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

ABSTRACT: The Pseudomonas aeruginosa type III secretion system protein PopB and its chaperon protein PcrH, when co-administered with the adjuvant curdlan, elicit Th17 responses after intranasal immunization of mice. These PopB/PcrH-curdlan vaccines protect mice against acute lethal pneumonia in an IL-17-dependent fashion involving CD4 helper T cells secreting IL-17 (Th17 cells). In this study, we tested whether encapsulation of PopB/PcrH in poly-lactic-co-glycolic acid (PLGA) nanoparticles could elicit Th17 responses to PopB. Recombinant PopB/PcrH or PcrH alone was encapsulated into PLGA nanoparticles. Mice (FVB/N) were intranasally immunized with the PLGA-PopB/PcrH nanoparticles, PLGA-PcrH nanoparticles, PLGA alone, or PopB/PcrH alone. The protective efficacy was assessed in an acute lung infection model with a lethal dose of an ExoU-producing version of P. aeruginosa strain PAO1. Th17 responses were assayed by intracellular flow cytometry and by ELISA for IL-17 in supernatants of splenocytes co-cultured with purified PopB/PcrH. PLGA-PopB/PcrH-immunized mice showed 3-4-fold higher Th17 responses both in the lung and in the spleen compared to mice immunized with empty PLGA or PopB/PcrH alone. After challenge with P. aeruginosa, PLGA-PopB/PcrH-immunized mice showed significantly lower bacterial counts in the lungs and improved survival. In conclusion, encapsulation of PopB/PcrH in PLGA nanoparticles can elicit Th17 responses to intranasal vaccination and protect mice against acute lethal P. aeruginosa pneumonia.

SUBMITTER: Schaefers MM

PROVIDER: S-EPMC6279603 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Schaefers Matthew M MM Duan Biyan B Mizrahi Boaz B Lu Roger R Reznor Gally G Kohane Daniel S DS Priebe Gregory P GP

Vaccine 20181009 46

The Pseudomonas aeruginosa type III secretion system protein PopB and its chaperon protein PcrH, when co-administered with the adjuvant curdlan, elicit Th17 responses after intranasal immunization of mice. These PopB/PcrH-curdlan vaccines protect mice against acute lethal pneumonia in an IL-17-dependent fashion involving CD4 helper T cells secreting IL-17 (Th17 cells). In this study, we tested whether encapsulation of PopB/PcrH in poly-lactic-co-glycolic acid (PLGA) nanoparticles could elicit Th ...[more]

PMID: 30314911

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Project description:Backgrounds and purposeThe theory of "entero-pulmonary axis" proves that pneumonia leads to gut microbiota disturbance and Treg/Th17 immune imbalance. This study is aimed to explore the potential mechanism of fecal microbiota transplantation (FMT) in the treatment of Pseudomonas aeruginosa pneumonia, in order to provide new insights into the treatment of pneumonia.MethodsPseudomonas aeruginosa and C57/BL6 mice were used to construct the acute pneumonia mouse model, and FMT was treated. Histopathological changes in lung and spleen were observed by HE staining. The expression of CD25, Foxp3 and IL-17 was observed by immunofluorescence. The proportion of Treg and Th17 cells was analyzed by flow cytometry. Serum IL-6, LPS, and IFN-γ levels were detected by ELISA. The expression of TNF-α, IFN-γ, IL-6, IL-2, Foxp3, IL-17, IL-10, and TGFβ1 in lung tissue homogenate was detected by qRT-PCR. 16S rRNA sequencing and non-targeted metabolomics were used to analyze gut microbiota and metabolism.ResultsPseudomonas aeruginosa caused the decrease of body weight, food and water intake, lung tissue, and spleen injury in mice with pneumonia. Meanwhile, it caused lung tissue and serum inflammation, and Treg/Th17 cell imbalance in mice with pneumonia. Pseudomonas aeruginosa reduced the diversity and number of gut microbiota in pneumonia mice, resulting in metabolic disorders, superpathway of quinolone and alkylquinolone biosynthesis. It also led to the decrease of 2-heptyl-3-hydroxy-4(1H)-quinolone biosynthesis, and the enrichment of Amino sugar and nucleotide sugar metabolism. FMT with or without antibiotic intervention restored gut microbiota abundance and diversity, suppressed inflammation and tissue damage, and promoted an immunological balance of Treg/Th17 cells in mice with pneumonia. In addition, FMT inhibited the aerobactin biosynthesis, 4-hydroxyphenylacetate degradation, superpathway of lipopolysaccharide biosynthesis and L-arabinose degradation IV function of microbiota, and improved amino sugar and nucleotide sugar metabolism.ConclusionsFMT restored the Treg/Th17 cells' balance and improved inflammation and lung injury in mice with Pseudomonas aeruginosa pneumonia by regulating gut microbiota disturbance and metabolic disorder.

Project description:Ventilator-associated pneumonia is an important clinical manifestation of the nosocomial pathogen Pseudomonas aeruginosa. We characterized the correlates of protection with MEDI3902, a bispecific human IgG1 monoclonal antibody that targets the P. aeruginosa type 3 secretion system PcrV protein and the Psl exopolysaccharide, in a rabbit model of ventilator-associated pneumonia using lung-protective, low-tidal-volume mechanical ventilation. Rabbits infused with MEDI3902 prophylactically were protected, whereas those pretreated with irrelevant isotype-matched control IgG (c-IgG) succumbed between 12 and 44 h postinfection (100% survival [8/8 rabbits] versus 0% survival [8/8 rabbits]; P < 0.01 by log rank test). Lungs from rabbits pretreated with c-IgG, but not those pretreated with MEDI3902, had bilateral, multifocal areas of marked necrosis, hemorrhage, neutrophilic inflammatory infiltrate, and diffuse fibrinous edema in alveolar spaces. All rabbits pretreated with c-IgG developed worsening bacteremia that peaked at the time of death, whereas only 38% of rabbits pretreated with MEDI3902 (3/8 rabbits) developed such high-grade bacteremia (two-sided Fisher's exact test, P = 0.026). Biomarkers associated with acute respiratory distress syndrome were evaluated longitudinally in blood samples collected every 2 to 4 h to assess systemic pathophysiological changes in rabbits pretreated with MEDI3902 or c-IgG. Biomarkers were sharply increased or decreased in rabbits pretreated with c-IgG but not those pretreated with MEDI3902, including the ratio of arterial oxygen partial pressure to the fraction of inspired oxygen of <300, hypercapnia or hypocapnia, severe lactic acidosis, leukopenia, and neutropenia. Cytokines and chemokines associated with acute respiratory distress syndrome were significantly downregulated in lungs from rabbits pretreated with MEDI3902, compared with c-IgG. These results suggest that MEDI3902 prophylaxis could have potential clinical utility for decreasing the severity of P. aeruginosa ventilator-associated pneumonia.

Dataset Information

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

Publications

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

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