Therapeutic effects of a human antiflagella monoclonal antibody in a neutropenic murine model of Pseudomonas aeruginosa pneumonia

Oishi, Kazunori; Sonoda, Fuminari; Iwagaki, Akitaka; P, Ponglertnapagorn; Watanabe, Kiwao; Nagatake, Tsuyoshi; Siadak, Anthony W.; Pollack, Matthew; Matsumoto, Keizō

doi:10.1128/aac.37.2.164

Cited by 31 publications

(25 citation statements)

References 33 publications

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“…However, no direct comparison of the protective efficacy against infection by immunization with flagellin or flagella has been reported for P. aeruginosa or, as far as we can determine, for other microorganisms. In vitro studies suggest that the protective activity of antibody to flagella or flagellin correlates with inhibition of motility (24,27,28) and opsonic killing (42). Here we found that polymeric flagella, which by nature contain, in addition to the polymerized FliC protein, components such as the FliD cap protein and possible basal body components, were clearly superior to monomeric flagellin at inducing antibodies that inhibited motility, mediated opsonic killing, and provided protective immunity against acute lung infection.…”

Section: Discussionmentioning

confidence: 70%

“…In regard to protection mediated by flagella or flagellin, immunization with flagella provided protection against infection and decreased the spread to major organs in the burned-mouse model (19). In a rat model of P. aeruginosa-induced pneumonia, administration of human monoclonal antibodies (MAbs) to flagella provided protection against infection and decreased lung injury (24), and another set of human MAbs provided protection in a murine model of pneumonia during neutropenia (28). A DNA vaccine encoding recombinant type a or type b P. aeruginosa flagellin also induced protective immunity against lethal P. aeruginosa lung infection (33), although this study curiously found better heterologous protection than homologous protection when DNA encoding wild-type flagellin was incorporated into the vaccine.…”

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confidence: 99%

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Evaluation of Flagella and Flagellin of Pseudomonas aeruginosa as Vaccines

et al. 2010

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Pseudomonas aeruginosa is a serious pathogen in hospitalized, immunocompromised, and cystic fibrosis (CF) patients. P. aeruginosa is motile via a single polar flagellum made of polymerized flagellin proteins differentiated into two major serotypes: a and b. Antibodies to flagella delay onset of infection in CF patients, but whether immunity to polymeric flagella and that to monomeric flagellin are comparable has not been addressed, nor has the question of whether such antibodies might negatively impact Toll-like receptor 5 (TLR5) activation, an important component of innate immunity to P. aeruginosa. We compared immunization with flagella and that with flagellin for in vitro effects on motility, opsonic killing, and protective efficacy using a mouse pneumonia model. Antibodies to flagella were superior to antibodies to flagellin at inhibiting motility, promoting opsonic killing, and mediating protection against P. aeruginosa pneumonia in mice. Protection against the flagellar type strains PAK and PA01 was maximal, but it was only marginal against motile clinical isolates from flagellum-immunized CF patients who nonetheless became colonized with P. aeruginosa. Purified flagellin was a more potent activator of TLR5 than were flagella and also elicited higher TLR5-neutralizing antibodies than did immunization with flagella. Antibody to type a but not type b flagella or flagellin inhibited TLR5 activation by whole bacterial cells. Overall, intact flagella appear to be superior for generating immunity to P. aeruginosa, and flagellin monomers might induce antibodies capable of neutralizing innate immunity due to TLR5 activation, but solid immunity to P. aeruginosa based on flagellar antigens may require additional components beyond type a and type b proteins from prototype strains.Pseudomonas aeruginosa is an opportunistic pathogen responsible for a large proportion of ventilator-associated, hospital acquired pneumonia and is also a major cause of morbidity and mortality in cystic fibrosis (CF) patients. P. aeruginosa is motile via a single polar flagellum that has the added structural feature of being glycosylated (39). Flagellin is the primary protein component of the flagellar filament, and it can be classified into two serotypes, types a and b. Flagella carry out many functions, such as motility and attachment of bacteria to host cells, and can also elicit the activation of the host inflammatory response via Toll-like receptor 5 (TLR5) (6,15,29,31). Importantly, promising results in terms of prevention of the acquisition of P. aeruginosa infection in CF patients immunized with a bivalent type a and b flagellum vaccine have been published (12).Several animal studies have not only demonstrated the importance of flagella as a virulence factor in P. aeruginosa but also validated them, or their flagellin component, as target antigens for vaccination. In the burned-mouse model of infection, chemically mutagenized or genetically produced flagellum-negative strains were less virulent than flagellum-positive strains (5, 26...

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Section: Discussionmentioning

confidence: 70%

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confidence: 99%

Evaluation of Flagella and Flagellin of Pseudomonas aeruginosa as Vaccines

et al. 2010

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“…DNA vaccination of mice induced flagellum-reactive antibodies and provided protection against lethal P. aeruginosa infection in the lungs without blocking TLR5 activation. In mouse and rat models of P. aeruginosa-induced pneumonia, administration of human monoclonal antibodies to flagella provided protection against infection and decreased bacterially induced lung injury (22,32). Active vaccination of mice with intact flagella induced protection against infection by PAK and PA01, although it was much less effective against P. aeruginosa clinical isolates (5).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-8 Production by Human Airway Epithelial Cells in Response to Pseudomonas aeruginosa Clinical Isolates Expressing Type a or Type b Flagellins

Shanks

Guang

Kim

et al. 2010

Clin Vaccine Immunol

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Pseudomonas aeruginosa lung infection is a major cause of morbidity and mortality worldwide. P. aeruginosa flagellin, the main structural protein of the flagellar filament, is a virulence factor with proinflammatory activity on respiratory epithelial cells. P. aeruginosa bacteria express one of two isoforms of flagellin (type a or b) that differ in their primary amino acid sequences as well as in posttranslational glycosylation. In this study, the distribution of type a and b flagellins among 3 P. aeruginosa laboratory strains and 14 clinical isolates (1 ulcerative keratitis, 3 cystic fibrosis, and 10 acute pneumonia isolates) was determined, and their abilities to stimulate interleukin-8 (IL-8) production by human airway epithelial cells was compared. By comparison with the PAK (type a) and PAO1 (type b) prototype laboratory strains, 10/14 (71.4%) of clinical isolates expressed type a and 4/14 (28.6%) expressed type b flagellins. Among four cell lines surveyed, BEAS-2B cells were found to give the greatest difference between constitutive and flagellin-stimulated IL-8 production. All 17 flagellins stimulated IL-8 production by BEAS-2B cells (range, 700 to 4,000 pg/ml). However, no discernible differences in IL-8 production were evident when comparing type a versus type b flagellins or flagellins from laboratory versus clinical strains or among the clinical strains.

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“…Neutropenic human patients (39,40) and laboratory mice (36,41,42) have enhanced susceptibility to pseudomonal pneumonia. Inefficient rapid, early neutrophil recruitment, even when corrected within 24 hours, resulted in 10-fold more bacteria in the airspaces at 48 hours in a murine model of pneumococcal pneumonia (43).…”

Section: High-affinity B 2 Integrins and Neutrophil Effector Functionmentioning

confidence: 99%

Activated β₂ Integrins Restrict Neutrophil Recruitment during Murine Acute Pseudomonal Pneumonia

Wilson

Ahn

Serratelli

et al. 2017

Am J Respir Cell Mol Biol

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Rapid neutrophil recruitment is critical for the efficient clearance of bacterial pathogens from the lungs. Although b 2 integrins and their activation are required for neutrophil recruitment from postcapillary venules of the systemic circulation into inflamed tissues, the involvement of integrins in neutrophil recruitment in response to respiratory infection varies among bacterial pathogens. For stimuli eliciting b 2 integrin-dependent neutrophil influx, including Pseudomonas aeruginosa, it remains unclear whether the activation of b 2 integrins is an essential step in this process. In the current study, we analyze neutrophil trafficking within the lungs of mice infected with Pseudomonas aeruginosa and evaluate the role of b 2 integrin activation through genetic deletion of talin-1 or Kindlin-3 or by pharmacological inhibition of high-affinity b 2 integrins using a small molecule allosteric antagonist. We observe that attenuation of high-affinity b 2 integrins leads to an enhancement of neutrophil emigration into lung interstitium and airspaces. Neutrophil effector functions, including the production of reactive oxygen species and the phagocytosis of bacteria, are only partially dependent on highaffinity b 2 integrins. These results reveal a mechanism by which activated b 2 integrins limit neutrophil entry into the lung tissue and airspaces during acute pseudomonal pneumonia and suggest potential strategies for modulating neutrophil-mediated host defense.

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Therapeutic effects of a human antiflagella monoclonal antibody in a neutropenic murine model of Pseudomonas aeruginosa pneumonia

Cited by 31 publications

References 33 publications

Evaluation of Flagella and Flagellin of Pseudomonas aeruginosa as Vaccines

Evaluation of Flagella and Flagellin of Pseudomonas aeruginosa as Vaccines

Interleukin-8 Production by Human Airway Epithelial Cells in Response to Pseudomonas aeruginosa Clinical Isolates Expressing Type a or Type b Flagellins

Activated β₂ Integrins Restrict Neutrophil Recruitment during Murine Acute Pseudomonal Pneumonia

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Therapeutic effects of a human antiflagella monoclonal antibody in a neutropenic murine model of Pseudomonas aeruginosa pneumonia

Cited by 31 publications

References 33 publications

Evaluation of Flagella and Flagellin of Pseudomonas aeruginosa as Vaccines

Evaluation of Flagella and Flagellin of Pseudomonas aeruginosa as Vaccines

Interleukin-8 Production by Human Airway Epithelial Cells in Response to Pseudomonas aeruginosa Clinical Isolates Expressing Type a or Type b Flagellins

Activated β2 Integrins Restrict Neutrophil Recruitment during Murine Acute Pseudomonal Pneumonia

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Activated β₂ Integrins Restrict Neutrophil Recruitment during Murine Acute Pseudomonal Pneumonia