Back to Search
Start Over
AI-guided discovery of the invariant host response to viral pandemics
- Source :
- EBioMedicine, Vol 68, Iss, Pp 103390-(2021), bioRxiv, vol 1, iss 09-29, EBioMedicine, bioRxiv
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- We sought to define the host immune response, a.k.a, the “cytokine storm” that has been implicated in fatal COVID-19 using an AI-based approach. Over 45,000 transcriptomic datasets of viral pandemics were analyzed to extract a 166-gene signature using ACE2 as a ‘seed’ gene; ACE2 was rationalized because it encodes the receptor that facilitates the entry of SARS-CoV-2 (the virus that causes COVID-19) into host cells. Surprisingly, this 166-gene signature was conserved in all viral pandemics, including COVID-19, and a subset of 20-genes classified disease severity, inspiring the nomenclatures ViP and severe-ViP signatures, respectively. The ViP signatures pinpointed a paradoxical phenomenon wherein lung epithelial and myeloid cells mount an IL15 cytokine storm, and epithelial and NK cell senescence and apoptosis determines severity/fatality. Precise therapeutic goals were formulated and subsequently validated in high-dose SARS-CoV-2-challenged hamsters using neutralizing antibodies that abrogate SARS-CoV-2•ACE2 engagement or a directly acting antiviral agent, EIDD-2801. IL15/IL15RA were elevated in the lungs of patients with fatal disease, and plasma levels of the cytokine tracked with disease severity. Thus, the ViP signatures provide a quantitative and qualitative framework for titrating the immune response in viral pandemics and may serve as a powerful unbiased tool to rapidly assess disease severity and vet candidate drugs.One Sentence SummaryThe host immune response in COVID-19.PANEL: RESEARCH IN CONTEXTEvidence before this studyThe SARS-CoV-2 pandemic has inspired many groups to find innovative methodologies that can help us understand the host immune response to the virus; unchecked proportions of such immune response have been implicated in fatality. We searched GEO and ArrayExpress that provided many publicly available gene expression data that objectively measure the host immune response in diverse conditions. However, challenges remain in identifying a set of host response events that are common to every condition. There are no studies that provide a reproducible assessment of prognosticators of disease severity, the host response, and therapeutic goals. Consequently, therapeutic trials for COVID-19 have seen many more ‘misses’ than ‘hits’. This work used multiple (> 45,000) gene expression datasets from GEO and ArrayExpress and analyzed them using an unbiased computational approach that relies upon fundamentals of gene expression patterns and mathematical precision when assessing them.Added value of this studyThis work identifies a signature that is surprisingly conserved in all viral pandemics, including Covid-19, inspiring the nomenclature ViP-signature. A subset of 20-genes classified disease severity in respiratory pandemics. The ViP signatures pinpointed the nature and source of the ‘cytokine storm’ mounted by the host. They also helped formulate precise therapeutic goals and rationalized the repurposing of FDA-approved drugs.Implications of all the available evidenceThe ViP signatures provide a quantitative and qualitative framework for assessing the immune response in viral pandemics when creating pre-clinical models; they serve as a powerful unbiased tool to rapidly assess disease severity and vet candidate drugs.
- Subjects :
- 0301 basic medicine
Medicine (General)
Boolean equivalent clusters
medicine.medical_treatment
Cytidine
Transcriptome
0302 clinical medicine
Cricetinae
Lung alveoli
Databases, Genetic
Receptors
Pandemic
Interleukin 15
Gene Regulatory Networks
Receptor
Lung
Neutralizing
Artificial intelligence/machine learning
Interleukin-15
biology
Receptors, Interleukin-15
General Medicine
Infectious Diseases
Cytokine
Virus Diseases
030220 oncology & carcinogenesis
Public Health and Health Services
Medicine
Autopsy
Angiotensin-Converting Enzyme 2
Antibody
Infection
Research Paper
Genetic Markers
Clinical Sciences
Hydroxylamines
Antiviral Agents
Article
Antibodies
General Biochemistry, Genetics and Molecular Biology
Virus
Vaccine Related
Databases
Natural Killer (NK) cells
03 medical and health sciences
Rare Diseases
R5-920
Immune system
Genetic
Interleukin 15 (IL15)
Artificial Intelligence
Clinical Research
Biodefense
Genetics
medicine
Animals
Humans
Immune response
Pandemics
Mesocricetus
Animal
business.industry
Gene Expression Profiling
Prevention
COVID-19
medicine.disease
Antibodies, Neutralizing
Angiotensin converting enzyme (ACE)-2
COVID-19 Drug Treatment
Gene expression profiling
Disease Models, Animal
Orphan Drug
Good Health and Well Being
Emerging Infectious Diseases
030104 developmental biology
Coronavirus COVID-19
Disease Models
Immunology
biology.protein
Cytokine storm
business
Subjects
Details
- ISSN :
- 23523964
- Volume :
- 68
- Database :
- OpenAIRE
- Journal :
- EBioMedicine
- Accession number :
- edsair.doi.dedup.....2d3b5d98366adb9f6a9e5387be66bda3