Cystic Fibrosis Transmembrane Conductance Regulator Attaches Tumor Suppressor PTEN to the Membrane and Promotes Anti Pseudomonas aeruginosa Immunity

Riquelme, Sebastián A.; Hopkins, Benjamin D.; Wolfe, Andrew L.; DiMango, Emily; Kitur, Kipyegon; Parsons, Ramon

doi:10.1016/j.immuni.2017.11.010

Cited by 48 publications

(63 citation statements)

References 54 publications

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“…These advantages include mucus viscosity, excessive production of reactive oxygen species (ROS), impaired autophagy, reduced airway acidity, and accumulation of ceramides, all factors that contribute to the genomic and metabolic plasticity of P. aeruginosa and its ability to colonize the airways [9]. Whether the exaggerated inflammatory response seen in CF facilitates the colonization and then chronicity of P. aeruginosa infection over other bacteria is not well understood, although recent findings suggest that mutant CFTR directly influences inflammatory signaling, and this favors P. aeruginosa over other respiratory pathogens, such as S. aureus and K. pneumoniae [10]. …”

Section: Gram-negative Bacteria and Lung Inflammation: Cystic Fibrosismentioning

confidence: 99%

Pseudomonas aeruginosa and Klebsiella pneumoniae Adaptation to Innate Immune Clearance Mechanisms in the Lung

Riquelme¹,

Ahn²,

Prince³

2018

J Innate Immun

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Many different species of gram-negative bacteria are associated with infection in the lung, causing exacerbations of chronic obstructive pulmonary disease, cystic fibrosis (CF), and ventilator-associated pneumonias. These airway pathogens must adapt to common host clearance mechanisms that include killing by antimicrobial peptides, antibiotics, oxidative stress, and phagocytosis by leukocytes. Bacterial adaptation to the host is often evident phenotypically, with increased extracellular polysaccharide production characteristic of some biofilm-associated organisms. Given the relatively limited repertoire of bacterial strategies to elude airway defenses, it seems likely that organisms sharing the same ecological niche might also share common strategies to persistently infect the lung. In this review, we will highlight some of the major factors responsible for the adaptation of Pseudomonas aeruginosa to the lung, addressing how growth in biofilms enables persistent infection, relevant to, but not limited to, the pathogenesis of infection in CF. In contrast, we will discuss how carbapenem-resistant Klebsiella pneumoniae evade immune clearance, an organism often associated with ventilator-associated pneumonia and health-care-acquired pneumonias, but not a typical pathogen in CF.

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Section: Gram-negative Bacteria and Lung Inflammation: Cystic Fibrosismentioning

confidence: 99%

Pseudomonas aeruginosa and Klebsiella pneumoniae Adaptation to Innate Immune Clearance Mechanisms in the Lung

Riquelme¹,

Ahn²,

Prince³

2018

J Innate Immun

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“…Not only does PTEN regulate cellular proliferation, it also induces the anti-inflammatory function of Akt and the PI3Kγ/δ subunits in phagocytes (68,71,72). These are proteins located in the inner leaflet of the plasma membrane during LPS-TLR4 interaction.…”

Section: Succinate Is Increased In Inflammation and In Cfmentioning

confidence: 99%

“…These are proteins located in the inner leaflet of the plasma membrane during LPS-TLR4 interaction. In CF cells, the lack of the CFTR-PTEN interaction unleashes the inflammatory response, increasing NF-kB and NLRP3 activation and resulting in increased production of IL-1β and succinate (54,(68)(69)(70) (Figure 1A). PTEN deficiency in mitochondrial membranes further impairs P. aeruginosa killing and ultimately its clearance from the murine airway (68).…”

Section: Succinate Is Increased In Inflammation and In Cfmentioning

confidence: 99%

“…In CF cells, the lack of the CFTR-PTEN interaction unleashes the inflammatory response, increasing NF-kB and NLRP3 activation and resulting in increased production of IL-1β and succinate (54,(68)(69)(70) (Figure 1A). PTEN deficiency in mitochondrial membranes further impairs P. aeruginosa killing and ultimately its clearance from the murine airway (68). The milieu of the CF airway, with decreased CFTR-PTEN interaction, increased succinate and oxidant generation provide an environment that favors P. aeruginosa proliferation and generates selective pressure for the organisms best suited for this environment, those protected from oxidants by their formation of biofilm (Figure 1D).…”

Section: Succinate Is Increased In Inflammation and In Cfmentioning

confidence: 99%

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Pulmonary Pathogens Adapt to Immune Signaling Metabolites in the Airway

Riquelme

Lung

2020

Front. Immunol.

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A limited number of pulmonary pathogens are able to evade normal mucosal defenses to establish acute infection and then adapt to cause chronic pneumonias. Pathogens, such as Pseudomonas aeruginosa or Staphylococcus aureus, are typically associated with infection in patients with underlying pulmonary disease or damage, such as cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD). To establish infection, bacteria express a well-defined set of so-called virulence factors that facilitate colonization and activate an immune response, gene products that have been identified in murine models. Less well-understood are the adaptive changes that occur over time in vivo, enabling the organisms to evade innate and adaptive immune clearance mechanisms. These colonizers proliferate, generating a population sufficient to provide selection for mutants, such as small colony variants and mucoid variants, that are optimized for long term infection. Such host-adapted strains have evolved in response to selective pressure such as antibiotics and the recruitment of phagocytes at sites of infection and their release of signaling metabolites (e.g., succinate). These metabolites can potentially function as substrates for bacterial growth and but also generate oxidant stress. Whole genome sequencing and quantified expression of selected genes have helped to explain how P. aeruginosa and S. aureus adapt to the presence of these metabolites over the course of in vivo infection. The serial isolation of clonally related strains from patients with cystic fibrosis has provided the opportunity to identify bacterial metabolic pathways that are altered under this immune pressure, such as the anti-oxidant glyoxylate and pentose phosphate pathways, routes contributing to the generation of biofilms. These metabolic pathways and biofilm itself enable the organisms to dissipate oxidant stress, while providing protection from phagocytosis. Stimulation of host immune signaling metabolites by these pathogens drives bacterial adaptation and promotes their persistence in the airways. The inherent metabolic flexibility of P. aeruginosa and S. aureus is a major factor in their success as pulmonary pathogens.

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“…P. aeruginosa is a Gram-negative opportunistic pathogenic bacterium able to causes chronic respiratory tract infections in patients with cystic fibrosis and in patients with compromised immune system ( Gellatly and Hancock, 2013 ). Due to the importance of P. aeruginosa , since long time ago scientists have started to use clinical isolates to study host-pathogen interaction, specifically ampicillin resistant strains ( Chmiel et al, 1999 , 2002 ; Parker et al, 2016 ; Riquelme et al, 2017 ). A recent study analyzed cytokine production, cellular recruitment and bacterial clearance during the first 12 h during an intraperitoneal infection with four MDR isolates, three non-MDR isolates and two reference strains of P. aeruginosa in mice ( Gomez-Zorrilla et al, 2017a ).…”

Section: The Opposing Role Of Il-10 During Multi-drug Resistant Bactementioning

confidence: 99%

Expanding the Current Knowledge About the Role of Interleukin-10 to Major Concerning Bacteria

et al. 2018

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Interleukin-10 (IL-10) is one of the most important anti-inflammatory cytokine produced during bacterial infection. Two related phenomena explain the importance of IL-10 production in this context: first, the wide range of cells able to produce this cytokine and second, the wide effects that it causes on target cells. In a previous report we described opposing roles of IL-10 production during bacterial infection. Overall, during infections caused by intracellular bacteria or by pathogens that modulate the inflammatory response, IL-10 production facilitates bacterial persistence and dissemination within the host. Whereas during infections caused by extracellular or highly inflammatory bacteria, IL-10 production reduces host tissue damage and facilitates host survival. Given that these data were obtained using antibiotic susceptible bacteria, the potential application of these studies to multi-drug resistant (MDR) bacteria needs to be evaluated. MDR bacteria can become by 2050 a major death cause worldwide, not only for its ability to resist antimicrobial therapy but also because the virulence of these strains is different as compared to antibiotic susceptible strains. Therefore, it is important to understand the interaction of MDR-bacteria with the immune system during infection. This review discusses the current data about the role of IL-10 during infections caused by major circulating antibiotic resistant bacteria. We conclude that the production of IL-10 improves host survival during infections caused by extracellular or highly inflammatory bacteria, however, it is detrimental during infections caused by intracellular bacteria or bacterial pathogens that modulate the inflammatory response. Importantly, during MDR-bacterial infections a differential IL-10 production has been described, compared to non-MDR bacteria, which might be due to virulence factors specific of MDR bacteria that modulate production of IL-10. This knowledge is important for the development of new therapies against infections caused by these bacteria, where antibiotics effectiveness is dramatically decreasing.

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Cystic Fibrosis Transmembrane Conductance Regulator Attaches Tumor Suppressor PTEN to the Membrane and Promotes Anti Pseudomonas aeruginosa Immunity

Cited by 48 publications

References 54 publications

<b><i>Pseudomonas aeruginosa</i></b> and <b><i>Klebsiella</i></b> <b><i>pneumoniae</i></b> Adaptation to Innate Immune Clearance Mechanisms in the Lung

<b><i>Pseudomonas aeruginosa</i></b> and <b><i>Klebsiella</i></b> <b><i>pneumoniae</i></b> Adaptation to Innate Immune Clearance Mechanisms in the Lung

Pulmonary Pathogens Adapt to Immune Signaling Metabolites in the Airway

Expanding the Current Knowledge About the Role of Interleukin-10 to Major Concerning Bacteria

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