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Immunogene therapy with fusogenic nanoparticles modulates macrophage response to Staphylococcus aureus.

ABSTRACT: The incidence of adverse effects and pathogen resistance encountered with small molecule antibiotics is increasing. As such, there is mounting focus on immunogene therapy to augment the immune system's response to infection and accelerate healing. A major obstacle to in vivo gene delivery is that the primary uptake pathway, cellular endocytosis, results in extracellular excretion and lysosomal degradation of genetic material. Here we show a nanosystem that bypasses endocytosis and achieves potent gene knockdown efficacy. Porous silicon nanoparticles containing an outer sheath of homing peptides and fusogenic liposome selectively target macrophages and directly introduce an oligonucleotide payload into the cytosol. Highly effective knockdown of the proinflammatory macrophage marker IRF5 enhances the clearance capability of macrophages and improves survival in a mouse model of Staphyloccocus aureus pneumonia.

SUBMITTER: Kim B

PROVIDER: S-EPMC5958120 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Immunogene therapy with fusogenic nanoparticles modulates macrophage response to Staphylococcus aureus.

Kim Byungji B Pang Hong-Bo HB Kang Jinyoung J Park Ji-Ho JH Ruoslahti Erkki E Sailor Michael J MJ

Nature communications 20180517 1

The incidence of adverse effects and pathogen resistance encountered with small molecule antibiotics is increasing. As such, there is mounting focus on immunogene therapy to augment the immune system's response to infection and accelerate healing. A major obstacle to in vivo gene delivery is that the primary uptake pathway, cellular endocytosis, results in extracellular excretion and lysosomal degradation of genetic material. Here we show a nanosystem that bypasses endocytosis and achieves poten ...[more]

PMID: 29773788

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Project description:To study the antimicrobial function of immune cells ex vivo, cells are commonly cultivated under atmospheric oxygen concentrations (20-21%; normoxia), although the physiological oxygen conditions in vivo are significantly lower in most tissues. Especially during an acute infection, oxygen concentration locally decreases to hypoxic levels around or below 1%. The goal of this study was to investigate the effect of hypoxia on the activity of mast cells (MCs). MCs were cultivated for 3 or 24?h at 1% O2 in a hypoxia glove box and co-incubated with heat-inactivated Staphylococcus aureus. When incubating the cells for 24?h under hypoxia, the transcriptional regulator hypoxia-inducible factor 1? (HIF-1?) was stabilized and resulted in increased extracellular trap formation and decreased phagocytosis. Interestingly, while phagocytosis of fluorescent S. aureus bioparticles as well as the release of extracellular traps remained unaffected at 3?h hypoxia, the secretion of the prestored mediator histamine was increased under hypoxia alone. In contrast, the release of TNF-? was generally reduced at 3?h hypoxia. Microarray transcriptome analysis revealed 13 genes that were significantly downregulated in MCs comparing 3?h hypoxia versus normoxia. One interesting candidate is sec24, a member of the pre-budding complex of coat protein complex II (COPII), which is responsible for the anterograde transport of proteins from the ER to the Golgi apparatus. These data lead to the suggestion that de novo synthesized proteins including crucial factors, which are involved in the response to an acute infection like TNF-?, may eventually be retained in the ER under hypoxia. Importantly, the expression of HIF-1? was not altered at 3?h. Thus, our data exhibit a HIF-1?-independent reaction of MCs to short-term hypoxia. We hypothesize that MCs respond to short-term low oxygen levels in a HIF-1?-independent manner by downregulating the release of proinflammatory cytokines like TNF-?, thereby avoiding uncontrolled degranulation, which could lead to excessive inflammation and severe tissue damage.

Dataset Information

Immunogene therapy with fusogenic nanoparticles modulates macrophage response to Staphylococcus aureus.

Publications

Immunogene therapy with fusogenic nanoparticles modulates macrophage response to Staphylococcus aureus.

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