Viruses employ different strategies to circumvent the antiviral actions of the innate immune response. SARS coronavirus (SARS-CoV), a virus that causes severe lung damage, encodes an array of proteins able to inhibit induction and signaling of type-I interferons. However, recent studies have demonstrated that interferons are produced during SARS-CoV infection in humans and macaques. Furthermore, nuclear translocation of activated STAT1 and a range of interferon-stimulated genes could be demonstrated in the lungs of SARS-CoV-infected macaques. In line with these observations, plasmacytoid dendritic cells have been shown to produce interferons upon SARS-CoV infection in vitro. Given the pivotal role of interferons during viral infections, (differential) induction of interferons may affect the outcome of the infection. Therefore, the functional implication of interferon production during SARS-CoV infection remains to be re-investigated.
Interferon induction during viral infection
Type-I interferons are induced in direct response to viral infection and play an important role in innate immunity. Although most mammalian cells are capable of producing type-I interferons, plasmacytoid dendritic cells, also known as ‘professional’ interferon producers, produce much higher amounts of IFN-α than other cell types.
Invading viruses are sensed by the host cell either though a cytoplasmatic pathway, using the RNA helicases RIG-I and MDA-5, or by the endosomal pathway, in which Toll-like receptors are involved.
After viral RNA is detected by the host cell, activation of several signaling pathways ultimately leads to phosphorylation of IRF-3 and IRF-7, which are subsequently translocated to the nucleus where they activate the interferon promoter together with other cofactors, resulting in the production of type-I interferons.
Interferon induction by SARS-CoV
SARS-CoV employs several mechanisms that inhibit induction of type-I interferons. As a result, most cell types do not produce type-I interferons upon SARS-CoV infection.
Despite blocks on interferon production, type-I interferons are detected in SARS-CoV-infected macaques and humans.
Plasmacytoid dendritic cells are able to produce interferons upon SARS-CoV infection and are a possible source for interferon production in vivo.
SARS-CoV blocks interferon signaling
When interferons activate the JAK/STAT signaling pathway, more than 300 interferon-stimulated genes are activated.
SARS-CoV not only blocks interferon induction but also interferon signaling through the JAK/STAT pathway.
Interferons produced during in vivo SARS-CoV infection activate STAT1 in uninfected cells.
Patients with severe cases of SARS develop pneumonia and acute respiratory distress syndrome (ARDS). Although ARDS-associated mortality remains very high, no successful pharmacological therapies have been developed for ARDS as yet.
Insights into the complex regulation of the interferon response during SARS-CoV may provide clues for intervention strategies based on the use of interferons. However, more research in appropriate SARS animal models should be performed to address this issue.
Reference & Source information: https://www.futuremedicine.com/
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