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

Abstract

The severe acute respiratory syndrome caused by the new coronavirus (SARS-CoV-2), termed COVID-19, has been highlighted as the most important infectious disease of our time, without a vaccine and treatment available until this moment, with a big impact on health systems worldwide, and with high mortality rates associated with respiratory viral disease. The medical and scientific communities have also been confronted by an urgent need to better understand the mechanism of host-virus interaction aimed at developing therapies and vaccines. Since this viral disease can trigger a strong innate immune response, causing severe damage to the pulmonary tract, immunotherapies have also been explored as a means to verify the immunomodulatory effect and improve clinical outcomes, whilst the comprehensive COVID-19 immunology still remains under investigation. In this review, both cellular and molecular immunopathology as well as hemostatic disorders induced by SARS-CoV-2 are summarized. The immunotherapeutic approaches based on the most recent clinical and nonclinical studies, emphasizing their effects for the treatment of COVID-19, are also addressed. The information presented elucidates helpful insights aiming at filling the knowledge gaps around promising immunotherapies that attempt to control the dysfunction of host factors during the course of this infectious viral disease.

Figure 1

Immune response during COVID-19. (a) After SARS-CoV-2 contact with the respiratory tract of a human, susceptible cells are infected by entry through ACE2 or CD147 surface receptors. Once in the lung compartment, the first line of defense made of dendritic cells and other cells, such as macrophages, are able to recruit other immune cells. Then, cell migration through blood vessels are directed to the lung compartment, where cell activation occurs, initiating the inflammation process on the first week of signals and symptoms (b), inducing natural killer cell (NK), neutrophil, and macrophage (MO) activation in the lungs, causing the phenomenon called “cytokine storm.” In the mean time, B cells are producing antibodies, and immature T cells are also activated attempting to control the viral infection, although apoptotic events can also occur, reducing the number of T cells in the lungs and in the peripheral blood. After that, in two or more weeks (c), adaptive immune response is raised to specific IgG and neutralizing antibodies to contribute to the recovery and viral elimination. At this time, CD8 T cells are activated as cytotoxic phenotype, with the same aim, driving towards virus elimination. Meanwhile, the differentiation of CD4 T cells can trigger for more help for viral elimination by Th1 cells, but it can also lead to more lung damage by inflammatory phenotypes, such as Th2 and Th17 cells. Physicians and clinicians should evaluate each case to introduce the immunotherapies attempting to control the immune dysfunction. Created with BioRender.com.

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.

Figure 3

Hemostatic disorder in SARS-CoV-2 infection. (a) In COVID-19 cases, there occurs a systemic activation of the circulatory system as a reflection of what occurs in the lungs. (b) In the lung compartment, monocytes expressing TF perform an intense diapedesis under stimuli of proinflammatory and chemoattractant cytokines, infiltrating activated macrophages in the lung that lead to tissue damage. The high production of proinflammatory cytokines, as well as vascular permeability and microthrombosis events are prompt to overexpress PAR-1 receptors and abnormal platelet activation. Overexpression of PAR-1 can be blocked with APC or PAR-1 antagonist therapy, while abnormal platelet activation can be avoided by P-selectin blocker therapy. Created with BioRender.com.

Figure 4

Good results of immunotherapies on clinical trials and nonclinical studies in the immune response against COVID-19. (a) Recent and preliminary positive findings with clinical trials using immunotherapy for COVID-19 treatment are summarized focusing on immune event alterations and recovery, as well as in nonclinical studies (b) for immunotherapeutic interventions using bioinformatics tools, cell cultivation, and animal models; they are also based on past information with other related viral respiratory diseases and autoimmune disorders. Created with BioRender.com.