ANG II signaling via angiotensin 1 receptors (AT-1Rs) (inhibited by ARBs), induces EC senescence and upregulates IL-6 and ROS, causing immune, and coagulation dysfunction

ANG II signaling via angiotensin 1 receptors (AT-1Rs) (inhibited by ARBs), induces EC senescence and upregulates IL-6 and ROS, causing immune, and coagulation dysfunction. We further hypothesize that angiotensin II blockers and immune checkpoint Rabbit Polyclonal to OR10Z1 inhibitors may be salutary for COVID-19 patients with crucial illness by reversing both the clotting and immune defects (Graphical Abstract). Open in a separate windows Graphical Abstract The SARS-CoV-2 computer virus engages the angiotensin-converting enzyme-2 (ACE-2) protein, displacing its physiological ligand. As a result, angiotensin II (ANG II) accumulates in endothelial cells (ECs), inducing vascular senescence with upregulation of interleukin-6 (IL-6) and reactive oxygen species (ROS), impairing both innate and adaptive immunity. These changes engender dysfunctional coagulation (not shown) and the expression of exhausting markers (EM). In return, these immune defects disrupt viral clearance, engendering a vicious cycle and poor COVID-19 prognosis. Keywords: SARS-CoV-2, cellular senescence, angiotensin II, prognosis, crucial illness, immune checkpoint inhibitors Introduction High transmissibility, asymptomatic service providers, and the absence of herd immunity have contributed to the quick worldwide spread of COVID-19 disease (1, 2). Although up to 50% of the affected individuals are free of clinical manifestations, about 5% of patients display serious complications, consisting of acute respiratory distress syndrome (ARDS), thromboembolism, sepsis, and multi-organ failure, often leading to death (3, 4). COVID-19 disease is usually caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is usually genetically related to SARS-CoV-1, known for engendering the 2002C2003 SARS epidemic. Several studies at the time have connected this computer virus to severe lymphopenia, including cytotoxic T-cells (CTCs), and natural killer (NK) cells, which are indispensable for antiviral immunity (5, 6). In addition, faulty coagulation, associated with deep venous thrombosis (DVT) and pulmonary embolism (PE), has further complicated the management of this syndrome (7). These prior findings have been replicated in relation to SARS-CoV-2 and seem to precede the development of crucial illness, suggesting that defective immunity may play a major role in this disease (8C10). Indeed, as in avian influenza, the Pitavastatin Lactone upregulation of NK cell, and CTC exhaustion markers (EMs) has been observed (11). This is somewhat surprising, as these molecules are uncommon in acute viral infections and characterize malignancy and viruses associated with chronic illness, such as human immunodeficiency computer virus (HIV), hepatitis C computer virus (HCV), or cytomegalovirus (CMV) (12). In oncology, lowering EMs with immune checkpoint inhibitors (ICIs) is an established anti-tumor therapy aimed at reinvigorating host immunity, a modality with potential benefits in COVID-19 (13). Under normal circumstances, EMs lower immune reactions to prevent autoimmunity. However, chronic inflammation can also elicit this response by prolonged activation of T cell receptors (TCRs) (14). Many viruses, likely including SARS-CoV-2, exploit EM pathways to avert detection. For example, SARS-CoV-2 gains access to host cells via angiotensin-converting enzyme-2 (ACE-2) associated with the renin-angiotensin system (RAS), which, aside from regulating arterial blood pressure, plays a major role in immunity (15). In this respect, SARS-CoV-2 appears to act like avian influenza viruses H5N1 and H7N9, elevating the serum levels of angiotensin II (ANG II), interleukin-6 (IL-6), and EMs (16C20). As viral replication is usually more efficient in senescent cells, many viruses, including CMV and probably SARS-CoV-2, promote this phenotype in host cells to facilitate invasion (19, 21, 22). Senescent cells are characterized by proliferation arrest and a specific secretome, senescence-associated secretory phenotype (SASP). This is marked by upregulated IL-6 and reactive oxygen species (ROS), which were also detected in COVID-19 disease (23). Indeed, SARS-CoV-2 has been associated with upregulation of ANG II, a molecule previously Pitavastatin Lactone shown to promote senescence in vascular easy muscle mass cells (VSMCs) and endothelial cells (ECs) (24C26). We hypothesize that vascular senescence-mediated upregulation of IL-6 and ROS is responsible for both coagulation and immune dysfunction. Furthermore, this pathology, evidenced by the elevated plasma levels of EMs and D-dimer, heralds a poor COVID-19 prognosis (27). We further hypothesize that ICIs and angiotensin II blockers may help critically ill COVID-19 patients by Pitavastatin Lactone reversing the Pitavastatin Lactone virus-induced premature vascular senescence. A Brief Pathophysiology of COVID-19 Disease The SARS-CoV-2 computer virus gains access to host cells by engaging ACE-2 proteins, which are abundantly expressed in many tissues, including alveolar epithelial cells type II (AEC II), intestinal epithelial cells (IECs), and ECs (26, 28, 29). Interestingly, these cells function as non-professional antigen-presenting cells (APCs), so viral invasion directly affects their immune function. It has been established that viruses often.