SOCS, Intrinsic Virulence Factors, and Treatment of COVID-19
The suppressor of cytokine signaling (SOCS) family of intracellular checkpoint inhibitors has received little recognition compared to other checkpoint inhibitors. Two members of this family, SOCS1 and SOCS3, are indispensable, since SOCS1 knockout in mice results in neonatal death due to interferon...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2020-10-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2020.582102/full |
| _version_ | 1818279982162509824 |
|---|---|
| author | Howard M. Johnson Alfred S. Lewin Chulbul M. Ahmed |
| author_facet | Howard M. Johnson Alfred S. Lewin Chulbul M. Ahmed |
| author_sort | Howard M. Johnson |
| collection | DOAJ |
| description | The suppressor of cytokine signaling (SOCS) family of intracellular checkpoint inhibitors has received little recognition compared to other checkpoint inhibitors. Two members of this family, SOCS1 and SOCS3, are indispensable, since SOCS1 knockout in mice results in neonatal death due to interferon gamma (IFNγ) induced inflammatory disease, and SOCS3 knockout leads to embryonic lethality. We have shown that SOCS1 and SOCS3 (SOCS1/3) function as virus induced intrinsic virulence factors for influenza A virus, EMC virus, herpes simplex virus 1 (HSV-1), and vaccinia virus infections. Other viruses such as pathogenic pig enteric coronavirus and coronavirus induced severe acute respiratory syndrome (SARS) spike protein also induce SOCS virus intrinsic virulence factors. SOCS1/3 exert their viral virulence effect via inhibition of type I and type II interferon (IFN) function. Specifically, the SOCS bind to the activation loop of receptor-associated tyrosine kinases JAK2 and TYK2 through the SOCS kinase inhibitory region (KIR), which inhibits STAT transcription factor activation by the kinases. Activated STATs are required for IFN function. We have developed a small peptide antagonist of SOCS1/3 that blocks SOCS1/3 inhibitory activity and prevents virus pathogenesis. The antagonist, pJAK2(1001-1013), is comprised of the JAK2 activation loop, phosphorylated at tyrosine 1007 with a palmitate for cell penetration. The remarkable thing about SOCS1/3 is that it serves as a broad, simple tool of perhaps most pathogenic viruses to avoid innate host IFN defense. We suggest in this Perspective that SOCS1/3 antagonist is a simple counter measure to SOCS1/3 and should be an effective mechanism as a prophylactic and/or therapeutic against the COVID-19 pandemic that is caused by coronavirus SARS-CoV2. |
| first_indexed | 2024-12-12T23:41:59Z |
| format | Article |
| id | doaj.art-89710bf294e34346aeb177d1c963eedd |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-12T23:41:59Z |
| publishDate | 2020-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-89710bf294e34346aeb177d1c963eedd2022-12-22T00:07:04ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-10-011110.3389/fimmu.2020.582102582102SOCS, Intrinsic Virulence Factors, and Treatment of COVID-19Howard M. Johnson0Alfred S. Lewin1Chulbul M. Ahmed2Department of Microbiology and Cell Science, University of Florida, Gainesville, FL, United StatesDepartment of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, United StatesDepartment of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, United StatesThe suppressor of cytokine signaling (SOCS) family of intracellular checkpoint inhibitors has received little recognition compared to other checkpoint inhibitors. Two members of this family, SOCS1 and SOCS3, are indispensable, since SOCS1 knockout in mice results in neonatal death due to interferon gamma (IFNγ) induced inflammatory disease, and SOCS3 knockout leads to embryonic lethality. We have shown that SOCS1 and SOCS3 (SOCS1/3) function as virus induced intrinsic virulence factors for influenza A virus, EMC virus, herpes simplex virus 1 (HSV-1), and vaccinia virus infections. Other viruses such as pathogenic pig enteric coronavirus and coronavirus induced severe acute respiratory syndrome (SARS) spike protein also induce SOCS virus intrinsic virulence factors. SOCS1/3 exert their viral virulence effect via inhibition of type I and type II interferon (IFN) function. Specifically, the SOCS bind to the activation loop of receptor-associated tyrosine kinases JAK2 and TYK2 through the SOCS kinase inhibitory region (KIR), which inhibits STAT transcription factor activation by the kinases. Activated STATs are required for IFN function. We have developed a small peptide antagonist of SOCS1/3 that blocks SOCS1/3 inhibitory activity and prevents virus pathogenesis. The antagonist, pJAK2(1001-1013), is comprised of the JAK2 activation loop, phosphorylated at tyrosine 1007 with a palmitate for cell penetration. The remarkable thing about SOCS1/3 is that it serves as a broad, simple tool of perhaps most pathogenic viruses to avoid innate host IFN defense. We suggest in this Perspective that SOCS1/3 antagonist is a simple counter measure to SOCS1/3 and should be an effective mechanism as a prophylactic and/or therapeutic against the COVID-19 pandemic that is caused by coronavirus SARS-CoV2.https://www.frontiersin.org/articles/10.3389/fimmu.2020.582102/fullantiviral peptidecytokine signalingtyrosine kinaseCOVID-19SARS-CoV-2 |
| spellingShingle | Howard M. Johnson Alfred S. Lewin Chulbul M. Ahmed SOCS, Intrinsic Virulence Factors, and Treatment of COVID-19 Frontiers in Immunology antiviral peptide cytokine signaling tyrosine kinase COVID-19 SARS-CoV-2 |
| title | SOCS, Intrinsic Virulence Factors, and Treatment of COVID-19 |
| title_full | SOCS, Intrinsic Virulence Factors, and Treatment of COVID-19 |
| title_fullStr | SOCS, Intrinsic Virulence Factors, and Treatment of COVID-19 |
| title_full_unstemmed | SOCS, Intrinsic Virulence Factors, and Treatment of COVID-19 |
| title_short | SOCS, Intrinsic Virulence Factors, and Treatment of COVID-19 |
| title_sort | socs intrinsic virulence factors and treatment of covid 19 |
| topic | antiviral peptide cytokine signaling tyrosine kinase COVID-19 SARS-CoV-2 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2020.582102/full |
| work_keys_str_mv | AT howardmjohnson socsintrinsicvirulencefactorsandtreatmentofcovid19 AT alfredslewin socsintrinsicvirulencefactorsandtreatmentofcovid19 AT chulbulmahmed socsintrinsicvirulencefactorsandtreatmentofcovid19 |