Regulation of inflammatory gene expression during SARS2 infection

NIH Pandemic-Era Grants

Pandemic Era Grants

2022

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Principal Investigator: Ivan  Marazzi
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2022
Award: $794,868
Funding agency: National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY
Infection causes inflammation, which contributes to pathogen clearance and survival of the host
organism. However, failure to regulate the inflammatory response can often lead to multiple organ
damage and lethality for the host. In the current COVID-19 pandemic caused by the severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2), patients with elevated cytokine levels are
often associated with severe symptoms and mortality. This indicates hyper-activation of specific
inflammatory molecules might be as much a contributing factor to mortality and morbidity as the
virus itself. Thus, there is a dire need to better understand the gene activation dynamics upon
infection and develop therapies to manage the inflammatory response. In 2016 we have shown
that epigenetic inhibition of factors controlling chromatin remodeling of inflammatory genes, like
Topoisomerase 1, can reduce inflammatory gene expression and rescue lethality during bacterial
and viral infection, suggesting that these effects may be applicable in the setting of COVID-19 as
well. Topoisomerase 1 inhibitors are FDA approved and in the list of WHO essential medicines,
thus their widespread usage and cheap cost can be leverage if they are active against COVID-19
as they are in many other infections. In this proposal, we will characterize the role of Top1 and
epigenetic factors controlling chromatin topology during SARS-CoV-2 infection and will test the
feasibility of use of Top1 inhibitors as drugs for the treatment of COVID-19 in animal models. We
will perform mechanistic and preclinical test using epigenetic inhibitors in comparison with
immune blockers used in clinical trials and the current standard of care (glucocorticoids).

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epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 infection><COVID19 pandemic><COVID19 patient><COVID19 positive patient><COVID19 public health crisis><COVID19 therapy><COVID19 treatment><COVID19 virus><CV-19><CV19><Cachectin><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cessation of life><Chemicals><Chemotactic Cytokines><Chromatin><Chronic><Clinical Trials><CoV-2><CoV2><Cytokeratin 18><Cytokine Signal Transduction><Cytokine Signaling><DNA><DNA-Dependent RNA Polymerase II><Death><Deoxyribonucleic Acid><Dexamethasone><Drug Therapy><Drug usage><Drugs><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Event><FDA approved><Failure><Gene Activation><Gene Expression><Gene Transcription><Generations><Genes><Genetic Transcription><Genome><Genomic approach><Glucocorticoids><Goals><HPGF><Hepatocyte-Stimulating Factor><Homologous Chemotactic Cytokines><Housekeeping Gene><Human><Hybridoma Growth 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pandemic><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><Symptoms><T Helper Factor><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Therapeutic><Therapeutic Intervention><Therapeutic Uses><Tissues><Topoisomerase><Topoisomerase Inhibitors><Topotecan><Transcription><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Transgenic Mice><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Viral><Viral 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