title: Mycobacterium tuberculosis controls microRNA-99b (miR-99b) expression in infected murine dendritic cells to modulate host immunity.
abstract: Mycobacterium tuberculosis resides and replicates within host phagocytes by modulating host microbicidal responses. In addition, it suppresses the production of host protective cytokines to prevent activation of and antigen presentation by M. tuberculosis-infected cells, causing dysregulation of host protective adaptive immune responses. Many cytokines are regulated by microRNAs (miRNAs), a newly discovered class of small noncoding RNAs, which have been implicated in modulating host immune responses in many bacterial and viral diseases. Here, we show that miRNA-99b (miR-99b), an orphan miRNA, plays a key role in the pathogenesis of M. tuberculosis infection. We found that miR-99b expression was highly up-regulated in M. tuberculosis strain H37Rv-infected dendritic cells (DCs) and macrophages. Blockade of miR-99b expression by antagomirs resulted in significantly reduced bacterial growth in DCs. Interestingly, knockdown of miR-99b in DCs significantly up-regulated proinflammatory cytokines such as IL-6, IL-12, and IL-1β. Furthermore, mRNA and membrane-bound protein data indicated that inhibition of miR-99b augments TNF-α and TNFRSF-4 production. Thus, miR-99b targets TNF-α and TNFRSF-4 receptor genes. Treatment of anti-miR-99b-transfected DCs with anti-TNF-α antibody resulted in increased bacterial burden. Thus, our findings unveil a novel host evasion mechanism adopted by M. tuberculosis via miR-99b, which may open up new avenues for designing miRNA-based vaccines and therapies.
authors.affiliation: Immunology Group, International Centre for Genetic Engineering and Biotechnology, ICGEB, New Delhi 110067, India. ysingh@rvc.ac.uk
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Singh
authors.forename: Vandana
authors.initials: V
authors.lastname: Kaul
authors.forename: Alka
authors.initials: A
authors.lastname: Mehra
authors.forename: Samit
authors.initials: S
authors.lastname: Chatterjee
authors.forename: Sultan
authors.initials: S
authors.lastname: Tousif
authors.forename: Ved Prakash
authors.initials: VP
authors.lastname: Dwivedi
authors.forename: Mrutyunjay
authors.initials: M
authors.lastname: Suar
authors.forename: Luc
authors.initials: L
authors.lastname: Van Kaer
authors.forename: William R
authors.initials: WR
authors.lastname: Bishai
authors.forename: Gobardhan
authors.initials: G
authors.lastname: Das
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology / Q000382:microbiology; D015964:Gene Expression Regulation, Bacterial; D007107:Immune System; D007249:Inflammation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D010586:Phagocytes / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D035683:MicroRNAs; C573158:Mirn99 microRNA, mouse