COVID-19 is a disease caused by a coronavirus, Severe Acute Respiratory Syndrome (SARS) -CoV-2. Infections by SARS-CoV-2 are now present in every country around the globe, causing unprecedented public health burden. SARS-CoV is known to interfere with IFN-I induction and signaling.
- COVID-19 and Broad Spectrum Antiviral
ISG15 and USP18 are considered to be bona fide negative regulators of IFN-I. Our ex vivo data suggest that both, ISG15 -/- and USP18 -/- patients have increased levels of IFN-I-induced gene expression. Our in vitro data suggest that cells from these individuals control viral infections more effectively than cells from WT individuals. We are currently trying to demonstrate enhanced resistance to Sars-CoV-2.
Based on these human genetic in vivo, ex vivo, in vitro and biochemical findings, we hypothesize that ISG15/USP18 inhibition by a small molecule would temporarily increase antiviral immunity in WT individuals. In parallel, we are developing deliverable therapeutics which would mimic ISG15-like transcriptional profile and thus augment antiviral immunity in WT individuals.
- COVID-19 in Down Syndrome Individuals
Down syndrome (DS) is the most common genetic cause of intellectual and developmental disabilities in children and young adults with Incidence in US of about 1 in 600 individuals. Individuals with DS often have cardiac and gastrointestinal abnormalities. Additionally, they have a number of immune-related problems from increased susceptibility to an array of infectious diseases to autoimmunity. Unfortunately, the exact molecular mechanism leading to these immune defects has not been elucidated.
DS is, in most cases, caused by an extra chromosome 21, on which the receptors for type I Interferons (IFNAR1 and IFNAR2) are encoded. How this gene dosage effects are contributing to SARS-CoV-2 pathophysiology is not understood. To which extent SARS-CoV-2 can cause illness in individuals with DS is currently unknown.We are currently addressing a number of scientific questions pertaining to this pathophysiology.
- COVID-19 – Genetic Susceptibility
Many otherwise healthy individuals below 30 years of age, infected with Sars-CoV-2 remain asymptomatic but select few succumb to disease. How host genetics influences these discrepant COVID-19 outcomes is unknown. By improving our understanding of the human determinants of Sars-CoV-2, we should be able to develop new hypotheses concerning both human susceptibility in vivo and drug development.