Understanding patient‐level immune response to COVID‐19 can inform treatment options
COVID‐19 is caused by an evolving pathogen that results in a disease that exhibits variability in progression and treatment response, highlighting the need for developing new and more precise therapies. Over the past two years, we have built a collection of tools to understand variability and mechan...
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| Published in: | The FASEB journal Vol. 36; no. S1 |
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| Main Authors: | , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
The Federation of American Societies for Experimental Biology
01-05-2022
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| Subjects: | |
| Online Access: | Get full text |
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| Summary: | COVID‐19 is caused by an evolving pathogen that results in a disease that exhibits variability in progression and treatment response, highlighting the need for developing new and more precise therapies. Over the past two years, we have built a collection of tools to understand variability and mechanisms of COVID‐19 immune responses, including the SARS‐CoV‐2 evolutionary/structural dynamicome, curated lists of SARS‐CoV‐2 protein‐protein interactions (PPI), NCBI SRA data integrations for SARS‐CoV‐2 exposed cells, data from thousands of blood‐based RNA‐Seq analyzed, and created a clinical cohort of blood‐based RNA‐Seq of COVID‐19 and other critical illness pathologies. The dynamicome and PPI list elucidated several viral proteins that modulate the host immune response, including the nucleocapsid (N) role in suppressing nonsense‐mediated decay leading to rare disease phenotypes, ORF8 interaction with innate immune components, and the Papain‐like protease (NSP3) regulation of intracellular ISG15 interferon signaling. This stimulation in hospitalized COVID‐19 patients exerts three diverse systemic blood RNA‐Seq changes noted on five independent cohorts processed with a precision transcriptomics multi‐data analysis pipeline. The first was patients that are immunosuppressed, which showed blunted interferon response and often secondary viral activation, suggesting antiviral treatments and immune stimulation. The second patient group is those who go into cytokine storm, often seen with overly active ISG15 levels in peripheral blood, who benefit from immunosuppressive agents. The third group often has normal interferon activation but a triggered systemic process of NETosis in blood, activating neutrophils through controlled death to build DNA/histone nets to contain the virus. The third group likely requires specialized treatment strategies to prevent the NETosis from driving vascular dysfunction and COVID long hauler syndromes. These three groups resulting from varied pathologic mechanisms, showcase the need for different therapeutic approaches, and may explain the many failed clinical trials for COVID‐19. Thus, it would be beneficial to develop a deeper understanding of each patient’s immune response moving forward to optimize treatment and outcomes. |
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| Bibliography: | This work was supported by the Spectrum Health and MSU Alliance Corporation, Spectrum Health Foundation, National Institutes of Health (K01ES025435 to JP), and Michigan State University. |
| ISSN: | 0892-6638 1530-6860 |
| DOI: | 10.1096/fasebj.2022.36.S1.R4198 |