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JAK-STAT Pathway: A Novel Target to Tackle Viral Infections.

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.

SUBMITTER: Ezeonwumelu IJ

PROVIDER: S-EPMC8704679 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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JAK-STAT Pathway: A Novel Target to Tackle Viral Infections.

Ezeonwumelu Ifeanyi Jude IJ Garcia-Vidal Edurne E Ballana Ester E

Viruses 20211127 12

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 viruse ...[more]

PMID: 34960648

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Project description:BackgroundIn this study, we have investigated the potential regulatory mechanisms of IL-35 to relieve lupus nephritis (LN) through regulating Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling pathway in mesangial cells.ResultsAmong 105 significant differentially expressed proteins (DEPs) between juvenile systemic lupus erythematosus (JSLE) patients with LN and healthy controls, LAIR1, PDGFRβ, VTN, EPHB4, and EPHA4 were downregulated in JSLE-LN. They consist of an interactive network with PTPN11 and FN1, which involved in IL-35-related JAK/STAT signaling pathway. Besides, urinary LAIR1 was significantly correlated with JSLE-LN clinical parameters such as SLEDAI-2K, %CD19+ B, and %CD3+ T cells. Through bioinformatics analysis of co-immunoprecipitation with mass spectrometry results, including GO, KEGG, and STRING, five genes interacted with Lair1 were upregulated by IL-35, but only Myh10 was downregulated. Therefore, we presumed an interactive network among these DEPs, JAK/STAT, and IL-35. Moreover, the downregulated phosphorylated (p)-STAT3, p-p38 MAPK, and p-ERK, and the upregulated p-JAK2/p-STAT1/4 in IL-35 overexpressed mesangial cells, and RNA-sequencing results validated the potential regulatory mechanisms of IL-35 in alleviating JSLE-LN disease. Moreover, the relieved histopathological features of nephritis including urine protein and leukocyte scores, a decreased %CD90+ αSMA+ mesangial cells and pro-inflammatory cytokines, the inactivated JAK/STAT signals and the significant upregulated Tregs in spleen, thymus and peripheral blood were validated in Tregs and IL-35 overexpression plasmid-treated lupus mice.ConclusionsOur study provided a reference proteomic map of urinary biomarkers for JSLE-LN and elucidated evidence that IL-35 may regulate the interactive network of LAIR1-PTPN11-JAK-STAT-FN1 to affect JAK/STAT and MAPK signaling pathways to alleviate inflammation in JSLE-LN. This finding may provide a further prospective mechanism for JSLE-LN clinical treatment.

Project description:BackgroundThe JAK/STAT pathway transduces signals from multiple cytokines and controls haematopoiesis, immunity and inflammation. In addition, pathological activation is seen in multiple malignancies including the myeloproliferative neoplasms (MPNs). Given this, drug development efforts have targeted the pathway with JAK inhibitors such as ruxolitinib. Although effective, high costs and side effects have limited its adoption. Thus, a need for effective low cost treatments remains.Methods & findingsWe used the low-complexity Drosophila melanogaster pathway to screen for small molecules that modulate JAK/STAT signalling. This screen identified methotrexate and the closely related aminopterin as potent suppressors of STAT activation. We show that methotrexate suppresses human JAK/STAT signalling without affecting other phosphorylation-dependent pathways. Furthermore, methotrexate significantly reduces STAT5 phosphorylation in cells expressing JAK2 V617F, a mutation associated with most human MPNs. Methotrexate acts independently of dihydrofolate reductase (DHFR) and is comparable to the JAK1/2 inhibitor ruxolitinib. However, cells treated with methotrexate still retain their ability to respond to physiological levels of the ligand erythropoietin.ConclusionsAminopterin and methotrexate represent the first chemotherapy agents developed and act as competitive inhibitors of DHFR. Methotrexate is also widely used at low doses to treat inflammatory and immune-mediated conditions including rheumatoid arthritis. In this low-dose regime, folate supplements are given to mitigate side effects by bypassing the biochemical requirement for DHFR. Although independent of DHFR, the mechanism-of-action underlying the low-dose effects of methotrexate is unknown. Given that multiple pro-inflammatory cytokines signal through the pathway, we suggest that suppression of the JAK/STAT pathway is likely to be the principal anti-inflammatory and immunosuppressive mechanism-of-action of low-dose methotrexate. In addition, we suggest that patients with JAK/STAT-associated haematological malignancies may benefit from low-dose methotrexate treatments. While the JAK1/2 inhibitor ruxolitinib is effective, a £43,200 annual cost precludes widespread adoption. With an annual methotrexate cost of around £32, our findings represent an important development with significant future potential.

Dataset Information

JAK-STAT Pathway: A Novel Target to Tackle Viral Infections.

Publications

JAK-STAT Pathway: A Novel Target to Tackle Viral Infections.

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