MORAXELLA CATARRHALIS OUTER MEMBRANE PROTEINS AND INTERACTIONS WITH THE HUMAN IMMUNE SYSTEM

Sammanfattning: Moraxella catarrhalis is frequently colonizing the human respiratory tract, particularly in children. This gram-negative bacterium has during the last two decades been recognized as a pathogen causing otitis media in children and lower respiratory tract infections in adults with predisposing conditions such as chronic obstructive pulmonary disease (COPD). The virulence determinants of M. catarrhalis are believed to be the lipooligosaccharide and the outer membrane proteins. Three important outer membrane proteins are Moraxella IgD-binding protein (MID), the ubiquitous surface proteins (Usp) A1 and A2. MID is an adhesin and it binds to IgD in a non-immune manner. We show that the mid gene was highly conserved, and that the MID expression varied without relation to the anatomical site of isolation or geographical origin of the isolates. The expression was also shown to be controlled by a poly(G)tract downstream of the startcodon. The region of MID with essentially preserved IgD-binding was determined to be located between the amino acid residues 962-1200 and was designated MID962-1200. MID962-1200 was shown to be a tetramer in native conditions and interestingly, this tetrameric form bound IgD 23-fold more efficiently than the monomeric form. Moreover, MID962-1200 stimulated purified B cells to proliferate independently of T cells. However, addition of IL-4 or IL-2 was required for efficient proliferation. We have also shown that M. catarrhalis interferes with both the classical and the alternative pathway of the complement system. It bound to the fluid phase inhibitor C4b-binding protein (C4BP) and the binding was mediated through UspA1 and UspA2. Importantly, C4BP retained its activity when bound to the surface of M. catarrhalis and was thus able to inhibit the activation through the classical pathway. We also showed that M. catarrhalis have the capacity to absorb C3 from serum independently of complement activation and UspA2 was determined to be the major binder of C3. In summary, MID is widely distributed among different M. catarrhalis strains. The IgD-binding region of MID is located between the amino acid residues 962-1200 and stimulates B cells independently of T cells. Finally, the M. catarrhalis outer membrane proteins UspA1 and UspA2 interfere with the complement system by binding C4BP and C3.