Bordetella pertussis filamentous hemagglutinin interacts with a leukocyte signal transduction complex and stimulates bacterial adherence to monocyte CR3 (CD11b/CD18).

Abstract

SummaryBordetella pertussis, the causative agent of whooping cough, adheres to human monocytes/macrophages by means of a bacterial surface-associated protein, filamentous hemagglutinin (FHA) and the leukocyte integrin, complement receptor 3 (CR3, ~xmfl2, CDllb/CD18). We show that an FHA Arg-Gly-Asp site induces enhanced R pertussis binding to monocytes, and that this enhancement is blocked by antibodies directed against CR3. Enhancement requires a monocyte signal transduction complex, composed of leukocyte response integrin (a~/33) and integrinassociated protein (CD47). This complex is known to upregulate CR3 binding activity. Thus, a bacterial pathogen enhances its own attachment to host cells by coopting a host cell signaling pathway.A tachment of the gram-negative bacterium Bordetella pertuss/s to host cells at or near the respiratory mucosal surface is a crucial feature of whooping cough pathogenesis in humans. Ciliated respiratory epithelial cells and leukocytes are the primary targets for adherence by this organism (1-3). This process leads to respiratory tract colonization, systemic intoxication, and altered host immune cell function. R pertussis attachment involves a bacterial surface-associated and secreted protein, filamentous hemagglutinin (FHA) 1, and host galactose-containing glycoconjugates (4-7). In addition, FHA recognizes a leukocyte B2-integrin, complement receptor type 3 (CR3, CDllb/CD18, ol~2) (8). The biologic significance of FHA-CR3 recognition and R pertuss/s binding to leukocytes in nature may reflect several possible outcomes, including competitive blockade of CR3 by secreted FHA, facilitated delivery of bacterial toxins to host leukocytes, and/or bacterial intracellular entry, survival, and persistence (9-13). A recent study suggests that cross-linking of the fibronectin 1 Abbreviations used in this paper: FHA, filamentous hemagglutinin; lAP, integrin-associated protein; LRI, leukocyte response integrin; MDM, monocyte-derived macrophages; PT, pertussis toxin; RGD, Arg-Gly-Asp.This work has been presented in part at the meeting of the American Federation for Clinical Research, Western Section, Carmel, CA, 5 February 1994, and submitted in abstract form to the Annual Meeting of the American Society for Microbiology, Las Vegas. receptor otsfll on human peripheral monocytes enhances CR3-mediated attachment ofR pertussis via FHA (14). Augmented fl2-integrin-binding activity can be elicited by a number of other receptor-ligand binding interactions, including CD14 recognition of the LPS-LPS binding protein complex (15) and a fl3-integrin-containing receptor signal transduction complex (description follows).FHA and an intrinsic host ligand for CR3, complement fragment iC3b, contain Arg-Gly-Asp (RGD) cell recognition sites. These tripeptide motifs often denote binding domains that are recognized by integrins (16--18). It was initially assumed that the FHA and iC3b RGD sites were directly recognized by CR3. This assumption was based on the following observations: (a) an FHA RGD site-directed muta...

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