Intranasal immunization with recombinant outer membrane protein P6 induces specific immune responses against nontypeable Haemophilus influenzae

Hotomi, Muneki; Yamanaka, Noboru; Shimada, Jun; Suzumoto, Masaki; Ikeda, Yorihiko; Sakai, Akihiro; Arai, Jun; Green, Bruce

doi:10.1016/s0165-5876(02)00076-9

Cited by 26 publications

(17 citation statements)

References 25 publications

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“…It is important to note that immune responses induced by native (i.e., nCT and nLT) or chimeric (CT-A/LT-B or LT-A/CT-B) enterotoxins could be different if these enterotoxins were used as adjuvants for more complex Ags or Ags with intrinsic biological activity (i.e., endotoxin). In this regard, high IgG1 and IgG2b Ab responses to Hemophilus influenzae were seen in mice immunized nasally with a recombinant outer membrane protein P6 of nontypeable H. influenzae and nCT as adjuvant (61). In contrast, no IgG1 and high IgG2a Ab responses as well as and CD4…”

Section: Discussionmentioning

confidence: 96%

Chimeras of Labile Toxin One and Cholera Toxin Retain Mucosal Adjuvanticity and Direct Th Cell Subsets Via Their B Subunit

Boyaka

Ohmura

Fujihashi

et al. 2003

The Journal of Immunology

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Native cholera toxin (nCT) and the heat-labile toxin 1 (nLT) of enterotoxigenic Escherichia coli are AB5-type enterotoxins. Both nCT and nLT are effective adjuvants that promote mucosal and systemic immunity to protein Ags given by either oral or nasal routes. Previous studies have shown that nCT as mucosal adjuvant requires IL-4 and induces CD4-positive (CD4+) Th2-type responses, while nLT up-regulates Th1 cell production of IFN-γ and IL-4-independent Th2-type responses. To address the relative importance of the A or B subunits in CD4+ Th cell subset responses, chimeras of CT-A/LT-B and LT-A/CT-B were constructed. Mice nasally immunized with CT-A/LT-B or LT-A/CT-B and the weak immunogen OVA developed OVA-specific, plasma IgG Abs titers similar to those induced by either nCT or nLT. Both CT-A/LT-B and LT-A/CT-B promoted secretory IgA anti-OVA Ab, which established their retention of mucosal adjuvant activity. The CT-A/LT-B chimera, like nLT, induced OVA-specific mucosal and peripheral CD4+ T cells secreting IFN-γ and IL-4-independent Th2-type responses, with plasma IgG2a anti-OVA Abs. Further, LT-A/CT-B, like nCT, promoted plasma IgG1 more than IgG2a and IgE Abs with OVA-specific CD4+ Th2 cells secreting high levels of IL-4, but not IFN-γ. The LT-A/CT-B chimera and nCT, but not the CT-A/LT-B chimera or nLT, suppressed IL-12R expression and IFN-γ production by activated T cells. Our results show that the B subunits of enterotoxin adjuvants regulate IL-12R expression and subsequent Th cell subset responses.

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Section: Discussionmentioning

confidence: 96%

Chimeras of Labile Toxin One and Cholera Toxin Retain Mucosal Adjuvanticity and Direct Th Cell Subsets Via Their B Subunit

Boyaka

Ohmura

Fujihashi

et al. 2003

The Journal of Immunology

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“…P6 induces protective immune responses in a variety of animal model systems, including the infant rat model of invasive infection (17,33,53), a rat pulmonary clearance model (27), otitis media models in the chinchilla and mouse (12,18,48), and nasopharyngeal colonization models (6,21,23,32). P6 is the target of bactericidal antibodies from rats, chinchillas, rabbits, and humans (12,17,27,38).…”

mentioning

confidence: 99%

Construction of a Mutant and Characterization of the Role of the Vaccine Antigen P6 in Outer Membrane Integrity of NontypeableHaemophilus influenzae

2006

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Outer membrane protein P6 is the subject of investigation as a vaccine antigen to prevent infections caused by nontypeable Haemophilus influenzae, which causes otitis media in children and respiratory tract infections in adults with chronic lung disease. P6 induces protective immune responses in animal models and is the target of potentially protective immune responses in humans. P6 is a 16-kDa lipoprotein that shares homology with the peptidoglycan-associated lipoproteins of gram-negative bacteria and is highly conserved among strains of H. influenzae. To characterize the function of P6, an isogenic mutant was constructed by replacing the P6 gene with a chloramphenicol resistance cassette. The P6 mutant showed altered colony morphology and slower growth in vitro than that of the parent strain. By electron microscopy, the P6 mutant cells demonstrated increased size, variability in size, vesicle formation, and fragility compared to the parent cells. The P6 mutant showed hypersensitivity to selected antibiotics with different mechanisms of action, indicating increased accessibility of the agents to their targets. The P6 mutant was more sensitive to complement-mediated killing by normal human serum. Complementation of the mutation in trans completely or partially restored the phenotypes. We concluded that P6 plays a structural role in maintaining the integrity of the outer membrane by anchoring the outer membrane to the cell wall. The observation that the absence of expression of P6 is detrimental to the cell is a highly desirable feature for a vaccine antigen, supporting further investigation of P6 as a vaccine candidate for H. influenzae.

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“…Moreover, mucosal (i.n.) immunization of mice with recombinant P6 combined with cholera toxin stimulated P6-specific mucosal IgA and systemic IgG responses, and enhanced clearance of NTHi from the nasopharynx and middle ear (Hotomi et al, 2002;Sabirov et al, 2001). Thus, these data suggest that the design of future NTHi vaccines should be directed toward mucosal immunization with H. influenzae surface lipoproteins and possibly other NTHi antigens, such as lipooligosaccharide, fimbriae, and outer membrane proteins, to limit colonization and disease.…”

Section: Vaccinementioning

confidence: 92%

Respiratory Bacterial Vaccines

Nicholson¹,

Janoff²

2015

Mucosal Immunology

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Intranasal immunization with recombinant outer membrane protein P6 induces specific immune responses against nontypeable Haemophilus influenzae

Cited by 26 publications

References 25 publications

Chimeras of Labile Toxin One and Cholera Toxin Retain Mucosal Adjuvanticity and Direct Th Cell Subsets Via Their B Subunit

Chimeras of Labile Toxin One and Cholera Toxin Retain Mucosal Adjuvanticity and Direct Th Cell Subsets Via Their B Subunit

Construction of a Mutant and Characterization of the Role of the Vaccine Antigen P6 in Outer Membrane Integrity of NontypeableHaemophilus influenzae

Respiratory Bacterial Vaccines

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