Biochemical and immunological properties of two forms of pertactin, the 69,000-molecular-weight outer membrane protein of Bordetella pertussis

Gotto, John W.; Eckhardt, Thomas; Reilly, Patricia A.; Scott, Jane V.; Cowell, J L; Metcalf, T N; Mountzouros, K T; Gibbons, James J.; Siegel, M

doi:10.1128/iai.61.5.2211-2215.1993

Cited by 23 publications

(9 citation statements)

References 18 publications

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“…By contrast, we did not observe any killing after incubation with hu1B7, hu11E6, or an isotype control antibody. These results are in agreement with previous studies using polyclonal serum containing antibodies to PTx, Fha, and pertactin, suggesting that opsonophagocytic activity is due primarily to antipertactin antibodies (Gotto et al, 1993;Hellwig et al, 2003) and possibly anti-Fha antibodies (Aase et al, 2011). Similarly, the ability of hu1B7 and hu11E6 to reduce bacterial load in animal models does not appear to result from direct bactericidal effects but indirectly by protecting innate immune cells from PTx activities (Nguyen et al, 2015;Sato & Sato, 1990).…”

Section: Neither Antibody Directly Binds Bordetella Pertussis Nor Msupporting

confidence: 92%

Humanised monoclonal antibodies neutralise pertussis toxin by receptor blockade and reduced retrograde trafficking

Acquaye-Seedah

Huang

Sutherland

et al. 2018

Cellular Microbiology

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Pertussis toxin (PTx) is a major protective antigen produced by Bordetella pertussis that is included in all current acellular vaccines. Of several well-characterized monoclonal antibodies binding this toxin, the humanised hu1B7 and hu11E6 antibodies are highly protective in multiple in vitro and in vivo assays. In this study, we determine the molecular mechanisms of protection mediated by these antibodies. Neither antibody directly binds the B. pertussis bacterium nor supports antibody-dependent complement cytotoxicity. Both antibodies, either individually or as a cocktail, form multivalent complexes with soluble PTx that bind the FcγRIIb receptor more tightly than antibody alone, suggesting that the antibodies may accelerate PTx clearance via immune complex formation. However, a receptor binding assay and cellular imaging indicate that the main mechanism used by hu11E6 is competitive inhibition of PTx binding to its cellular receptor. In contrast, the main hu1B7 neutralising mechanism appears to be inhibition of PTx internalisation and retrograde trafficking. We assessed the effects of hu1B7 on PTx retrograde trafficking in CHO-K1 cells using quantitative immunofluorescence microscopy. In the absence of hu1B7 or after incubation with an isotype control antibody, PTx colocalizes to organelles in a manner consistent with retrograde transport. However, after preincubation with hu1B7, PTx appears restricted to the membrane surface with colocalization to organelles associated with retrograde transport significantly reduced. Together, these data support a model whereby hu11E6 and hu1B7 interfere with PTx receptor binding and PTx retrograde trafficking, respectively.

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Section: Neither Antibody Directly Binds Bordetella Pertussis Nor Msupporting

confidence: 92%

Humanised monoclonal antibodies neutralise pertussis toxin by receptor blockade and reduced retrograde trafficking

Acquaye-Seedah

Huang

Sutherland

et al. 2018

Cellular Microbiology

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“…In the pertussis field, the complement-mediated bactericidal activity of antibodies has been assessed by a radial diffusion serum assay (Weiss et al, 1999;Oliver and Fernandez, 2001) or a bactericidal assay using as complement source either guinea pig serum (Weingart et al, 2000a;Riaz et al, 2015), precolostral calf serum (Gotto et al, 1993;Kubler-Kielb et al, 2011) or endogenous complement present in the sample (Weiss et al, 1999). Studies performed on N. meningitidis suggest that the source of complement is important to accurately quantify serostatus and human complement is the preferred source of complement to use for serogroup B N. meningitidis assays (Santos et al, 2001;Gill et al, 2011;Findlow et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Acellular Pertussis Vaccines Induce Anti-pertactin Bactericidal Antibodies Which Drives the Emergence of Pertactin-Negative Strains

et al. 2020

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Despite high vaccination coverage, Bordetella pertussis the causative agent of whooping cough is still a health concern worldwide. A resurgence of pertussis cases has been reported, particularly in countries using acellular vaccines with waning immunity and pathogen adaptation thought to be responsible. A better understanding of protective immune responses is needed for the development of improved vaccines. In our study, B. pertussis strain B1917 variants presenting a single gene deletion were generated to analyze the role of vaccine components or candidate vaccine antigens as targets for bactericidal antibodies generated after acellular vaccination or natural infection. Our results show that acellular vaccination generates bactericidal antibodies that are only directed against pertactin. Serum bactericidal assay performed with convalescent samples show that disease induces bactericidal antibodies against Prn but against other antigen(s) as well. Four candidate vaccine antigens (CyaA, Vag8, BrkA, and TcfA) have been studied but were not targets for complement-mediated bactericidal antibodies after natural infection. We confirm that Vag8 and BrkA are involved in complement resistance and would be targeted by blocking antibodies. Our study suggests that the emergence and the widespread circulation of Prn-deficient strains is driven by acellular vaccination and the generation of bactericidal antibodies targeting Prn.

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“…Of the protein antigens that are being considered for the expanded-spectrum acellular vaccines, only pertactin and fimbriae are surface localized. Pertactin has been shown to elicit bactericidal antibodies (12), and acellular vaccines containing pertactin have been reported to give better protection than vaccines lacking this component (13,30). Its role as a bactericidal target needs to be evaluated further in vaccine recipients that have received this antigen.…”

Section: Figmentioning

confidence: 99%

“…Unlike the highly polymerized LPS of the enteric bacteria, the LPS of B. pertussis does not appear to protect from complement killing, since monoclonal antibodies to band A LPS have been shown to be bactericidal (35). Monoclonal antibodies to the outer membrane protein, pertactin, have also been shown to be bactericidal (12).…”

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confidence: 99%

Characterization of Human Bactericidal Antibodies toBordetella pertussis

et al. 1999

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The Bordetella pertussis BrkA protein protects against the bactericidal activity of complement and antibody; however, some individuals mount an immune response that overcomes this bacterial defense. To further characterize this process, the bactericidal activities of sera from 13 adults with different modes of exposure toB. pertussis (infected as adults, occupational exposure, immunized with an acellular vaccine, or no identified exposure) against a wild-type strain and a BrkA complement-sensitive mutant were evaluated. All of the sera killed the BrkA mutant, suggesting past exposure to B. pertussis or cross-reactive organisms. Several samples had no or minimal activity against the wild type. All of the sera collected from the infected and occupationally exposed individuals but not all of the sera from vaccinated individuals had bactericidal activity against the wild-type strain, suggesting that some types of exposure can induce an immune response that can overcome the BrkA resistance mechanism. Adsorbing serum with the wild-type strain removed the bactericidal antibodies; however, adsorbing the serum with a lipopolysaccharide (LPS) mutant or an avirulent (bvg mutant) strain did not always result in loss of bactericidal activity, suggesting that antibodies to either LPS orbvg-regulated proteins could be bactericidal. All the samples, including those that lacked bactericidal activity, contained antibodies that recognized the LPS of B. pertussis. Bactericidal activity correlated best with the presence of the immunoglobulin G3 (IgG3) antibodies to LPS, the IgG subtype that is most effective at fixing complement.

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Biochemical and immunological properties of two forms of pertactin, the 69,000-molecular-weight outer membrane protein of Bordetella pertussis

Cited by 23 publications

References 18 publications

Humanised monoclonal antibodies neutralise pertussis toxin by receptor blockade and reduced retrograde trafficking

Humanised monoclonal antibodies neutralise pertussis toxin by receptor blockade and reduced retrograde trafficking

Acellular Pertussis Vaccines Induce Anti-pertactin Bactericidal Antibodies Which Drives the Emergence of Pertactin-Negative Strains

Characterization of Human Bactericidal Antibodies toBordetella pertussis

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