Therapy Targets SARS-CoV-2 Infection-Induced Cell Death

Abstract

Coronavirus Disease 2019 (COVID-19) caused by SARS-CoV-2 has become a global health issue. The clinical presentation of COVID-19 is highly variable, ranging from asymptomatic and mild disease to severe. However, the mechanisms for the high mortality induced by SARS-CoV-2 infection are still not well understood. Recent studies have indicated that the cytokine storm might play an essential role in the disease progression in patients with COVID-19, which is characterized by the uncontrolled release of cytokines and chemokines leading to acute respiratory distress syndrome (ARDS), multi-organ failure, and even death. Cell death, especially, inflammatory cell death, might be the initiation of a cytokine storm caused by SARS-CoV-2 infection. This review summarizes the forms of cell death caused by SARS-CoV-2 in vivo or in vitro and elaborates on the dedication of apoptosis, necroptosis, NETosis, pyroptosis of syncytia, and even SARS-CoV-2 E proteins forming channel induced cell death, providing insights into targets on the cell death pathway for the treatment of COVID-19.

COVID-19 Syndemic: Convergence of COVID-19, Pulmonary Aspergillosis (CAPA), Pulmonary Tuberculosis, Type 2 Diabetes Mellitus, and Arterial Hypertension

“…Moreover, immunosuppressive therapy, such as the corticosteroids used alone in our patients, has been used in subjects with mild/severe COVID-19 to diminish and control hyperinflammation and CSS [ 6 , 32 ]; however, their principal diseases (i.e., uncontrolled T2DM/hypertension) worsened these infectious health conditions, favoring the proliferation of infectious pathogens and causing major damage. SARS-CoV-2 induces cellular death of pneumocytes by pyroptosis and apoptosis in endothelial cells [ 33 ], thickening of the alveolar wall, and worsening of hypoxia. In addition, uncontrolled intracellular proliferation of Mtb by failure of the IFN-γ IL-12/IL-23 axis and TNFα reduces acidification of lysosomes with less destruction of Mtb.…”

Cellular and Molecular Mechanisms of Pathogenic and Protective Immune Responses to SARS-CoV-2 and Implications of COVID-19 Vaccines

“…This can take place in immune cells and is also reported to occur in keratinocytes and some epithelial cells. As a consequence of pyroptosis, the release of proinflammatory cytokines is triggered in COVID-19 patients, which possibly affects macrophage and lymphocyte functions [ 110 , 111 , 112 , 113 , 114 , 115 ]. This is, perhaps, responsible for peripheral lymphopenia in severe COVID-19 patients.…”

“…This is, perhaps, responsible for peripheral lymphopenia in severe COVID-19 patients. The role of inflammasome is also related to development of severe inflammation in COVID-19 patients [ 111 , 112 , 113 , 114 , 115 , 116 ]. In addition to this, attention should be focused on the initial failure or suboptimal induction of innate immunity in the host during initial exposure to SARS-CoV-2 in order to allow for the development of proper insights into the cellular and molecular mechanisms underlying severe COVID-19.…”

Repurposing clinically available drugs and therapies for pathogenic targets to combat SARS‐CoV‐2

“… 50 Several proteins, including Mpro, 3CLpro, and PLpro, are essential for the viral infection cycle and replication. In addition, the envelope protein can form cation channels, inducing host cell death in vitro and a cytokine storm in vivo 71 (Figure 1 ). Moreover, some effective therapeutic, United States Food and Drug Administration (US FDA)‐approved agents with a well‐established safety profile have been identified to combat this viral disease with activity against key proteins.…”