Individual and Synergistic Anti-Coronavirus Activities of SOCS1/3 Antagonist and Interferon α1 Peptides

Abstract

Suppressors of Cytokine Signaling (SOCS) are intracellular proteins that negatively regulate the induction of cytokines. Amongst these, SOCS1 and SOCS3 are particularly involved in inhibition of various interferons. Several viruses have hijacked this regulatory pathway: by inducing SOCS1and 3 early in infection, they suppress the host immune response. Within the cell, SOCS1/3 binds and inhibits tyrosine kinases, such as JAK2 and TYK2. We have developed a cell penetrating peptide from the activation loop of the tyrosine kinase, JAK2 (residues 1001-1013), denoted as pJAK2 that acts as a decoy and suppresses SOCS1 and 3 activity. This peptide thereby protects against several viruses in cell culture and mouse models. Herein, we show that treatment with pJAK2 inhibited the replication and release of the beta coronavirus HuCoV-OC43 and reduced production of the viral RNA, as measured by RT-qPCR, Western blot and by immunohistochemistry. We confirmed induction of SOCS1 and 3 in rhabdomyosarcoma (RD) cells, and this induction was suppressed by pJAK2 peptide. A peptide derived from the C-terminus of IFNα (IFNα-C) also inhibited replication of OC43. Furthermore, IFNα-C plus pJAK2 provided more potent inhibition than either peptide alone. To extend this study to a pandemic beta-coronavirus, we determined that treatment of cells with pJAK2 inhibited replication and release of SARS-CoV-2 in Calu-3 cells. We propose that these peptides offer a new approach to therapy against the rapidly evolving strains of beta-coronaviruses.

How do deer respiratory epithelial cells weather the initial storm of SARS-CoV-2 WA1/2020 strain?

“…Another transcription factor of Jak-STAT signaling associated with IL-6 production during virus infection is SOCS3 ( 48 ), a negative feedback regulator in cytokine signaling, which also plays an important role during apoptosis, inflammation, T-cell development, and viral infection ( 49 ). The presence of SOCS3 reduces the induction of various types of IFNs, and in turn, a delayed IFN response can result in early viral spread leading to pulmonary and systemic inflammation in critical cases of SARS-CoV-2 ( 50 ). Moreover, using SOCS1/3 antagonists can block the replication and release of SARS-CoV-2 in human lung cell lines ( 50 ).…”

“…The presence of SOCS3 reduces the induction of various types of IFNs, and in turn, a delayed IFN response can result in early viral spread leading to pulmonary and systemic inflammation in critical cases of SARS-CoV-2 ( 50 ). Moreover, using SOCS1/3 antagonists can block the replication and release of SARS-CoV-2 in human lung cell lines ( 50 ). While there were no changes in the expression of SOCS3 in HRECs over the course of infection, Deer-RECs showed significant downregulation in response to SARS-CoV-2 infection by 24 hpi.…”

FEOpti-ACVP: identification of novel anti-coronavirus peptide sequences based on feature engineering and optimization

“…Devlin et al. [ 47 , 48 ] introduced a pre-trained language representation model, BERT. It uses a masked language model (MLM) to pre-train bidirectional transformers, where each token attends to ‘all tokens’.…”

How Do Deer Respiratory Epithelial Cells Weather The Initial Storm of SARS-CoV-2?

“…SARS-CoV-2 target the upstream mediators of the Jak-STAT pathway to impair interferon signaling across several human cell types 48 Another transcription factor of Jak-STAT signaling associated with IL-6 production during virus infection is SOCS3 49 , a negative feedback regulator in cytokine signaling, which also plays an important role during apoptosis, inflammation, T-cell development, and viral infection 50 . The presence of SOCS3 reduces the induction of various types of IFNs, and in turn, a delayed IFN response can result in early viral spread leading to pulmonary and systemic inflammation in critical cases of SARS-CoV-2 51 . Moreover, using SOCS1/3 antagonists can block the replication and release of SARS-CoV-2 in human lung cell lines 51 .…”

“…The presence of SOCS3 reduces the induction of various types of IFNs, and in turn, a delayed IFN response can result in early viral spread leading to pulmonary and systemic inflammation in critical cases of SARS-CoV-2 51 . Moreover, using SOCS1/3 antagonists can block the replication and release of SARS-CoV-2 in human lung cell lines 51 . While there were no changes in the expression of SOCS3 in HRECs over the course of infection, Deer-RECs showed significant downregulation in response to SARS-CoV-2 infection by 24 hpi.…”