrane Proteins / metabolism*
  • Child
  • Complement C4b-Binding Protein / metabolism*
  • Complement System Proteins / metabolism
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Female
  • Haemophilus Infections / immunology*
  • Haemophilus Infections / microbiology
  • Haemophilus influenzae / genetics
  • Haemophilus influenzae / metabolism*
  • Humans
  • Ligands
  • Male
  • Middle Aged
  • Organisms, Genetically Modified
  • Protein Binding / genetics
  • Pulmonary Disease, Chronic Obstructive / immunology*
  • Pulmonary Disease, Chronic Obstructive / microbiology
  • Recombinant Proteins / metabolism
  • Signal Transduction / genetics
  • Tonsillitis / immunology*
  • Tonsillitis / microbiology


  • Bacterial Outer Membrane Proteins
  • C4BPA protein, human
  • Complement C4b-Binding Protein
  • Ligands
  • Recombinant Proteins
  • OMPA outer membrane proteins
  • Complement System Proteins