The SARS-CoV-2 makes its way into the cell via the ACE2 receptor and the proteolytic action of TMPRSS2. In response to the SARS-CoV-2 infection, the innate immune response is the first line of defense, triggering multiple signaling pathways to produce interferons, pro-inflammatory cytokines and chemokines, and initiating the adaptive immune response against the virus. Unsurprisingly, the virus has developed strategies to evade detection, which can result in delayed, excessive activation of the innate immune system. The response elicited by the host depends on multiple factors, including health status, age, and sex. An overactive innate immune response can lead to a cytokine storm, inflammation, and vascular disruption, leading to the vast array of symptoms exhibited by COVID-19 patients. What is known about the expression and epigenetic regulation of the ACE2 gene and the various players in the host response are explored in this review.

SARS-CoV-2, the causing agent of the ongoing COVID-19 pandemic, is a betacoronavirus which has 80% genetic homology with SARS-CoV, but displays increased virulence and transmissibility. Initially, SARS-CoV-2 was considered a respiratory virus generally causing a mild disease, only severe and fatal in the elderly and individuals with underlying conditions. Severe illnesses and fatalities were attributed to a cytokine storm, an excessive response from the host immune system. However, with the number of infections over 10 millions and still soaring, the insidious and stealthy nature of the virus has emerged, as it causes a vast array of diverse unexpected symptoms among infected individuals, including the young and healthy. It has become evident that besides infecting the respiratory tract, SARS-CoV-2 can affect many organs, possibly through the infection of the endothelium. This review presents an overview of our learning curve with the novel virus emergence, transmission, pathology, biological properties and host-interactions. It also briefly describes remedial measures taken until an effective vaccine is available, that is nonpharmaceutical interventions to reduce the viral spread and the repurposing of existing drugs, approved or in development for other conditions to eliminate the virus or mitigate the cytokine storm.

Background: Natural Killer (NK) cells play a key role in innate immunity against viral, microbial infections and transformed cells and their migration for effector function to peripheral tissues or inflamed lymph nodes are tightly regulated. Of interest, production of Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) by cancer cells is correlated to host immune suppression and tumor metastasis, suggesting an immune evasion property of GM-CSF. Here we examined role(s) of recombinant GM-CSF in the regulation of NK-cell migratory properties in vitro. Methods: Previously published “Y” shape microfluidic platform was used to study the roles of GM-CSF gradient on NK-cell migrations. IL-2 activated human primary NK cells were used in the migration studies. Results: Our microfluidic-based migration study demonstrated a novel role of GM-CSF in regulating repulsive NK-cell migration under the stable GM-CSF gradient (at 20 ng/ml), followed by subsequent arrest in cell migration. Blocking of GM-CSF-Rα abolished the repulsive migratory behavior but not the arrest. In contrast, lower concentrations of GM-CSF induced hyper-polarization, immediate arrest of NK cells, and little/or no NK-cell migrations. Circularity measurement in controls and above experiments confirmed statistically the correlation between hyperpolarization and migration arrest. Future analyses will elucidate the mechanisms underlying the dual roles of GM-CSF in the regulation of NK-cell migratory properties.