Mechanistic insight into the protective and pathogenic immune-responses against SARS-CoV-2.

COVID-19 is a severe respiratory illness that has emerged as a devasting health problem worldwide. The disease outcome is heterogeneous, which is most likely dependent on the immunity of an individual. Asymptomatic and mildly/moderate symptomatic (non-severe) patients likely develop an effective early immune response and clear the virus. However, severe symptoms dominate due to a failure in the generation of an effective and specific early immune response against SARS-CoV-2. Moreover, a late surge in pathogenic inflammation involves dysregulated innate and adaptive immune responses leading to local and systemic tissue damage and the emergence of severe disease symptoms. In this review, we describe the potential mechanisms of protective and pathogenic immune responses in "mild/moderate" and "severe" symptomatic SARS-CoV-2 infected people, respectively, and discuss the immune components that are currently targeted for therapeutic intervention.

COVID-19 and gut immunomodulation.

The disease coronavirus disease 2019 (COVID-19) is a severe respiratory illness that has emerged as a devastating health problem worldwide. The disease outcome is heterogeneous, and severity is likely dependent on the immunity of infected individuals and comorbidities. Although symptoms of the disease are primarily associated with respiratory problems, additional infection or failure of other vital organs are being reported. Emerging reports suggest a quite common co-existence of gastrointestinal (GI) tract symptoms in addition to respiratory symptoms in many COVID-19 patients, and some patients show just the GI symptoms. The possible cause of the GI symptoms could be due to direct infection of the epithelial cells of the gut, which is supported by the fact that (1) The intestinal epithelium expresses a high level of angiotensin-converting enzyme-2 and transmembrane protease serine 2 protein that are required for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into the cells; (2) About half of the severe COVID-19 patients show viral RNA in their feces and various parts of the GI tract; and (3) SARS-CoV-2 can directly infect gut epithelial cells in vitro (gut epithelial cells and organoids) and in vivo (rhesus monkey). The GI tract seems to be a site of active innate and adaptive immune responses to SARS-CoV-2 as clinically, stool samples of COVID-19 patients possess proinflammatory cytokines (interleukin 8), calprotectin (neutrophils activity), and immunoglobulin A antibodies. In addition to direct immune activation by the virus, impairment of GI epithelium integrity can evoke immune response under the influence of systemic cytokines, hypoxia, and changes in gut microbiota (dysbiosis) due to infection of the respiratory system, which is confirmed by the observation that not all of the GI symptomatic patients are viral RNA positive. This review comprehensively summarizes the possible GI immunomodulation by SARS-CoV-2 that could lead to GI symptoms, their association with disease severity, and potential therapeutic interventions.

Antiviral drug screen identifies DNA-damage response inhibitor as potent blocker of SARS-CoV-2 replication.

SARS-CoV-2 has currently precipitated the COVID-19 global health crisis. We developed a medium-throughput drug-screening system and identified a small-molecule library of 34 of 430 protein kinase inhibitors that were capable of inhibiting the SARS-CoV-2 cytopathic effect in human epithelial cells. These drug inhibitors are in various stages of clinical trials. We detected key proteins involved in cellular signaling pathways mTOR-PI3K-AKT, ABL-BCR/MAPK, and DNA-damage response that are critical for SARS-CoV-2 infection. A drug-protein interaction-based secondary screen confirmed compounds, such as the ATR kinase inhibitor berzosertib and torin2 with anti-SARS-CoV-2 activity. Berzosertib exhibited potent antiviral activity against SARS-CoV-2 in multiple cell types and blocked replication at the post-entry step. Berzosertib inhibited replication of SARS-CoV-1 and the Middle East respiratory syndrome coronavirus (MERS-CoV) as well. Our study highlights key promising kinase inhibitors to constrain coronavirus replication as a host-directed therapy in the treatment of COVID-19 and beyond as well as provides an important mechanism of host-pathogen interactions.