PLGA-encapsulation of the Pseudomonas aeruginosa PopB vaccine antigen improves Th17 responses and confers protection against experimental acute pneumonia

Azithromycin (AZM) is a 15-membered-ring macrolide that presents a broad-spectrum antimicrobial activity against Gram-positive bacteria and atypical microorganisms but suffers from a poor diffusion across the outer-membrane of Gram-negative bacilli, including Pseudomonas aeruginosa (PA). However, AZM has demonstrated clinical benefits in patients suffering from chronic PA respiratory infections, especially cystic fibrosis patients. Since the rise of multidrug-resistant PA has led to a growing need for new therapeutic options, this macrolide has been proposed as an adjunctive therapy. Clinical trials assessing AZM in PA acute pneumonia are scarce. However, a careful examination of the available literature provides good rationales for its use in that context. In fact, 14- and 15-membered-ring macrolides have demonstrated immunomodulatory and immunosuppressive effects that could be of major interest in the management of acute illness. Furthermore, growing evidence supports a downregulation of PA virulence dependent on direct interaction with the ribosomes, and based on the modulation of several key regulators from the Quorum Sensing network. First highlighted in vitro, these interesting properties of AZM have subsequently been confirmed in the animal models. In this review, we systematically analyzed the literature regarding AZM immunomodulatory and anti-PA effects. In vitro and in vivo studies, as well as clinical trials were reviewed, looking for rationales for AZM use in PA acute pneumonia.

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Differential ASC requirements reveal a key role for neutrophils and a noncanonical IL-1β response to Pseudomonas aeruginosa

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00228.2015 ◽

2015 ◽

Vol 309 (8) ◽

pp. L902-L913 ◽

Cited By ~ 18

Author(s):

Yash R. Patankar ◽

Rodwell Mabaera ◽

Brent Berwin

Keyword(s):

Pseudomonas Aeruginosa ◽

Acute Infection ◽

Adaptor Protein ◽

Ocular Infection ◽

Lethal Challenge ◽

Type Three Secretion System ◽

Acute Pneumonia ◽

Marked Deficit

The NLRC4 inflammasome is responsible for IL-1β processing by macrophages in response to Pseudomonas aeruginosa infection. We therefore hypothesized that mice that lack ASC, an NLRC4 inflammasome adaptor protein necessary for in vitro IL-1β production by macrophages, would be preferentially protected from a hyperinflammatory lethal challenge that is dependent on bacterial type three secretion system (T3SS) activity. We report herein that lack of ASC does not confer preferential protection in response to P. aeruginosa acute infection and that ASC−/− mice are capable of producing robust amounts of IL-1β comparable with C57BL/6 mice. We now identify that neutrophils represent the ASC-independent source of IL-1β production during the acute phases of infection both in models of acute pneumonia and peritonitis. Consequently, depletion of neutrophils in ASC−/− mice leads to a marked deficit in IL-1β production in vivo. The pulmonary neutrophil IL-1β response is predominantly dependent on caspase-1, which contrasts with data derived from ocular infection. These studies therefore identify a noncanonical mechanism of IL-1β production by neutrophils independent of ASC and demonstrate the first physiological contribution of neutrophils as an important source of IL-1β in response to acute P. aeruginosa infection during acute pneumonia and peritonitis.

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Intradermal vaccination with a Pseudomonas aeruginosa vaccine adjuvanted with a mutant bacterial ADP-ribosylating enterotoxin protects against acute pneumonia

Vaccine ◽

10.1016/j.vaccine.2018.12.053 ◽

2019 ◽

Vol 37 (6) ◽

pp. 808-816 ◽

Cited By ~ 5

Author(s):

Sarah M. Baker ◽

Derek Pociask ◽

John D. Clements ◽

James B. McLachlan ◽

Lisa A. Morici

Keyword(s):

Pseudomonas Aeruginosa ◽

Intradermal Vaccination ◽

Acute Pneumonia

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Effects of Pseudomonas aeruginosa and Streptococcus mitis mixed infection on TLR4-mediated immune response in acute pneumonia mouse model

BMC Microbiology ◽

10.1186/s12866-017-0999-1 ◽

2017 ◽

Vol 17 (1) ◽

Cited By ~ 5

Author(s):

Chao Song ◽

Hongdong Li ◽

Yunhui Zhang ◽

Jialin Yu

Keyword(s):

Immune Response ◽

Pseudomonas Aeruginosa ◽

Mouse Model ◽

Mixed Infection ◽

Streptococcus Mitis ◽

Acute Pneumonia

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The Anti-Pseudomonas aeruginosa Antibody Panobacumab Is Efficacious on Acute Pneumonia in Neutropenic Mice and Has Additive Effects with Meropenem

PLoS ONE ◽

10.1371/journal.pone.0073396 ◽

2013 ◽

Vol 8 (9) ◽

pp. e73396 ◽

Cited By ~ 25

Author(s):

Thomas Secher ◽

Stefanie Fas ◽

Louis Fauconnier ◽

Marieke Mathieu ◽

Oliver Rutschi ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Additive Effects ◽

Acute Pneumonia

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Pseudomonas aeruginosa Cytotoxin ExoU Is Injected into Phagocytic Cells during Acute Pneumonia

Infection and Immunity ◽

10.1128/iai.01134-09 ◽

2010 ◽

Vol 78 (4) ◽

pp. 1447-1456 ◽

Cited By ~ 61

Author(s):

Maureen H. Diaz ◽

Alan R. Hauser

Keyword(s):

Pseudomonas Aeruginosa ◽

Immune Cells ◽

Type Iii Secretion ◽

Cell Types ◽

Secretion System ◽

Host Cells ◽

Phagocytic Cells ◽

Acute Pneumonia

ABSTRACT ExoU, a cytotoxin translocated into host cells via the type III secretion system of Pseudomonas aeruginosa, is associated with increased mortality and disease severity. We previously showed that impairment of recruited phagocytic cells allowed survival of ExoU-secreting P. aeruginosa in the lung. Here we analyzed types of cells injected with ExoU in vivo using translational fusions of ExoU with a β-lactamase reporter (ExoU-Bla). Cells injected with ExoU-Bla were detectable in vitro but not in vivo, presumably due to the rapid cytotoxicity induced by the toxin. Therefore, we used a noncytotoxic ExoU variant, designated ExoU(S142A)-Bla, to analyze injection in vivo. We determined that phagocytic cells in the lung were frequently injected with ExoU(S142A). Early during infection, resident macrophages constituted the majority of cells into which ExoU was injected, but neutrophils and monocytes became the predominant types of cells into which ExoU was injected upon recruitment into the lung. We observed a modest preference for injection into neutrophils over injection into other cell types, but in general the repertoire of injected immune cells reflected the relative abundance of these cells in the lung. Our results indicate that phagocytic cells in the lung are injected with ExoU and support the hypothesis that ExoU-mediated impairment of phagocytes has a role in the pathogenesis of pneumonia caused by P. aeruginosa.

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Murine Acute Pneumonia Model of Pseudomonas aeruginosa Lung Infection

BIO-PROTOCOL ◽

10.21769/bioprotoc.3805 ◽

2020 ◽

Vol 10 (21) ◽

Author(s):

Xiaolei Pan ◽

Weihui Wu

Keyword(s):

Pseudomonas Aeruginosa ◽

Lung Infection ◽

Acute Pneumonia

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Two Novel Bacteriophages Improve Survival in Galleria mellonella Infection and Mouse Acute Pneumonia Models Infected with Extensively Drug-Resistant Pseudomonas aeruginosa

Applied and Environmental Microbiology ◽

10.1128/aem.02900-18 ◽

2019 ◽

Vol 85 (9) ◽

Cited By ~ 7

Author(s):

Jongsoo Jeon ◽

Dongeun Yong

Keyword(s):

Pseudomonas Aeruginosa ◽

In Silico ◽

Galleria Mellonella ◽

Drug Resistant ◽

Content Type ◽

Bacteriolytic Activity ◽

Extensively Drug Resistant ◽

Acute Pneumonia

ABSTRACT Extensively drug-resistant Pseudomonas aeruginosa (XDR-PA) is a life-threatening pathogen that causes serious global problems. Here, we investigated two novel P. aeruginosa bacteriophages (phages), Bϕ-R656 and Bϕ-R1836, in vitro, in silico, and in vivo to evaluate the potential of phage therapy to control XDR-PA clinical strains. Bϕ-R656 and Bϕ-R1836 belong to the Siphoviridae family and exhibited broad host ranges which could lyse 18 (64%) and 14 (50%) of the 28 XDR-PA strains. In addition, the two phages showed strong bacteriolytic activity against XDR-PA host strains from pneumonia patients. The whole genomes of Bϕ-R656 and Bϕ-R1836 have linear double-stranded DNA of 60,919 and 37,714 bp, respectively. The complete sequence of Bϕ-R656 had very low similarity to the previously discovered P. aeruginosa phages in GenBank, but phage Bϕ-R1836 exhibited 98% and 91% nucleotide similarity to Pseudomonas phages YMC12/01/R24 and PA1/KOR/2010, respectively. In the two in vivo infection models, treatment with Bϕ-R656 and Bϕ-R1836 enhanced the survival of Galleria mellonella larvae (50% and 60%, respectively) at 72 h postinfection and pneumonia-model mice (66% and 83%, respectively) at 12 days postinfection compared with untreated controls. Treatment with Bϕ-R656 or Bϕ-R1836 also significantly decreased the bacterial load in the lungs of the mouse pneumonia model (>6 log10 CFU and >4 log10 CFU, respectively) on day 5. IMPORTANCE In this study, two novel P. aeruginosa phages, Bϕ-R656 and Bϕ-R1836, were evaluated in vitro, in silico, and in vivo for therapeutic efficacy and safety as an alternative antibacterial agent to control XDR-PA strains collected from pneumonia patients. Both phages exhibited potent bacteriolytic activity and greatly improved survival in G. mellonella larva infection and a mouse acute pneumonia model. Based on these results, we strongly predict that these two new phages could be used as fast-acting and safe alternative biological weapons against XDR-PA infections.

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