Double-edged sword of JAK/STAT signaling pathway in viral infections: novel insights into virotherapy

Abstract

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) is an intricate signaling cascade composed of various cytokines, interferons (IFN, growth factors, and other molecules. This pathway provides a delicate mechanism through which extracellular factors adjust gene expression, thereby acting as a substantial basis for environmental signals to influence cell growth and differentiation. The interactions between the JAK/STAT cascade and antiviral IFNs are critical to the host’s immune response against viral microorganisms. Recently, with the emergence of therapeutic classes that target JAKs, the significance of this cascade has been recognized in an unprecedented way. Despite the functions of the JAK/STAT pathway in adjusting immune responses against viral pathogens, a vast body of evidence proposes the role of this cascade in the replication and pathogenesis of viral pathogens. In this article, we review the structure of the JAK/STAT signaling cascade and its role in immuno-inflammatory responses. We also highlight the paradoxical effects of this pathway in the pathogenesis of viral infections. Graphical Abstract

STAT1-Deficient HPV E6/E7-Associated Cancers Maintain Host Immunocompetency against Therapeutic Intervention

“…In pathogenic studies, the use of STAT1 −/− mice has facilitated extensive research on various pathogens such as Cryptococcus neoformans, lymphocytic choriomeningitis virus, Crimean-Congo hemorrhagic fever virus, and Machupo virus [50][51][52][53]. There is a consensus that upregulation of STAT1 activation confers antiviral properties, with STAT1 deficiency often increasing the susceptibility to death from viral infections [13,54]. Ultimately, these pathogenic studies established the foundation for understanding the critical role of STAT1 in immune regulation.…”

“…Following HPV infection, pattern-recognition receptors identify the viral components and induce interferon synthesis, triggering the Janus protein tyrosine kinase (JAK)/STAT signaling pathway [13]. The signal transducer and activator of transcription (STAT) protein family, a group of intracellular transcription factors, orchestrates a wide array of key biological processes, spanning from cell differentiation to immune system regulation [14].…”

Cumulative incidence and risk of infection in patients with rheumatoid arthritis treated with janus kinase inhibitors: A systematic review and meta-analysis

“…In our analysis, patients receiving the JAKi baricitinib were significantly more likely to develop opportunistic infections compared to patients in the control group. The increased risk of opportunistic infections in patients receiving JAKi has been attributed to down-modulation of cytokines responsible for mounting T-cell specific responses against pathogens [ 64 ], impaired granuloma formation necessary for containment of infections, such as tuberculosis [ 65 ], and diminished interferon-mediated antiviral responses that protect against viral infections [ 66 ]. The most common infections as a result of JAKi therapy reported in our analysis and other published studies, in addition to herpes zoster, include Candida spp., followed by infections from cytomegalovirus, Cryptococcus spp., Pneumocystis jirovecii , and tuberculosis [ 57 , 67 ].…”

Novel Janus Kinase Inhibitors in the Treatment of Dermatologic Conditions

“…STAT proteins are signal transducers and activators of transcription that are intracellular transcription factors. The family of these proteins includes seven members: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6 [13,19]. STATs are involved in many key cellular processes: processes of proliferation, differentiation, apoptosis and functional activation [19,20].…”

“…The family of these proteins includes seven members: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6 [13,19]. STATs are involved in many key cellular processes: processes of proliferation, differentiation, apoptosis and functional activation [19,20]. These proteins are composed of an N-terminal domain, a coiled-coil-type domain, a DNA-binding domain, a transcription activation domain, an SH2 domain and a tyrosine activation domain [21].…”