Molecular Basis of Cancer Virus Replication, Transformation, and Innate Defense

Coronavirus disease (COVID-19) and its causative agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are currently a most pressing health concern. Much more needs to be learned about the pathology of the virus, as well as the host response to viral infection. Acute respiratory distress syndrome (ARDS), the final state of severe COVID-19, is caused by the uncontrollable immune response of the host, so called cytokine release syndrome (CRS). What predisposes some patients to progress to severe COVID-19 is not known, but certain populations - such as the elderly and cancer patients - are at higher risk. Therefore, we are investigating whether host microRNAs (miRNAs) can serve as biomarkers for COVID-19 prognosis. Since miRNAs regulate virtually every cellular process, and are often dysregulated during disease, including viral infections, it is highly likely that SARS-CoV-2 infection impacts miRNA levels. Aberrant miRNA profiles during viral infection are known to be caused both by host responses to counteract the infecting agent and by deliberate actions of the virus, usually to dampen the immune system Our group has contributed significantly to the realization that some herpesviral transcripts selectively bind host miRNAs and induce their degradation in a process known as target-directed miRNA degradation (TDMD). Such selective miRNA degradation is beneficial for the virus, as exemplified by decreased levels of host miR 27a causing prolonged T cell activation that aids oncogenic transformation by herpesvirus saimiri. It is possible that SARS-CoV-2 selectively affects the miRNAs that regulate crucial cytokines, as many miRNAs are known to regulate immune factors involved in antiviral defense. One of these is a key player during severe COVID19: interleukin 6 (IL-6), which is regulated by miR-146a, miR-142-3p and let-7. Documenting the dysregulation of particular miRNAs during infection by SARS-CoV-2 can therefore have therapeutic potential, as well as providing biomarkers for COVID progression. We will use state-of-the art small RNA sequencing, as well as RNA detection by TaqMan reverse transcription quantitative PCR (RT-qPCR) to investigate miRNA populations at various times after infection of several lung cell lines with SARS-CoV-2. In addition, we are employing custom bioinformatic predictions to search for viral transcripts that could selectively regulate host miRNAs and have already identified several potential candidates. Providing fundamental insights into the biology of SARS-CoV-2 as regards these important host noncoding RNAs will be important for mankind's ability to manage both the current and future pandemics.