Dr Jeremy W Prokop

SARS-CoV-2 mechanisms of severe outcomes

A Talk by Dr Jeremy W Prokop (Department of Pharmacology & Toxicology, Michigan State University, Grand Rapids, USA)

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About this Talk

SARS-CoV-2 (COVID-19) has infected millions of people worldwide, with lethality in hundreds of thousands. Our knowledge has grown for how the virus enters cells, utilize components within the cell to drive replication and release, drive stress and intracellular signaling, how the immune system responds to cellular signals, and when this goes wrong to result in sepsis and acute respiratory distress syndrome (ARDS). Through integration of Coronavirus evolution, structural assessments, and molecular dynamic simulations we have built an amino acid knowledgebase within the Viral Integrated Structural Evolution Dynamic Database (VIStEDD), a publicly available resource. Bringing this together with SARS-CoV-2 human interactions and genomic screening, we have identified potential causal variants within ACE2 expression, the human receptor for the virus, and human variants connected to endoplasmic reticulum stress related disorders that may impact intracellular host immune response. Finally, through integrating SARS-CoV-2 transcriptomics with our precision medicine transcriptomic workflow of patients having viral/bacterial severe outcomes, we have identified a rare disease mechanism where Nucleocapsid (N) inhibition of nonsense-mediated decay (NMD) can drive Viral Induced Genetics (VIG), where suppressed human variants are activated to drive dominant-negative outcomes within cells. In a patient with EBV, we have shown that this VIG process can drive cytokine storm, hyperferritinemic sepsis, and multiple organ dysfunction including ARDS much like those patients with the most severe outcomes from SARS-CoV-2. The insights gained from these intracellular mechanisms driving adverse immune responses are critical as we begin to identify drugs such as biologics or dexamethasone that can control severe infections.

21 September 2020, 12:00 PM

12:00 PM - 12:20 PM

About The Speaker

Dr Jeremy W Prokop

Dr Jeremy W Prokop

Department of Pharmacology & Toxicology, Michigan State University, Grand Rapids, USA