At the onset of the corona virus disease 19 (COVID-19) pandemic, there were concerns that patients with sickle cell disease (SCD) might be especially vulnerable to severe sequelae of SARS-CoV-2 infection. While two reports support this conclusion, multiple studies have reported unexpectedly favorable outcomes in patients with SCD. However, mechanisms explaining these disparate conclusions are lacking. Here, we review recent studies indicating that the majority of patients with SCD express elevated levels of anti-viral type 1 interferons (IFNα/β) and interferon stimulated genes, independent of COVID-19, during their baseline state of health. We also present our data from the pre-COVID-19 era, illustrating elevated expression of a well-characterized interferon stimulated gene in a cohort of patients with SCD, compared to race-matched controls. These type 1 interferons and interferon stimulated genes have the potential to contribute to the variable progression of COVID-19 and other viral infections in patients with SCD. While the majority of evidence supports a protective role, the role of IFNα/β in COVID-19 severity in the general population remains an area of current investigation. We conclude that type 1 interferon responses in patients with SCD may contribute to the variable COVID-19 responses reported in prior studies. Additional studies investigating the mechanisms underlying IFNα/β production and other clinical consequences of IFNα/β-mediated inflammation in SCD disease are warranted. Graphical Abstract Hypothesis: Baseline type I interferon activity may contribute to variable COVID-19 progression in SCD. (Top) At early stages of SARS-CoV-2 infection, high baseline IFNα/β activity may contribute to the anti-viral response in patients with SCD. Recognition of damage-associated molecular patterns by pattern recognition receptors (PRRs) induces IFNα/β production. Heme released from hemolyzed sickle cells binds Toll-like receptor 4 (TLR4), which may induce IFNα/β in vascular endothelial cells. IFNα/β bind to the IFNα/β receptor (IFNAR) in neutrophils and other cells types, leading to production of MxA and other interferon-stimulated genes (ISGs). ISGs can directly inhibit viral replication and promote B cell production of neutralizing antibodies. The IFNα/β response is one of multiple responses, including production of IL-6, TNFα, and IL-1b, by innate and adaptive immune cells that have the potential to limit COVID-19 progression. (Bottom) In contrast, reduced or absent IFNα/β activity may increase susceptibility to viral infection, leading to airway epithelial cell death and COVID-19. Dashed lines indicate potentially connected pathways, while solid lines are supported by prior studies.
【저자키워드】 COVID-19, SARS-CoV-2, Sickle cell disease, type 1 interferons, myxovirus resistance interferon stimulated genes, 【초록키워드】 Inflammation, viral infection, pandemic, adaptive, Neutralizing antibodies, IL-6, TLR4, SARS-COV-2 infection, susceptibility, neutrophil, COVID-19 severity, interferon, progression, outcome, type I interferon, airway, Anti-viral, B cell, Health, heme, viral replication, response, Patient, receptor, General population, cell death, disease, expression, epithelial, early stage, mechanism, ISGs, ISG, Evidence, Immune cell, Pathways, pattern recognition receptor, Virus Disease, Support, COVID-19 progression, damage-associated molecular pattern, Recognition, PRRs, IFNAR, vascular endothelial cells, TNFα, anti-viral response, protective role, Express, while, interferon-stimulated gene, Genes, responses, type 1 interferon, controls, limit, Cell, SCD, independent, bind, stimulated, reported, inhibit, elevated, reduced, supported, majority, contribute, promote, induce, released, disparate, multiple study, clinical consequence, baseline, cohort of patient, 【제목키워드】 chronic, signature, Type, Potential, Sickle,