Effect of anti-PcrV antibody in a murine chronic airway Pseudomonas aeruginosa infection model

Imamura, Yoshifumi; Yanagihara, K.; Fukuda, Yuichi; Kaneko, Yukihiro; Seki, Masafumi; Izumikawa, Kohichi; Miyazaki, Yoshitsugu; Hirakata, Yoichi; Sawa, Teiji; Wiener-Kronish, Jeanine P.; Kohno, Shigeru

doi:10.1183/09031936.00147406

Cited by 50 publications

(27 citation statements)

References 15 publications

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“…Such a combination could force P. aeruginosa out of the protective environment of the biofilm and into a free-swimming mode of lifestyle, thus increasing antimicrobial efficacy. Since we have previously demonstrated that these free-swimming cells are also associated with type III secretion, use of an effective anti-type III secretion therapeutic (15, 21, 35) to prevent acute injury in combination with a QSI and antimicrobial administration may provide an excellent means of resolving recalcitrant chronic infection while preserving epithelial integrity in a number of patient groups. The effects of these types of therapeutic combinations to combat P. aeruginosa infections have yet to be determined.…”

Section: Discussionmentioning

confidence: 99%

Secretion of Pseudomonas aeruginosa type III cytotoxins is dependent on pseudomonas quinolone signal concentration

Singh

Baek

et al. 2010

Microbial Pathogenesis

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Pseudomonas aeruginosa is an opportunistic pathogen that can, like other bacterial species, exist in antimicrobial resistant sessile biofilms and as free-swimming, planktonic cells. Specific virulence factors are typically associated with each lifestyle and several two-component response regulators have been shown to reciprocally regulate transition between biofilm-associated chronic, and free-swimming acute infections. Quorum sensing (QS) signal molecules belonging to the las and rhl systems are known to regulate virulence gene expression by P. aeruginosa. However the impact of a recently described family of novel quorum sensing signals produced by the Pseudomonas Quinolone Signal (PQS) biosynthetic pathway, on the transition between these modes of infection is less clear. Using clonal isolates from a patient developing ventilator-associated pneumonia, we demonstrated that clinical observations were mirrored by an in vitro temporal shift in isolate phenotype from a non-secreting, to a Type III cytotoxin secreting (TTSS) phenotype and further, that this phenotypic change was PQS-dependent. While intracellular type III cytotoxin levels were unaffected by PQS concentration, cytotoxin secretion was dependent on this signal molecule. Elevated PQS concentrations were associated with inhibition of cytotoxin secretion coincident with expression of virulence factors such as elastase and pyoverdin. In contrast, low concentrations or the inability to biosynthesize PQS resulted in a reversal of this phenotype. These data suggest that expression of specific P. aeruginosa virulence factors appears to be reciprocally regulated and that an additional level of PQS-dependent posttranslational control, specifically governing type III cytotoxin secretion, exists in this species.

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Section: Discussionmentioning

confidence: 99%

Secretion of Pseudomonas aeruginosa type III cytotoxins is dependent on pseudomonas quinolone signal concentration

Singh

Baek

et al. 2010

Microbial Pathogenesis

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“…Active immunization with recombinant PcrV protects mice from lethal infection even under induced-leukocytopenia or immunosuppression induced by a burn injury (Sawa et al, 1999; Holder et al, 2001; Moriyama et al, 2009). Passive immunization with polyclonal antisera, affinity-purified antibodies, or F(ab′) 2 were effective against cellular intoxication, lung injury, bacteremia, and sepsis in animal models (Sawa et al, 1999; Shime et al, 2001; Frank et al, 2002; Neely et al, 2005; Imamura et al, 2007; Baer et al, 2009). Polyclonal anti-PcrV antibodies block T3SS-mediated hemolysis of erythrocytes and cytotoxicity of macrophages in vitro (Goure et al, 2005; Sato et al, 2011) and reduce inflammatory response and lung injury in infected BALB/c mice (Sawa et al, 1999).…”

Section: Immunization and Therapeutics Targeting T3ssmentioning

confidence: 99%

Multi-Functional Characteristics of the Pseudomonas aeruginosa Type III Needle-Tip Protein, PcrV; Comparison to Orthologs in other Gram-negative Bacteria

Satō¹,

Frank²

2011

Front. Microbio.

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Pseudomonas aeruginosa possesses a type III secretion system (T3SS) to intoxicate host cells and evade innate immunity. This virulence-related machinery consists of a molecular syringe and needle assembled on the bacterial surface, which allows delivery of T3 effector proteins into infected cells. To accomplish a one-step effector translocation, a tip protein is required at the top end of the T3 needle structure. Strains lacking expression of the functional tip protein fail to intoxicate host cells. P. aeruginosa encodes a T3S that is highly homologous to the proteins encoded by Yersinia spp. The needle-tip proteins of Yersinia, LcrV, and P. aeruginosa, PcrV, share 37% identity and 65% similarity. Other known tip proteins are AcrV (Aeromonas), IpaD (Shigella), SipD (Salmonella), BipD (Burkholderia), EspA (EPEC, EHEC), Bsp22 (Bordetella), with additional proteins identified from various Gram-negative species, such as Vibrio and Bordetella. The tip proteins can serve as a protective antigen or may be critical for sensing host cells and evading innate immune responses. Recognition of the host microenvironment transcriptionally activates synthesis of T3SS components. The machinery appears to be mechanically controlled by the assemblage of specific junctions within the apparatus. These junctions include the tip and base of the T3 apparatus, the needle proteins and components within the bacterial cytoplasm. The tip proteins likely have chaperone functions for translocon proteins, allowing the proper assembly of translocation channels in the host membrane and completing vectorial delivery of effector proteins into the host cytoplasm. Multi-functional features of the needle-tip proteins appear to be intricately controlled. In this review, we highlight the functional aspects and complex controls of T3 needle-tip proteins with particular emphasis on PcrV and LcrV.

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“…10,13,14 Active immunization with recombinant PcrV protects animals from lethal P. aeruginosa infections [14][15][16] , and anti-PcrV antibodies also protect infected animals from acute lung injury, bacteremia, and sepsis. 14,[17][18][19][20][21][22] Based on these experimental results, an engineered human anti-PcrV antibody was tested in patients in Phase II trials [23][24][25] , but no therapies based on it have been adapted for clinical use as yet.…”

Section: Introductionmentioning

confidence: 99%

The prophylactic effects of human IgG derived from sera containing high anti-PcrV titers against pneumonia-causingPseudomonas aeruginosa

Kinoshita

Kato

Yanagimoto

et al. 2016

Human Vaccines & Immunotherapeutics

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The PcrV cap structure of the type III secretory apparatus of Pseudomonas aeruginosa is a vaccine target. Human immunoglobulin G (IgG) molecules extracted from sera containing high or low antiPcrV titers were tested for their effects against P. aeruginosa pneumonia in a mouse model. Among 198 volunteers, we selected the top 10 high anti-PcrV titer sera and the bottom 10 low anti-PcrV titer sera and extracted the IgG fraction from each serum sample. First, we examined the effects of the IgG against virulent P. aeruginosa. A lethal dose of P. aeruginosa premixed with saline, low titer human IgG, high titer human IgG, or rabbit-derived polyclonal anti-PcrV IgG was intratracheally administered into the lungs of mice, and their survival and lung inflammation were evaluated for 24 h. The high anti-PcrV titer human IgG had a prophylactic effect. Next, the prophylactic effects of intravenous administration of extracted and pooled high or low anti-PcrV titer human IgG were examined. Here, prophylactic intravenous administration of pooled high anti-PcrV titer human IgG, which showed binding capacity to P. aeruginosa PcrV, was more effective than the administration of its low titer pooled equivalent, and the measured physiological and inflammatory parameters correlated with the anti-PcrV titer levels. This result indirectly implies that high anti-PcrV titers in blood can help to protect against virulent P. aeruginosa infections. In addition, the IgG fractions from such high titer sera have potential to be a source of specific intravenous immunoglobulin products for passive vaccination against virulent P. aeruginosa infections.

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Effect of anti-PcrV antibody in a murine chronic airway Pseudomonas aeruginosa infection model

Cited by 50 publications

References 15 publications

Secretion of Pseudomonas aeruginosa type III cytotoxins is dependent on pseudomonas quinolone signal concentration

Secretion of Pseudomonas aeruginosa type III cytotoxins is dependent on pseudomonas quinolone signal concentration

Multi-Functional Characteristics of the Pseudomonas aeruginosa Type III Needle-Tip Protein, PcrV; Comparison to Orthologs in other Gram-negative Bacteria

The prophylactic effects of human IgG derived from sera containing high anti-PcrV titers against pneumonia-causingPseudomonas aeruginosa

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