Chemotoxicity of doxorubicin and surface expression of P-glycoprotein (MDR1) is regulated by the <i>Pseudomonas aeruginosa</i> toxin Cif

Ye, Siying; MacEachran, Daniel P.; Hamilton, Joshua W.; O’Toole, George A.

doi:10.1152/ajpcell.00234.2008

Cited by 26 publications

(19 citation statements)

References 45 publications

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“…17 To date, Cif, a secreted toxin from Pseudomonas aeruginosa, is the only bacterial component identified to selectively reduce the apical plasma membrane expression of P-gp in a variety of epithelial cells, including airway, intestinal and renal epithelial cells. 20 These results are consistent with a role for P-gp in the maintenance of homeostasis in the gastrointestinal tract and support the emerging concept of a protective role for this transporter in shielding the host not only from harmful xenobiotics, but also from invading bacterial pathogens. Of note, attempts are currently being made to harness the ability to S. typhimurium and Cif to impair P-gp for the purposes of enhancing the utility of chemotherapeutics towards their target.…”

Section: Introductionsupporting

confidence: 85%

The interaction of gut microbes with host ABC transporters

Mercado–Lubo¹,

McCormick

2010

Gut Microbes

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Section: Introductionsupporting

confidence: 85%

The interaction of gut microbes with host ABC transporters

Mercado–Lubo¹,

McCormick

2010

Gut Microbes

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“…1). Cif has also been shown to reduce the epithelial cell expression of another ABC transporter, P-glycoprotein, a drug efflux pump highly expressed in cancer; however, other drug efflux ABC transporters like MPR1 and MPR2 are not affected by Cif (56). These studies have been performed with cultured epithelial cells, which may limit the possible range of Cif targets; thus, additional Cif virulence effects may be seen in an animal model.…”

Section: Cif a Novel Virulence Factormentioning

confidence: 99%

Pouring Salt on a Wound: Pseudomonas aeruginosa Virulence Factors Alter Na+ and Cl- Flux in the Lung

Ballok

O’Toole

2013

Journal of Bacteriology

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Pseudomonas aeruginosa is a ubiquitous opportunistic pathogen with multiple niches in the human body, including the lung. P. aeruginosa infections are particularly damaging or fatal for patients with ventilator-associated pneumonia, chronic obstructive pulmonary disease, and cystic fibrosis (CF). To establish an infection, P. aeruginosa relies on a suite of virulence factors, including lipopolysaccharide, phospholipases, exoproteases, phenazines, outer membrane vesicles, type III secreted effectors, flagella, and pili. These factors not only damage the epithelial cell lining but also induce changes in cell physiology and function such as cell shape, membrane permeability, and protein synthesis. While such virulence factors are important in initial infection, many become dysregulated or nonfunctional during the course of chronic infection. Recent work on the virulence factors alkaline protease (AprA) and CF transmembrane conductance regulator inhibitory factor (Cif) show that P. aeruginosa also perturbs epithelial ion transport and osmosis, which may be important for the long-term survival of this microbe in the lung. Here we discuss the literature regarding host physiology-altering virulence factors with a focus on Cif and AprA and their potential roles in chronic infection and immune evasion.

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“…Helicobacter pylori infection was also shown to be associated with P-gp overexpression in the intestine (68), whereas Salmonella enterica serovar Typhimurium was shown to dampen P-gp function in order to promote epithelial cell invasion (69). In the case of Pseudomonas aeruginosa, it was shown that the bacteria secrete a toxin, called Cif, which selectively inhibits P-gp expression in a variety of epithelial cells (70). Taken together, these examples indicate an intimate interaction between bacterial pathogens and P-gp, though the molecular mechanisms that govern this interaction and their association with the innate immune system are not clear.…”

Section: Discussionmentioning

confidence: 99%

The Human P-Glycoprotein Transporter Enhances the Type I Interferon Response to Listeria monocytogenes Infection

et al. 2015

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bHuman multidrug efflux transporters are known for their ability to extrude antibiotics and toxic compounds out of cells, yet accumulating data indicate they have additional functions in diverse physiological processes not related to drug efflux. Here, we show that the human multidrug transporter P-glycoprotein (P-gp) (also named MDR1 and ABCB1) is transcriptionally induced in the monocytic cell line THP-1 upon infection with the human intracellular bacterial pathogen Listeria monocytogenes. Notably, we found that P-gp is important for full activation of the type I interferon response elicited against L. monocytogenes bacteria. Both inhibition of P-gp function by verapamil and inhibition of its transcription using mRNA silencing led to a reduction in the magnitude of the type I response in infected cells. This function of P-gp was specific to type I interferon cytokines elicited against cytosolic replicating bacteria and was not observed in response to cyclic di-AMP (c-di-AMP), a molecule that was shown to be secreted by L. monocytogenes during infection and to trigger type I interferons. Moreover, P-gp was not involved in activation of other proinflammatory cytokines, such as those triggered by vacuolar-restricted L. monocytogenes or lipopolysaccharide (LPS). Taken together, these findings demonstrate a role for P-gp in proper development of an innate immune response against intracellular pathogens, highlighting the complexity in employing therapeutic strategies that involve inhibition of multidrug resistance (MDR) efflux pumps. Multidrug transporters mediate the active efflux of a wide range of drugs and xenobiotics, including antibiotics and chemotherapeutics (1). This permissive efflux ability engenders multidrug resistance (MDR)-a phenomenon that largely underlies the failure of various chemotherapeutic treatments (2-4). Human MDR transporters harbor an ATP-binding cassette (ABC), which defines the ABC-type superfamily, comprising more than 45 proteins in the human genome (5). Among these, several transporters have been extensively studied, such as the P-glycoprotein (P-gp) (also named MDR1 and ABCB1) (6), BCRP (ABCG2) (7), and MRP1 (ABCC1) (8), which were all shown to exhibit clinically relevant MDR functions (9). P-gp, encoded by the MDR1 gene, is the most prominent and best-characterized member of the ABCtype superfamily, first isolated in clinical cancers (6, 10). Aside from its well-documented multidrug resistance function in cancer cells, P-gp is naturally expressed in a variety of normal tissues and cells, including immune cells, such as macrophages, dendritic cells, T and B lymphocytes, and natural killer (NK) cells, and was shown to possess physiological functions beyond detoxification (11-15). Several studies have indicated roles for P-gp in lipid transport, intracellular trafficking of cholesterol, cell death, cell differentiation, and immune responses (16,17). Regarding the last, P-gp was shown to exhibit immunomodulatory activity and to influence the secretion of various inflammatory mediators,...

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Chemotoxicity of doxorubicin and surface expression of P-glycoprotein (MDR1) is regulated by the Pseudomonas aeruginosa toxin Cif

Abstract: Ye S, MacEachran DP, Hamilton JW, O'Toole GA, Stanton BA. Chemotoxicity of doxorubicin and surface expression of Pglycoprotein (MDR1) is regulated by the Pseudomonas aeruginosa toxin Cif.

Cited by 26 publications

References 45 publications

The interaction of gut microbes with host ABC transporters

The interaction of gut microbes with host ABC transporters

Pouring Salt on a Wound: Pseudomonas aeruginosa Virulence Factors Alter Na+ and Cl- Flux in the Lung

The Human P-Glycoprotein Transporter Enhances the Type I Interferon Response to Listeria monocytogenes Infection

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