Future Perspectives
Over the last several months, a large number of clinical and histological studies have illustrated the underlying pathophysiological changes and tissue damage in COVID-19. However, we are just beginning to understand the fundamental molecular and signaling pathways implicated in this disease pathogenesis. Close sequence similarity with SARS-CoV does help us understand some co-existing pathological features but owing to reasonable genomic and structural variations, and it is essential to decoding the molecular mechanisms specific to SARS-CoV-2 infection. Differences in S protein, ORF3b, ORF6 and ORF8 between SARS-CoV and SARS-CoV-2 are functionally relevant (Chan et al., 2020; Mantlo et al., 2020). Similarly, the differential immune responses generated by the two viruses needs to be delineated well to develop targeted therapies to modulate these specific molecular networks (Moreno-Eutimio et al., 2020; Yao et al., 2020). Importantly, heterogeneous T cell response in COVID-19 patients has remained an enigma, with lymphocytopenia and activated T cell state in some patients versus an increased presence of exhausted T cells in others.
Further, the increased activation status of these cells at the site of infection (lungs) in severe cases adds more complexity to the T cell immune response in COVID-19 patients and hence may pose difficulty in devising a universal therapeutic intervention. Similarly, the presence of reactive T cells in healthy individuals is another area that needs a comprehensive understanding, mainly while designing a vaccine. Keeping these challenges in mind and till the time an effective vaccine becomes available, existing immunomodulatory approaches like mesenchymal stem cell-based therapies (currently under clinical trials), anti-IL6 and anti-GMCSF drugs to counter cytokine storm, as well as antiviral drugs remain the standard therapeutic interventions. While the antiviral drug remdesivir has shown promise in some patients, severe side effects were also reported in others (Wang Y. et al., 2020). Considering the number of factors that affect the complexity of immune response during COVID-19, it is crucial to understand that a single type of intervention may not work for all patients. Thus, it appears that exploring a combination therapy may be more compelling at present. However, determination of the optimal combination, dose, and time of treatment needs thorough investigation. These targeted therapies become critical, considering the chance of reinfection. A recent study on ten healthy individuals throughout 35-years revealed short-lasting immunity against four common seasonal coronaviruses, with chances of reinfection in a year after infection (Edridge et al., 2020). It is plausible that SARS-CoV-2 may exhibit the same tendency of reinfection, which may be a growing concern for vaccine research. Thus, a more comprehensive understanding of the immunopathological changes and sustainability of protective immunity is needed. In this review, we highlight some of these immunological responses, which are central to the progression and outcome of COVID-19 patients. Ongoing research in this direction should lead to effective therapies sooner rather than later, alongside with the vaccines.