Human mAbs to <i>Pseudomonas aeruginosa</i> alginate that protect against infection by both mucoid and nonmucoid strains.

Pier, Gerald B.; Boyer, Darra; Preston, M J; Coleman, Fadie T.; Llosa, Nicolás J.; Mueschenborn-Koglin, S.; Theilacker, Christian; Goldenberg, Hannah; Uchin, J.; Priebe, Gregory P.; Grout, Martha; Posner, Marshall R.; Cavacini, Lisa A.

doi:10.4049/jimmunol.178.11.7485

Cited by 12 publications

(15 citation statements)

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“…This ADP-ribose unit stays attached to ETA and is transferred to elongation factor-2 (EF-2), a protein involved in the translation and elongation of proteins. This, in turn, blocks protein synthesis in host cells, causing damage to target tissues (9). In this study, we demonstrate that HN5 head and neck squamous carcinoma cells overexpress CLDN4 and that targeting the CLDN4 receptor by CPE-ETA' (an immunotoxin created by fusing the c-terminal CLDN4-binding domain of CPE to the ETA domain) efficiently and specifically kills HN5 cells.…”

Section: Introductionmentioning

confidence: 74%

Immunotoxin-mediated targeting of claudin-4 inhibits the proliferation of cancer cells

Hashimi

Alqurashi

et al. 2013

International Journal of Oncology

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Immunotoxins are engineered chimeric proteins that consist of a fragment of a toxin fused to a modified antibody or growth factor capable of targeting specific cells. Furthermore, these proteins can be targeted to receptors that are commonly overexpressed on cancer cells. The majority of immunotoxins function by binding to cells, translocating into the cytosol and inhibiting protein synthesis. In this study, the expression of claudin‑4 (CLDN4) in various cancer cells was analysed as a potential target for immunotoxins. To target CLDN4-expressing cancer cells, the c-terminal CLDN4‑binding domain of Clostridium perfringens enterotoxin (CPE) was fused to the Pseudomonas aeruginosa exotoxin A (ETA) domain to create an immunotoxin (CPE‑ETA'). Subsequently, the capacity of such an immunotoxin in suppressing the proliferation of CLDN4-positive cancer cells was investigated. We report that head and neck squamous carcinoma cells (HN5) have an elevated CLDN4 expression compared to the other cell lines tested. Our findings further demonstrate that CPE‑ETA' is highly potent against MCF-7 breast [50% inhibitory concentration (IC50) 9.8 ng/ml] and HN5 head/neck (IC50 8.8 ng/ml) cancer cell lines, while it has no cytotoxic effects on HeLa cells (CLDN4‑negative). The immunotoxin was subsequently expressed in the tumour colonising oncolytic strain, Clostridium ghonii. Most importantly, the strictly anaerobic Clostridium ghonii was able to overexpress and secrete a functional CPE‑ETA' fusion protein. Our findings open the possibility of the targeted delivery of the immunotoxin locally to tumour sites at a high concentration using strictly anaerobic Clostridium ghonii for the treatment of CLDN4-positive cancer cells.

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Section: Introductionmentioning

confidence: 74%

Immunotoxin-mediated targeting of claudin-4 inhibits the proliferation of cancer cells

Hashimi

Alqurashi

et al. 2013

International Journal of Oncology

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“…Protection is additionally afforded by the ability of alginate to scavenge reactive oxygen intermediates (126,127) and inhibit killing by cationic antimicrobial peptides (128)(129)(130). Although antibodies to alginate are found in the sera of chronically infected CF patients, these antibodies fail to mediate opsonic killing of P. aeruginosa in vitro (131). Additionally, the anionic nature of alginate promotes cation chelation (Ca 2+ preferentially) (132).…”

Section: Alginatementioning

confidence: 99%

Bacterial Extracellular Polysaccharides in Biofilm Formation and Function

2015

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Microbes produce a biofilm matrix consisting of proteins, extracellular DNA, and polysaccharides that is integral in the formation of bacterial communities. Historical studies of polysaccharides revealed that their overproduction often alters the colony morphology and can be diagnostic in identifying certain species. The polysaccharide component of the matrix can provide many diverse benefits to the cells in the biofilm, including adhesion, protection, and structure. Aggregative polysaccharides act as molecular glue, allowing the bacterial cells to adhere to each other as well as surfaces. Adhesion facilitates the colonization of both biotic and abiotic surfaces by allowing the bacteria to resist physical stresses imposed by fluid movement that could separate the cells from a nutrient source. Polysaccharides can also provide protection from a wide range of stresses, such as desiccation, immune effectors, and predators such as phagocytic cells and amoebae. Finally, polysaccharides can provide structure to biofilms, allowing stratification of the bacterial community and establishing gradients of nutrients and waste products. This can be advantageous for the bacteria by establishing a heterogeneous population that is prepared to endure stresses created by the rapidly changing environments that many bacteria encounter. The diverse range of polysaccharide structures, properties, and roles highlight the importance of this matrix constituent to the successful adaptation of bacteria to nearly every niche. Here, we present an overview of the current knowledge regarding the diversity and benefits that polysaccharide production provides to bacterial communities within biofilms.

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“…Prior work revealed the presence of antibodies to P. aeruginosa alginate in CF patients, although no mucoid cultures were detectable in sputum samples (Pedersen et al ., 1990a). Moreover, using alginate‐specific antibodies, others have shown that alginate is expressed by non‐mucoid strains under limiting oxygen conditions in vitro , and within 1 h after infection of mice (Worlitzsch et al ., 2002; Pier et al ., 2004). Although these studies suggest alginate expression occurs in non‐mucoid strains (i.e.…”

Section: Alginate and Biofilm Developmentmentioning

confidence: 99%

“…In the CF lung, biofilm development becomes more complex. Recent data using alginate‐specific antibodies have shown that alginate may be expressed by non‐mucoid strains in the mouse lung within 1 h post infection (Pier et al ., 2004). Analyses of biofilm microenvironments reveal heterogeneous populations, including regions displaying metabolic and oxygen gradients (Xu et al ., 1998).…”

Section: Potential Therapies Future Perspectives and Conclusionmentioning

confidence: 99%

Understanding the control of Pseudomonas aeruginosa alginate synthesis and the prospects for management of chronic infections in cystic fibrosis

Ramsey¹,

Wozniak²

2005

Molecular Microbiology

335

301

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SummaryDecades of research have been dedicated to the study of the opportunistic pathogen Pseudomonas aeruginosa , a Gram-negative, environmental bacterium that secretes the exopolysaccharide alginate during chronic lung infection of cystic fibrosis (CF) patients. Although P. aeruginosa utilizes a variety of factors to establish a successful infection in the lungs of CF patients, alginate has stood out as one of the beststudied prognostic indicators of chronic lung infection. While the genetics, biosynthesis and regulation of alginate are well understood, questions still remain concerning its role in biofilm development and its potential as a therapeutic target. The purpose of this review is to provide a brief summary of alginate biosynthesis and regulation, and to highlight recent discoveries in the areas of alginate production, biofilm formation and vaccine design. This information is placed in context with a proposed P. aeruginosa infectious pathway, highlighting avenues for the use of existing therapies as well as the potential for novel agents to reduce or eliminate chronic infections in CF patients.

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Human mAbs to Pseudomonas aeruginosa alginate that protect against infection by both mucoid and nonmucoid strains.

Cited by 12 publications

References 0 publications

Immunotoxin-mediated targeting of claudin-4 inhibits the proliferation of cancer cells

Immunotoxin-mediated targeting of claudin-4 inhibits the proliferation of cancer cells

Bacterial Extracellular Polysaccharides in Biofilm Formation and Function

Understanding the control of Pseudomonas aeruginosa alginate synthesis and the prospects for management of chronic infections in cystic fibrosis

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