PMC:7796072 / 9303-14190 JSONTXT

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is the HbE Trait Protective?\nThe hypothesis we posit is that thalassemia traits in general, and particularly HbE, are protective against COVID-19 infection in similar ways to the numerous thalassemia traits conferring protection against malaria [30,42] and the dengue virus [43]. Herd immunity development traditionally requires that 60% of the population becomes homogeneously infected by or vaccinated against an infectious disease. However, recent mathematical models introducing age and activity heterogeneities into population models predict that herd immunity can be achieved at 43% [44], a level substantially lower than the observed prevalence of HbE in some areas of SE Asia [13–15]. In fact, in countries where the HbE trait is above 43%, the numbers of both COVID-19 infections and deaths have been minimal (Table 1, Figures 1, 2).\nThe genetic and molecular mechanisms of this hypothesized protection are as yet elusive, but biological evidence is suggestive. Hemoglobinopathy-induced red blood cell structural modifications hinder invasion, growth, and migration of plasmodium [42,45]. Recent studies in thalassemias have pointed to the involvement of microRNAs (miRNAs) in malarial pathogenesis and anti-plasmodial defense [45]. MicroRNAs (miRNAs) are 18–25 nucleotide long, small, non-coding RNA molecules whose production is strictly regulated and abundant in all human cells [46]. miRNAs can downregulate gene expression in translational repression and target around 60% of all genes [46]. They exhibit decisive regulatory functions associated with a variety of disease processes, including microbial defense [46]. In dengue virus infection, which is perennially endemic in SE Asia, red blood cell precursors in Thai carriers of thalassemia and HbE trait were significantly less susceptible to the dengue virus compared to normal controls [43]. This was the first report documenting an antiviral effect of the HbE trait akin to its anti-malarial effect [43]. A large number of miRNAs have also been implicated in dengue virus defense via structural protein integrity alterations inhibiting access of viral replication machinery to the cytoskeletal apparatus (miR-223) [47], but also through modulations of the host immune interferon response (miR-155) [48]. Remarkably, increased levels of the latter molecule have been reported in β-thalassemia/HbE patients and linked to BACH1 downregulation [49]. The same miRNA molecule was also reported to inhibit dengue virus replication by inducing antiviral interferon responses through the same BACH1 pathway downregulation and heme oxygenase-1-(HO-1) induction [48]. Rare putative loss-of-function variants of X-chromosomal toll-like receptor 7 (TLR7) causing immunological defects in type I and II interferon production have been very recently identified in 4 young male patients with severe COVID-19 [50]. Type I and II interferon (IFN) responses have been implicated in the initiation of an early immune response to clear the SARS-CoV-2 coronavirus and prevent the development of COVID-19 [50]. Moreover, the addition of interferon beta-1b to other antivirals in the clinical setting was also more effective in treating COVID-19 patients and rendering them noninfectious [51]. HO-1 pathway derangements have been implicated in severe COVID-19 infection [52] and in causing exhaustion of hematopoietic stem cells, possibly leading to immune system failure [53]. Similar structural and molecular mechanisms might be operative in immune effector cells of HbE heterozygotes.\nThe hypothesized conferred protection against COVID-19 could also derive from local SE Asian HLA-class allotypes, possibly in linkage disequilibrium with the thalassemia mutations. Protection from and resistance to severe malaria has been described in association with HLA antigens in the African continent [54,55] and the ABO blood group system [56]. However, no HLA associations with COVID-19 infection have been noted in a recent report [57] but an association with the ABO blood group system was confirmed, with bearers of the blood group A phenotype showing an increased risk for COVID-19 infection compared to blood group O [58]. The O phenotype appears protective to malaria [56] and its worldwide distribution seems to have been shaped by the parasite’s selective genetic pressure [56]. The frequency of the O blood group in Thailand is 40.5% [59] and its relatively high prevalence along with the high HbE heterozygote frequency could further potentiate the hypothesized antiviral protective effect.\nA similarly intriguing hypothesis querying whether Italian β-thalassemia subjects are immunized against COVID-19 has been put forward [60]. We believe that the diluted carrier population sizes available in southern European countries are not of the magnitude presently observed in SE Asia and could lead to erroneous interpretation [60,61]."}

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Herd immunity development traditionally requires that 60% of the population becomes homogeneously infected by or vaccinated against an infectious disease. However, recent mathematical models introducing age and activity heterogeneities into population models predict that herd immunity can be achieved at 43% [44], a level substantially lower than the observed prevalence of HbE in some areas of SE Asia [13–15]. In fact, in countries where the HbE trait is above 43%, the numbers of both COVID-19 infections and deaths have been minimal (Table 1, Figures 1, 2).\nThe genetic and molecular mechanisms of this hypothesized protection are as yet elusive, but biological evidence is suggestive. Hemoglobinopathy-induced red blood cell structural modifications hinder invasion, growth, and migration of plasmodium [42,45]. Recent studies in thalassemias have pointed to the involvement of microRNAs (miRNAs) in malarial pathogenesis and anti-plasmodial defense [45]. MicroRNAs (miRNAs) are 18–25 nucleotide long, small, non-coding RNA molecules whose production is strictly regulated and abundant in all human cells [46]. miRNAs can downregulate gene expression in translational repression and target around 60% of all genes [46]. They exhibit decisive regulatory functions associated with a variety of disease processes, including microbial defense [46]. In dengue virus infection, which is perennially endemic in SE Asia, red blood cell precursors in Thai carriers of thalassemia and HbE trait were significantly less susceptible to the dengue virus compared to normal controls [43]. This was the first report documenting an antiviral effect of the HbE trait akin to its anti-malarial effect [43]. A large number of miRNAs have also been implicated in dengue virus defense via structural protein integrity alterations inhibiting access of viral replication machinery to the cytoskeletal apparatus (miR-223) [47], but also through modulations of the host immune interferon response (miR-155) [48]. Remarkably, increased levels of the latter molecule have been reported in β-thalassemia/HbE patients and linked to BACH1 downregulation [49]. The same miRNA molecule was also reported to inhibit dengue virus replication by inducing antiviral interferon responses through the same BACH1 pathway downregulation and heme oxygenase-1-(HO-1) induction [48]. Rare putative loss-of-function variants of X-chromosomal toll-like receptor 7 (TLR7) causing immunological defects in type I and II interferon production have been very recently identified in 4 young male patients with severe COVID-19 [50]. Type I and II interferon (IFN) responses have been implicated in the initiation of an early immune response to clear the SARS-CoV-2 coronavirus and prevent the development of COVID-19 [50]. Moreover, the addition of interferon beta-1b to other antivirals in the clinical setting was also more effective in treating COVID-19 patients and rendering them noninfectious [51]. HO-1 pathway derangements have been implicated in severe COVID-19 infection [52] and in causing exhaustion of hematopoietic stem cells, possibly leading to immune system failure [53]. Similar structural and molecular mechanisms might be operative in immune effector cells of HbE heterozygotes.\nThe hypothesized conferred protection against COVID-19 could also derive from local SE Asian HLA-class allotypes, possibly in linkage disequilibrium with the thalassemia mutations. Protection from and resistance to severe malaria has been described in association with HLA antigens in the African continent [54,55] and the ABO blood group system [56]. However, no HLA associations with COVID-19 infection have been noted in a recent report [57] but an association with the ABO blood group system was confirmed, with bearers of the blood group A phenotype showing an increased risk for COVID-19 infection compared to blood group O [58]. The O phenotype appears protective to malaria [56] and its worldwide distribution seems to have been shaped by the parasite’s selective genetic pressure [56]. The frequency of the O blood group in Thailand is 40.5% [59] and its relatively high prevalence along with the high HbE heterozygote frequency could further potentiate the hypothesized antiviral protective effect.\nA similarly intriguing hypothesis querying whether Italian β-thalassemia subjects are immunized against COVID-19 has been put forward [60]. We believe that the diluted carrier population sizes available in southern European countries are not of the magnitude presently observed in SE Asia and could lead to erroneous interpretation [60,61]."}