Next generation sequencing reveals miR-431-3p/miR-1303 as immune-regulating microRNAs for active tuberculosis.
J Infect
; 85(5): 519-533, 2022 11.
Article
em En
| MEDLINE
| ID: mdl-36057384
ABSTRACT
OBJECTIVES:
RNA therapeutics is an emerging field that widens the range of treatable targets and would improve disease outcome through bypassing the antibiotic bactericidal targets to kill Mycobacterium tuberculosis (M.tb).METHODS:
We screened for microRNA with immune-regulatory functions against M.tb by next generation sequencing of peripheral blood mononuclear cells, followed by validation in an independent cohort.RESULTS:
Twenty three differentially expressed microRNAs were identified between 12 active pulmonary TB patients and 4 healthy subjects, and 35 microRNAs before and after 6-month anti-TB therapy. Enriched predicted target pathways included proteoglycan, HIF-1 signaling, longevity-regulating, central carbon metabolism, and autophagy. We validated miR-431-3p down-regulation and miR-1303 up-regulation accompanied with corresponding changes in their predicted target genes in an independent validation cohort of 46 active TB patients, 30 latent TB infection subjects, and 24 non-infected healthy subjects. In vitro experiments of transfections with miR-431-3p mimic/miR-1303 short interfering RNA in THP-1 cells under ESAT-6 stimuli showed that miR-431-3p and miR-1303 were capable to augment and suppress autophagy/apoptosis/phagocytosis of macrophage via targeting MDR1/MMP16/RIPOR2 and ATG5, respectively.CONCLUSIONS:
This study provides a proof of concept for microRNA-based host-directed immunotherapy for active TB disease. The combined miR-431-3p over-expression and miR-1303 knock-down revealed new vulnerabilities of treatment-refractory TB disease.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
3_ND
Base de dados:
MEDLINE
Assunto principal:
Tuberculose
/
MicroRNAs
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
J Infect
Ano de publicação:
2022
Tipo de documento:
Article