Dataset Information

Synchronized Orchestration of miR-99b and let-7g Positively Regulates Rotavirus Infection by Modulating Autophagy.

ABSTRACT: Rotavirus (RV), the major etiological agent of viral gastroenteritis in young children, kills over 200 thousand infants each year. In spite of available vaccines, rotaviral diarrhoea is still a major problem in developing countries of Asia and Africa. Therefore, the studies on RV infection and host antiviral responses are warranted. The active correlation between virus infection and activation of autophagy machinery and positive influence of autophagy on RV replication have been documented recently. Previous study from our group showed dysregulation of several cellular miRNAs during RV infection, though their significance remained largely unknown. Since cellular microRNAs (miRNAs) have been implicated in the control of several fundamental biological processes including stress response and autophagy, we focused on two miRNAs, miR-99b and let-7g, and analyzed their function to gain insight into the miRNA-autophagy crosstalk during RV infection. This study shows that RV suppresses let-7g expression but enhances miR-99b that in turn augment major autophagy regulators. Ectopic expression of let-7g and knockdown of miR-99b resulted in inhibition of autophagy, hence, reduction of RV replication. Overall, our study highlights new mechanistic insights for understanding the role of miRNAs in modulating RV infection and possibility of using RNA interference as an antiviral therapeutic target.

SUBMITTER: Mukhopadhyay U

PROVIDER: S-EPMC6362297 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Synchronized Orchestration of miR-99b and let-7g Positively Regulates Rotavirus Infection by Modulating Autophagy.

Mukhopadhyay Urbi U Chanda Shampa S Patra Upayan U Mukherjee Arpita A Rana Santanu S Mukherjee Anupam A Chawla-Sarkar Mamta M

Scientific reports 20190204 1

Rotavirus (RV), the major etiological agent of viral gastroenteritis in young children, kills over 200 thousand infants each year. In spite of available vaccines, rotaviral diarrhoea is still a major problem in developing countries of Asia and Africa. Therefore, the studies on RV infection and host antiviral responses are warranted. The active correlation between virus infection and activation of autophagy machinery and positive influence of autophagy on RV replication have been documented recen ...[more]

PMID: 30718795

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Project description:Antigen-presenting cells (APCs) regulate the balance of our immune response toward microbes. Whereas immunogenic APCs boost inflammation and activate lymphocytes, the highly plastic cells can switch into a tolerogenic/suppressive phenotype that dampens and resolves the response. Thereby the initially mediated inflammation seems to prime the switch of APCs while the strength of activation determines the grade of the suppressive phenotype. Recently, we showed that pathogen recognition receptor-mediated pro-inflammatory cytokines reprogram differentiating human blood monocytes in vitro toward an immunosuppressive phenotype through prolonged activation of signal transducer and activator of transcription (STAT) 3. The TLR7/8 ligand R848 (Resiquimod) triggers the high release of cytokines from GM-CSF/IL-4-treated monocytes. These cytokines subsequently upregulate T cell suppressive factors, such as programmed death-ligand 1 (PD-L1) and indolamin-2,3-dioxygenase (IDO) through cytokine receptor-mediated STAT3 activation. Here, we reveal an essential role for the microRNA (miR, miRNA) hsa-miR-99b/let-7e/miR-125a cluster in stabilizing the suppressive phenotype of R848-stimulated APCs on different levels. On the one hand, the miR cluster boosts R848-stimulated cytokine production through regulation of MAPkinase inhibitor Tribbles pseudokinase 2, thereby enhancing cytokine-stimulated activation of STAT3. One the other hand, the STAT3 inhibitor suppressor of cytokine signaling-1 is targeted by the miR cluster, stabilizing the STAT3-induced expression of immunosuppressive factors PD-L1 and IDO. Finally, hsa-miR-99b/let-7e/miR-125a cluster regulates generation of the suppressive tryptophan (Trp) metabolite kynurenine by targeting the tryptophanyl-tRNA synthetase WARS, the direct competitor of IDO in terms of availability of Trp. In summary, our results reveal the hsa-miR-99b/let-7e/miR-125a cluster as an important player in the concerted combination of mechanisms that stabilizes STAT3 activity and thus regulate R848-stimulated suppressive APCs.

Dataset Information

Synchronized Orchestration of miR-99b and let-7g Positively Regulates Rotavirus Infection by Modulating Autophagy.

Publications

Synchronized Orchestration of miR-99b and let-7g Positively Regulates Rotavirus Infection by Modulating Autophagy.

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