Cellular and Molecular Immunology Approaches for the Development of Immunotherapies against the New Coronavirus (SARS-CoV-2): Challenges to Near-Future Breakthroughs

Figure 2

Summary of immunopathogenesis in early and late SARS-CoV-2 infections. (a) Early in the lung compartment, activated macrophages, neutrophils, NK cells, and T CD4+ helper cells release an exacerbated production of an immune mediator called “cytokine storm” that contributes to lung damage. Entry of T CD4+ helper cells is facilitated not just for ACE2 and CD147 receptors, which may contribute to carrying virus to other organs. (b) Still in the early phase, virus-cell interaction leads to an innate cellular response. During viral replication, dsRNA is recognized by RIG-I that interacts with MAVs leading to the activation of NF-κB transcription factors and IRF which induce the expression of IFNs and proinflammatory cytokines. However, SARS-CoV-2 can evade PRRP recognition shielding dsRNA by membrane-bound compartments that form during viral replication. (c) Following IFN release, the first activated pathway is type I IFN. IFN-α/β interaction with IFNAR receptor activates TYK-2 and JAK-1. This interaction could be blocked by SARS-CoV-2 by viral ORF3 and NSP. Virus can interact directly with STAT1 inhibiting interaction with STAT2 and IRF9. Next, type III IFN (IFN-λ) interaction with IFNLR/IL-10R leads to activation of TYK-2 and JAK-1, followed by STAT2-IRF9 interaction. Both type I and III IFN pathways activate IRF3, which is a target of viral NSP proteins. The last IFN pathway activated after SARS-CoV-2 infections is type II IFN (IFN-γ), related to adaptive responses. IFN-γ interaction with IFNGR receptor activates JAK-1 and JAK-2, followed by STAT1, target of viral evasion by NSP. All IFN pathways lead to expression of antiviral ISGFs. (d) Finally, the cellular profiles change to adaptive immune response with B cell expansion and specific antibody production. At this time, CD8 T cells are activated as a cytotoxic phenotype, and CD4 T cells differentiate in Th1 cells that help viral elimination, as well as inflammatory phenotypes Th2 and Th17. Created with BioRender.com.