Abstract
Modulation of the antiviral innate immune response has been proposed as a putative cellular target for the development of novel pan-viral therapeutic strategies. The Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway is especially relevant due to its essential role in the regulation of local and systemic inflammation in response to viral infections, being, therefore, a putative therapeutic target. Here, we review the extraordinary diversity of strategies that viruses have evolved to interfere with JAK-STAT signaling, stressing the relevance of this pathway as a putative antiviral target. Moreover, due to the recent remarkable progress on the development of novel JAK inhibitors (JAKi), the current knowledge on its efficacy against distinct viral infections is also discussed. JAKi have a proven efficacy against a broad spectrum of disorders and exhibit safety profiles comparable to biologics, therefore representing good candidates for drug repurposing strategies, including viral infections.
Highlights
Innate immunity acts as our first line of defense for the detection and clearance of viral infections
After infection, all viruses trigger an antiviral response that relies on elements of innate immunity, such as physical barriers and the production of interferons (IFN) and groups of cytokines, a process orchestrated by innate immune cells—in particular, monocytes/macrophages, dendritic cells (DC), and natural killer (NK) cells [1,2]
Cytokine storms released during the acute viral infection of distinct viruses such as influenza, coronavirus, Ebola virus, and dengue virus can result in single- or multiple-organ damage and even death [6,7,8,9,10,11,12,13]
Summary
Innate immunity acts as our first line of defense for the detection and clearance of viral infections. The secreted IFNs bind to their respective receptors and activate the Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway [3], resulting in the production of hundreds of downstream antiviral. IFN-stimulated genes (ISGs) and the secretion of proinflammatory cytokines This process establishes an antiviral state that inhibits viral replication, stimulates the adaptive immune response, and recruits other immune cells to the site of infection [4,5] (Figure 1). Secreted proinflammatory cytokines can cause local and systemic inflammation [1,2], resulting in the overactivation of innate immunity. A dysregulated immune response rare cases the nucleus, resulting in the target gene expression of antiviral ISGs, and proinflammatoryincytokines might result in fatal outcomes due to hyperinflammation and the cytokine storm. Gene; RIG-I, retinoic acid-inducible gene I; TRAF, tumor necrosis factor receptor-related factor; TBK1, TANK-binding kinase 1; IKKε, IκB kinase ε
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