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Antagonism of miR-328 increases the antimicrobial function of macrophages and neutrophils and rapid clearance of non-typeable Haemophilus influenzae (NTHi) from infected lung.

Tay HL, Kaiko GE, Plank M, Li J, Maltby S, Essilfie AT, Jarnicki A, Yang M, Mattes J, Hansbro PM, Foster PS - PLoS Pathog. (2015)

Bottom Line: Manipulation miRNA directly regulating anti-microbial machinery of the innate immune system may boost host defence responses.Here we demonstrate that miR-328 is a key element of the host response to pulmonary infection with non-typeable haemophilus influenzae and pharmacological inhibition in mouse and human macrophages augments phagocytosis, the production of reactive oxygen species, and microbicidal activity.Thus, miRNA pathways can be targeted in the lung to enhance host defence against a clinically relevant microbial infection and offer a potential new anti-microbial approach for the treatment of respiratory diseases.

View Article: PubMed Central - PubMed

Affiliation: Priority Research Centre for Asthma and Respiratory Disease, Department of Microbiology and Immunology, School of Pharmacy and Biomedical Sciences, Faculty of Health and Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia.

ABSTRACT
Pathogenic bacterial infections of the lung are life threatening and underpin chronic lung diseases. Current treatments are often ineffective potentially due to increasing antibiotic resistance and impairment of innate immunity by disease processes and steroid therapy. Manipulation miRNA directly regulating anti-microbial machinery of the innate immune system may boost host defence responses. Here we demonstrate that miR-328 is a key element of the host response to pulmonary infection with non-typeable haemophilus influenzae and pharmacological inhibition in mouse and human macrophages augments phagocytosis, the production of reactive oxygen species, and microbicidal activity. Moreover, inhibition of miR-328 in respiratory models of infection, steroid-induced immunosuppression, and smoke-induced emphysema enhances bacterial clearance. Thus, miRNA pathways can be targeted in the lung to enhance host defence against a clinically relevant microbial infection and offer a potential new anti-microbial approach for the treatment of respiratory diseases.

No MeSH data available.


Related in: MedlinePlus

Inhibiting miR-328 increases bacterial uptake in human monocyte-derived macrophages and neutrophils.Human monocytes and neutrophils were isolated from healthy adult blood and macrophages were differentiated in vitro. Cells were pre-treated with ant-328 or a scrambled control. (A) Human monocyte-derived macrophages were infected with NTHi for 8 h at MOI 100. (B) Human neutrophils were infected with NTHi for 1 h at MOI 10. Intracellular bacteria colony counts were determined using the gentamicin exclusion assay. Results are expressed as mean ± SEM (n = 6 human subjects per group; *** p<0.001 compared to Scr + NTHi).
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ppat.1004549.g006: Inhibiting miR-328 increases bacterial uptake in human monocyte-derived macrophages and neutrophils.Human monocytes and neutrophils were isolated from healthy adult blood and macrophages were differentiated in vitro. Cells were pre-treated with ant-328 or a scrambled control. (A) Human monocyte-derived macrophages were infected with NTHi for 8 h at MOI 100. (B) Human neutrophils were infected with NTHi for 1 h at MOI 10. Intracellular bacteria colony counts were determined using the gentamicin exclusion assay. Results are expressed as mean ± SEM (n = 6 human subjects per group; *** p<0.001 compared to Scr + NTHi).

Mentions: MiR-328 is conserved across species, with an identical sequence in mice and humans. Therefore, we investigated if miR-328 plays a similar role in human macrophages and neutrophils infected with NTHi in vitro. Neutrophils were purified from healthy adult blood and macrophages were differentiated in culture from monocytes derived from the PBMC fraction. Similar to the results observed with murine cells, inhibition of miR-328 significantly increased bacterial uptake by human macrophages (Fig 6A) and neutrophils (Fig 6B) in vitro.


Antagonism of miR-328 increases the antimicrobial function of macrophages and neutrophils and rapid clearance of non-typeable Haemophilus influenzae (NTHi) from infected lung.

Tay HL, Kaiko GE, Plank M, Li J, Maltby S, Essilfie AT, Jarnicki A, Yang M, Mattes J, Hansbro PM, Foster PS - PLoS Pathog. (2015)

Inhibiting miR-328 increases bacterial uptake in human monocyte-derived macrophages and neutrophils.Human monocytes and neutrophils were isolated from healthy adult blood and macrophages were differentiated in vitro. Cells were pre-treated with ant-328 or a scrambled control. (A) Human monocyte-derived macrophages were infected with NTHi for 8 h at MOI 100. (B) Human neutrophils were infected with NTHi for 1 h at MOI 10. Intracellular bacteria colony counts were determined using the gentamicin exclusion assay. Results are expressed as mean ± SEM (n = 6 human subjects per group; *** p<0.001 compared to Scr + NTHi).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4404141&req=5

ppat.1004549.g006: Inhibiting miR-328 increases bacterial uptake in human monocyte-derived macrophages and neutrophils.Human monocytes and neutrophils were isolated from healthy adult blood and macrophages were differentiated in vitro. Cells were pre-treated with ant-328 or a scrambled control. (A) Human monocyte-derived macrophages were infected with NTHi for 8 h at MOI 100. (B) Human neutrophils were infected with NTHi for 1 h at MOI 10. Intracellular bacteria colony counts were determined using the gentamicin exclusion assay. Results are expressed as mean ± SEM (n = 6 human subjects per group; *** p<0.001 compared to Scr + NTHi).
Mentions: MiR-328 is conserved across species, with an identical sequence in mice and humans. Therefore, we investigated if miR-328 plays a similar role in human macrophages and neutrophils infected with NTHi in vitro. Neutrophils were purified from healthy adult blood and macrophages were differentiated in culture from monocytes derived from the PBMC fraction. Similar to the results observed with murine cells, inhibition of miR-328 significantly increased bacterial uptake by human macrophages (Fig 6A) and neutrophils (Fig 6B) in vitro.

Bottom Line: Manipulation miRNA directly regulating anti-microbial machinery of the innate immune system may boost host defence responses.Here we demonstrate that miR-328 is a key element of the host response to pulmonary infection with non-typeable haemophilus influenzae and pharmacological inhibition in mouse and human macrophages augments phagocytosis, the production of reactive oxygen species, and microbicidal activity.Thus, miRNA pathways can be targeted in the lung to enhance host defence against a clinically relevant microbial infection and offer a potential new anti-microbial approach for the treatment of respiratory diseases.

View Article: PubMed Central - PubMed

Affiliation: Priority Research Centre for Asthma and Respiratory Disease, Department of Microbiology and Immunology, School of Pharmacy and Biomedical Sciences, Faculty of Health and Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia.

ABSTRACT
Pathogenic bacterial infections of the lung are life threatening and underpin chronic lung diseases. Current treatments are often ineffective potentially due to increasing antibiotic resistance and impairment of innate immunity by disease processes and steroid therapy. Manipulation miRNA directly regulating anti-microbial machinery of the innate immune system may boost host defence responses. Here we demonstrate that miR-328 is a key element of the host response to pulmonary infection with non-typeable haemophilus influenzae and pharmacological inhibition in mouse and human macrophages augments phagocytosis, the production of reactive oxygen species, and microbicidal activity. Moreover, inhibition of miR-328 in respiratory models of infection, steroid-induced immunosuppression, and smoke-induced emphysema enhances bacterial clearance. Thus, miRNA pathways can be targeted in the lung to enhance host defence against a clinically relevant microbial infection and offer a potential new anti-microbial approach for the treatment of respiratory diseases.

No MeSH data available.


Related in: MedlinePlus