Genetic and clinical data are rapidly emerging and suggest strong similarities with two previous highly pathogenic human β-coronaviruses, SARS-CoV and MERS-CoV. SARS-CoV-2 shares approximately 79% and 50% sequence identity with SARS-CoV and MERS-CoV, respectively [1], similar cell entry mechanisms [2], and the propensity to induce hyper inflammation in severe cases [3]. Currently, there is very limited knowledge of the host immune response to SARS-CoV-2. However, based on the accumulated clinical and experimental data on these previous viruses, predictions can be made on how the host immune system may deal with this virus and how the virus may evade such host responses
Viral recognition by the innate immune system
The first line of defense against viral infection comprises a set of pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs) that recognize the RNA viral genome and its replication intermediates. Evidence suggests that upon entry into the alveolar epithelium, the virus is sensed by the endosomal single-stranded (ss)RNA sensors, TLR7/8, and the cytosolic double-stranded (ds)RNA sensor, RIG-I/MDA-5. Upon recognition, these sensors recruit the adaptor proteins, MyD88 and MAVS, respectively, and induce downstream signaling. Ultimately, this leads to the activation of the transcription factors, IRF3/7 and NF-κB, and the subsequent production of type I interferons (IFN-α and IFN-β) and proinflammatory cytokines (e.g. IL-6 and TNF-α), respectively [5]. Additionally, the virus is thought to activate the inflammasome sensor, NLRP3, resulting in the secretion of the highly inflammatory cytokine IL-1β and the induction of pyroptosis, an inflammatory form of cell death. Indeed, SARS-CoV has previously been shown to induce the formation of the NLRP3 inflammasome through the action of viral proteins such as the E and 3a proteins [6,7]. Still, our understanding of the viral recognition mechanisms is far from being fully elucidated.
Immunopathology of SARS-CoV-2
The immunopathology of COVID-19 greatly resembles that seen in SARS and MERS infections. Recent studies found that increased cytokine levels (e.g. IL-6, IL-10, and TNFα) and lymphopenia (significantly reduced CD4+ and CD8+ T cells) correlate with disease severity of COVID-19 [3, 20]. In addition to reduced T cell counts, the surviving T cells appear dysfunctional [21]. In the more severe cases of COVID-19, this dysregulated immune response can lead to a cytokine storm, causing increased pulmonary pathology and respiratory distress and, a higher risk of poor clinical outcomes (e.g. death). Therefore, treatment with antiviral agents alone may not be sufficient to stop the devastating cytokine storm and pulmonary destruction in these patients. Thus, further studies to develop a better understanding of how the virus is recognized by the host and which viral factors drive immune dysregulation in COVID-19 will provide essential insights to help shape vaccine responses towards protective immunity.
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