Pneumonia is a typical symptom of COVID-19 infection, while acute respiratory distress syndrome (ARDS) and multiple organ failure are common in severe COVID-19 patients
Another indirect route of SARS-CoV-2-induced NET production is platelet activation
SARS-CoV-2 infection has also been linked to increased neutrophil-to-lymphocyte ratios, which is associated with disease severity and clinical prognosis
NETosis is a special form of programmed cell death in neutrophils, which is characterized by the extrusion of DNA, histones, and antimicrobial proteins in a web-like structure known as neutrophil extracellular traps (NETs)
increased generation of reactive oxygen species (ROS) is a crucial intracellular process that causes NETosis
NETs are important for preventing pathogen invasion, their excessive formation can result in a slew of negative consequences, such as autoimmune inflammation and tissue damage
When NETs are activated in the circulation, they can also induce hypercoagulability and thrombosis
In COVID-19, major NET protein cargos of NETs (i.e., NE, MPO, and histones) are significantly elevated.
SARS-CoV-2 can also infect host cells through noncanonical receptors such as C-type lectin receptors
Immunopathological manifestations, including cytokine storms and impaired adaptive immunity, are the primary drivers behind COVID-19, with neutrophil infiltration being suggested as a significant cause
NETosis, leading to aberrant immunity such as cytokine storms, autoimmune disorders, and immunosuppression.
SARS-CoV-2 and its components (e.g., spike proteins and viral RNA) attach to platelets and increase their activation and aggregation in COVID-19, resulting in vascular injury and thrombosis, both of which are linked to NET formation
Connects SARS-CoV-2 to TLR on Platelets to NETosis to metastasis.
NET formation may be caused by activated platelets rather than SARS-CoV-2 itself
NETosis and NETs are increasingly recognized as causes of vascular injury
early bacterial coinfections were more prevalent in COVID-19 patients than those infected with other viruses
NETosis and NETs may also have a role in the development of post COVID-19 syndromes, including lung fibrosis, neurological disorders, tumor growth, and worsening of concomitant disease
NETs and other by-products of NETosis have been shown to act as direct inflammation amplifiers. Hyperinflammation
“cytokine storm”
SARS-CoV-2 drives NETosis and NET formation to allow for the release of free DNA and by-products (e.g., elastases and histones). This may trigger surrounding macrophages and endothelial cells to secrete excessive proinflammatory cytokines and chemokines, which, in turn, enhance NET formation and form a positive feedback of cytokine storms in COVID-19
NET release enables self-antigen exposure and autoantibody production, thereby increasing the autoinflammatory response
patients with COVID-19 who have higher anti-NET antibodies are more likely to be detected with positive autoantibodies [e.g., antinuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibodies (ANCA)]
can enhance this process by interacting with neutrophils through toll-like receptor 4 (TLR4), platelet factor 4 (PF4), and extracellular vesicle-dependent processes
have weakened adaptive immunity as well as a high level of inflammation
tumor-associated NETosis and NETs promote an immunosuppressive environment in which anti-tumor immunity is compromised
NETs have also been shown to enhance macrophage pyroptosis in sepsis
facilitating an immunosuppressive microenvironment
persistent immunosuppression may result in bacterial co-infection or secondary infection
COVID-19 NETs may act as potential inducers for autoimmune responses
NET-induced immunosuppression in COVID-19 in the context of co-existing bacterial infection
Following initial onset of COVID-19, an estimated 50% or more of COVID-19 survivors may develop multi-organ problems (e.g., pulmonary dysfunction and neurologic impairment) or have worsening concomitant chronic illness
NETs in the bronchoalveolar lavage fluid of severe COVID-19 patients cause EMT in lung epithelial cells
COVID-19 also has a long-term influence on tumor progression
Patients with tumors have been shown to be more vulnerable to SARS-CoV-2 infection and subsequent development of severe COVID-19
patients who have recovered from COVID-19 may have an increased risk of developing cancer or of cancer progression and metastasis
awaken cancer cells
NETs have been shown to change the tumor microenvironment
enhance tumor progression and metastasis
vitamin C has been tested in phase 2 clinical trials aimed at reducing COVID-19-associated mortality by reducing excessive activation of the inflammatory response
vitamin C is an antioxidant that significantly attenuates PMA-induced NETosis in healthy neutrophils by scavenging ROS
vitamin C may also inhibit NETosis and NET production in COVID-19