Ferroptosis and aging: Inducing and catalyzing neurodegenerative diseases.

Coronavirus disease 2019 (COVID-19), caused by the betacoronavirus SARS-CoV-2, is characterized by a range of clinical severities even among individuals with similar demographics [,]. Accordingly, SARS-CoV-2 infections are categorized into asymptomatic, mild, moderate, severe, and critical illnesses [,]. A majority of SARS-CoV-2 infections result in asymptomatic or non-critical COVID-19 with influenzae-like symptoms such as headache, fever, cough, myalgia, fatigue, shortness of breath, and sore throat; however, a smaller proportion may progress to critical, life-threatening diseases [,]. Patients with critical COVID-19 often present with pneumonia, acute respiratory distress syndrome (ARDS), and/or multi-organ failure requiring external respiratory support and intensive care, which are often associated with high mortality rates [,,,,]. Disease severity is associated with a range of host factors, such as age [,], sex [,,], presence of comorbidities [], blood group status [,], presence of neutralizing autoantibodies [,,,], and genetic variants [,,]. Additionally, during active infection, a highly dysregulated innate immune response—consisting of impaired production of interferons (IFNs) and interferon-stimulated genes (ISGs), along with excessive NF-kB driven inflammatory response—is a key feature distinguishing patients with critical compared to non-critical COVID-19 [,,,]. SARS-CoV-2 is a single-stranded, positive-sense RNA virus []. Upon infection, viral pathogen-associated molecular patterns (PAMPs), including replication intermediaries, are detected by innate immune receptors [,]. Viral recognition triggers a downstream antiviral cascade resulting in the production of IFNs and ISGs. There are three main types of IFNs, namely, type I (IFN-α/β), type II (IFN-γ), and type III (IFN-λ) []. These IFNs bind to interferon-stimulated response elements (ISREs) to induce transcription of interferon-stimulated genes (ISGs), that act through direct and indirect mechanisms to establish an antiviral state [,]. Genetic variants in type I and III IFN pathway genes and autoantibodies against type I IFNs (IFN-α2 and IFN-ω) have been observed in patients with critical COVID-19 [,,]. Furthermore, IFN levels vary according to disease severity and delayed or impaired production of type I (characterized by low levels and activity of IFN-α and absence of IFN-β), III IFNs and ISGs, is observed in patients with critical disease [,,]. However, contrasting studies also exist where critical COVID-19 patients displayed increased levels of IFNs and ISG expression [,]. These differences observed in the levels of IFNs and ISGs from different studies could be attributed to the multiple factors, including differences in the populations studied, differences in the anatomical site being studied, differences in the subtype of IFN-α reported, and differences in assays used to measure the levels of cytokines (technical approaches) []. Nevertheless, differences in expression of IFNs and ISGs are widely observed between patients who develop critical compared to non-critical COVID-19, underscoring the importance of IFNs and their downstream effectors in determining COVID-19 severity []. Among hundreds of ISGs produced in response to SARS-CoV-2 infection is Adenosine Deaminase Acting on RNA 1 (ADAR1), specifically, the longer cytoplasmic isoform ADARp150, whose promoter region incorporates an ISRE. This ADAR edits RNA molecules post-transcriptionally to convert adenosines (A) to inosines (I), within double-stranded RNA (dsRNA) regions. These substitutions are then interpreted as A-to-G substitutions by cellular machinery, including elements involved in translation. Thus, ADAR-mediated editing is a key player in the dynamic regulation of gene expression and proteomic diversity through introduction of recoding sites within proteins or through its effect on various regulatory mechanisms such as alternative splicing, microRNA biogenesis and targeting [,]. In addition to ADARp150, ADAR1 also exists as the constitutively expressed, predominantly nuclear isoform ADARp110 []. It is noteworthy that ADARp110 is coexpressed with ADARp150 due to leaky ribosomal scanning downstream of the ADARp150 start codon []. Additionally, increased levels of ADARp110 have also been observed during SARS-CoV-2 and other viral infections [,]. In addition to ADAR1 (ADAR), the human genomes encode for two other ADAR genes, ADAR2 (ADARB1) and ADAR3 (ADARB2). While most viral infections are associated with changes in the expression and activity of ADAR1 and its isoforms, alterations in ADAR1 expression can also affect the expression and activity of other ADARs, such as through competition for substrates [] and formation of heterodimers [].