New Insight into Filamentous Hemagglutinin Secretion Reveals a Role for Full-Length FhaB in Bordetella Virulence.
Bordetella filamentous hemagglutinin (FHA), a primary component of acellular pertussis vaccines, contributes to virulence, but how it functions mechanistically is unclear. FHA is first synthesized as an ~370-kDa preproprotein called FhaB. Removal of an N-terminal signal peptide and a large C-terminal prodomain (PD) during secretion results in "mature" ~250-kDa FHA, which has been assumed to be the biologically active form of the protein. Deletion of two C-terminal subdomains of FhaB did not affect production of functional FHA, and the mutant strains were indistinguishable from wild-type bacteria for their ability to adhere to the lower respiratory tract and to suppress inflammation in the lungs of mice. However, the mutant strains, which produced altered FhaB molecules, were eliminated from the lower respiratory tract much faster than wild-type B. bronchiseptica, suggesting a defect in resistance to early immune-mediated clearance. Our results revealed, unexpectedly, that full-length FhaB plays a critical role in B. bronchiseptica persistence in the lower respiratory tract.


OBJECTIVE
The Bordetella filamentous hemagglutinin (FHA) is a primary component of the acellular pertussis vaccine and an important virulence factor. FHA is initially produced as a large protein that is processed during secretion to the bacterial surface. As with most processed proteins, the mature form of FHA has been assumed to be the functional form of the protein. However, our results indicate that the full-length form plays an essential role in virulence in vivo. Furthermore, we have found that FHA contains intramolecular regulators of processing and that this control of processing is integral to its virulence activities. This report highlights the advantage of studying protein maturation and function simultaneously, as a role for the full-length form of FHA was evident only from in vivo infection studies and not from in vitro studies on the production or maturation of FHA or even from in vitro virulence-associated activity assays.
Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Jeffrey A
JA
Melvin
Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Erich V
EV
Scheller
Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Christopher R
CR
Noël
Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA peggy_cotter@med.unc.edu.
Peggy A
PA
Cotter
D018829:Adhesins, Bacterial / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001422:Bacterial Adhesion; D016950:Bordetella bronchiseptica / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000472:pathogenicity*; D022681:Diphtheria-Tetanus-acellular Pertussis Vaccines / Q000737:chemistry; D005260:Female; D008168:Lung / Q000382:microbiology; D051379:Mice; D009154:Mutation; D017434:Protein Structure, Tertiary; D020545:Respiratory Mucosa / Q000382:microbiology*; D016415:Sequence Alignment; D014774:Virulence / Q000235:genetics; D010566:Virulence Factors, Bordetella / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D018829:Adhesins, Bacterial; D022681:Diphtheria-Tetanus-acellular Pertussis Vaccines; D010566:Virulence Factors, Bordetella; C065273:filamentous hemagglutinin adhesin, Bordetella pertussis