MicroRNome Analysis Unravels the Molecular Basis of SARS Infection in Bronchoalveolar Stem Cells

Abstract

Severe acute respiratory syndrome (SARS), caused by the coronavirus SARS-CoV, is an acute infectious disease with significant mortality. A typical clinical feature associated with SARS is pulmonary fibrosis and associated lung failure. In the aftermath of the SARS epidemic, although significant progress towards understanding the underlying molecular mechanism of the infection has been made, a large gap still remains in our knowledge regarding how SARS-CoV interacts with the host cell at the onset of infection. The rapidly changing viral genome adds another variable to this equation. We have focused on a novel concept of microRNA (miRNA)–mediated host–virus interactions in bronchoalveolar stem cells (BASCs) at the onset of infection by correlating the “BASC–microRNome” with their targets within BASCs and viral genome. This work encompasses miRNA array data analysis, target prediction, and miRNA–mRNA enrichment analysis and develops a complex interaction map among disease-related factors, miRNAs, and BASCs in SARS pathway, which will provide some clues for diagnostic markers to view an overall interplay leading to disease progression. Our observation reveals the BASCs (Sca-1+ CD34+ CD45- Pecam-), a subset of Oct-4+ ACE2+ epithelial colony cells at the broncho-alveolar duct junction, to be the prime target cells of SARS-CoV infection. Upregulated BASC miRNAs-17*, -574-5p, and -214 are co-opted by SARS-CoV to suppress its own replication and evade immune elimination until successful transmission takes place. Viral Nucleocapsid and Spike protein targets seem to co-opt downregulated miR-223 and miR-98 respectively within BASCs to control the various stages of BASC differentiation, activation of inflammatory chemokines, and downregulation of ACE2. All these effectively accounts for a successful viral transmission and replication within BASCs causing continued deterioration of lung tissues and apparent loss of capacity for lung repair. Overall, this investigation reveals another mode of exploitation of cellular miRNA machinery by virus to their own advantage.

miR-223 inhibits dengue virus replication by negatively regulating the microtubule-destabilizing protein STMN1 in EAhy926 cells

“…Specifically, it has been reported that miR-223 plays a role in the pathogenesis of certain infectious diseases, such as influenza and chronic hepatitis B virus infection [23,25]. Moreover, an anti-viral effect for miR-223 was observed in SARS coronavirusinfected bronchoalveolar stem cells and in freshly isolated HIV-1-infected monocytes [24,30]. However, less is known about the roles of miRNAs, especially miR-223, in DENV infection.…”

miR‐223: infection, inflammation and cancer

“…Severe acute respiratory syndrome (SARS), a twenty‐first‐century pandemic infection with typical clinical features of pulmonary fibrosis and lung failure that led to significant mortality, is caused by the coronavirus SARS‐CoV . Although SARS‐CoV cannot infect or replicate in fully differentiated cells, it is possible to study the virus in infected bronchoalveolar stem cells . Using this method, Mallick et al .…”

MicroRNA reins in embryonic and cancer stem cells

“…26 Some emerging evidences suggest that miRNAs may play an essential role in self-renewal and differentiation. [26][27][28][29][30][31][32] miRNAs are also harnessed in generating induced pluripotent stem cells (iPS cells). The mouse embryonic stem (ES) cell specific miRNAs-miR-291-3p, miR-294 and miR-295 helped in somatic cell reprogramming by enhancing the reprogramming efficiency of Klf4, Oct4 and Sox2.…”