Abstract
Type-I interferon (IFN-I) production is an early response to viral infection and pathogenic viruses have evolved multiple strategies to evade this cellular defense. Some viruses can establish and maintain persistent infections by altering the IFN-I signaling pathway. Here, we studied IFN-I synthesis and response in an in vitro model of persistent infection by respiratory syncytial virus (RSV) in a murine macrophage-like cell line. In this model, interferon regulatory factor 3 was constitutively active and located at nuclei of persistently infected cells, inducing expression of IFN-beta mRNA and protein. However, persistently infected macrophages did not respond in an autocrine manner to the secreted-IFN-beta or to recombinant-IFN-beta, since phosphorylated-STAT1 was not detected by western blot and transcription of the interferon-stimulated genes (ISGs) Mx1 and ISG56 was not induced. Treatment of non-infected macrophages with supernatants from persistently infected cells induced STAT1 phosphorylation and ISGs expression, mediated by the IFN-I present in the supernatants, because blocking the IFN-I receptor inhibited STAT1 phosphorylation. Results suggest that the lack of autocrine response to IFN-I by the host cell may be one mechanism for maintenance of RSV persistence. Furthermore, STAT1 phosphorylation and ISGs expression induced in non-infected cells by supernatants from persistently infected macrophages suggest that RSV persistence may trigger a proinflammatory phenotype in non-infected cells as part of the pathogenesis of RSV infection.
Highlights
Respiratory syncytial virus (RSV), a negative-sense, single-stranded RNA virus of the family Paraxmyxoviridae, is considered the main cause of bronchiolitis and pneumonia in children under two years of age [1,2,3]
Whereas most studies that were focused on determining the mechanisms by which RSV evades the IFN-I response have been performed during acute infections, we studied the state of activation of the IFN-I signaling pathway at the level of synthesis and response during persistent RSV infection by using a previously established in vitro model of persistently RSV-infected murine macrophages (MφP) [14]
We report that MφP constitutively expressed the active form of Interferon regulatory factor 3 (IRF3) and IFN-β, but these macrophages were not competent to respond to this cytokine in an autocrine manner, as phosphorylation of STAT1 was not detected, neither expression of the interferon-stimulated genes (ISGs) myxovirus-resistance gene 1 (Mx1) nor ISG56
Summary
Respiratory syncytial virus (RSV), a negative-sense, single-stranded RNA virus of the family Paraxmyxoviridae (genus Pneumovirus), is considered the main cause of bronchiolitis and pneumonia in children under two years of age [1,2,3]. IRF3 undergoes phosphorylation, dimerization, and nuclear translocation where along with the transcription factors NF-kB and AP-1, it binds the IFN-β promoter to induce gene expression [27,28]. Whereas most studies that were focused on determining the mechanisms by which RSV evades the IFN-I response have been performed during acute infections, we studied the state of activation of the IFN-I signaling pathway at the level of synthesis and response during persistent RSV infection by using a previously established in vitro model of persistently RSV-infected murine macrophages (MφP) [14]. We report that MφP constitutively expressed the active form of IRF3 and IFN-β, but these macrophages were not competent to respond to this cytokine in an autocrine manner, as phosphorylation of STAT1 was not detected, neither expression of the ISGs Mx1 nor ISG56. IFN-β secreted by MφP was able to activate STAT1 in non-infected macrophages along with Mx1 and ISG56 mRNA expression, thereby suggesting that persistent RSV infection may affect the host cell, and indirectly affect surrounding cells by altering their state of activation, contributing with the pathogenesis of RSV infection
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