Bordetella filamentous hemagglutinin and fimbriae: critical adhesins with unrealized vaccine potential

Abstract

Pertussis, or whooping cough, is a highly contagious respiratory disease that is caused by the Gram-negative bacterium Bordetella pertussis, which is transmitted exclusively from human to human. While vaccination against B. pertussis has been successful, replacement of the whole cell vaccine with an acellular component vaccine has correlated with reemergence of the disease, especially in adolescents and infants. Based on their presumed importance in mediating adherence to host tissues, filamentous hemagglutinin (FHA) and fimbria (FIM) were selected as components of most acellular pertussis vaccines. In this review, we describe the biogenesis of FHA and FIM, recent data that show that these factors do, in fact, play critical roles in adherence to respiratory epithelium, and evidence that they also contribute to persistence in the lower respiratory tract by modulating the host immune response. We also discuss shortcomings of whole cell and acellular pertussis vaccines and the possibility that FHA and FIM could serve as effective protective antigens in next-generation vaccines.

Keywords: Bordetella pertussis; filamentous hemagglutinin; fimbriae; immunity.

Graphical Abstract Figure.

Bordetella fimbriae and filamentous hemagglutinin are critical adhesins and are potential protective antigens for next-generation vaccines.

Figure 1.

FHA biogenesis. FhaB is an ∼370 kDa polypeptide. After removal of the 71 aa signal sequence, the TPS domain of FhaB (gold) interacts with the POTRA domains of FhaC (blue), initiating translocation across the outer membrane (om). The N-terminal ∼2500 aa of FhaB fold into a β-helix on the cell surface. The C-terminal proline-rich region (PRR) may interact with a periplasmic protein or protein domain, and the extreme C-terminal domain (ECT) inhibits an unknown protease. The N-terminus of the prodomain (PNT, dark green) prevents translocation of the prodomain across the om. In response to an unknown signal, the ECT releases inhibition of the unknown protease and the prodomain is degraded. FhaB is also processed by the serine protease SphB1 (purple) to form ‘mature’ ∼240 kDa FHA. FHA is released from the cell surface by an unknown mechanism.

Figure 2.

FIM biogenesis. The FimC protein is predicted to be an integral outer membrane (om) β-barrel usher protein. FimB is predicted to function as a chaperone that binds FimD, Fim2 and Fim3 proteins, preventing their degradation in the periplasm and directing them to FimC for translocation across the om. Within FimC, the FimB chaperone transfers the fimbrial subunit to the next subunit in the channel by donor strand exchange, resulting in elongation of the FIM structure.

Figure 3.

The bvgAS-fhaB-fimA-fimBCDfhaC gene cluster. The arrangement of the bvgAS-fhaB-fimA-fimBCDfhaC genes on the chromosome is shown. The pointed end of the box for each gene represents the 3^′ end. Promoters are shown as arrows.