The 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.