B. pertussis, the causative agent of whooping cough, is estimated to cause 600,000 deaths annually on a worldwide basis. Adherence and intoxication are the key elements of the interactions between B. pertussis and the human host. Filamentous hemagglutinin (FHA) is the dominant adhesin for this organism and a component of most acellular pertussis vaccines. It mediates attachment to a variety of host cells, including monocytes and macrophages. Recognition of FHA by leukocytes involves at least two integrin receptors: the complement 3 receptor (CR3) and the leukocyte response integrin (LRI). Recent data indicate that FHA induces signaling events in monocytes through LRI that enhance FHA recognition by CR3, and that FHA is necessary for B. pertussis inhibition of monocyte-dependent T- cell proliferative responses to antigen. Thus, the interactions between FHA and leukocyte integrins are proposed to be significant for two reasons: 1) FHA-mediated attachment of B. pertussis to monocytes may facilitate bacterial colonization, as well as modify host cellular immune responses; and 2) FHA can be used to study the binding and signaling capabilities of leukocyte integrins. The broad, long-term objectives of this application are to understand the mechanisms and implications of bacterial-integrin interactions. The more immediate goals of this proposal are to characterize FHA as a ligand for CR3 and LRI, to examine signaling molecules associated with FHA receptor ligation, and to examine the consequences of these interactions for B. pertussis pathogenesis.
The specific aims of this proposal are: 1) To map the FHA domain(s) recognized by the complement receptor CR3. 2) To characterize signaling mechanisms associated with FHA-induced upregulated CR3 binding activity. 3) To examine the effect of B. pertussis binding on the topological distribution of monocyte integrin receptors and associated signaling molecules. 4) To examine B. pertussis inhibition of antigen-dependent T- cell proliferation.
