The activation of the IFN-induced signalling pathway limits viral replication and induces the subsequent adaptive immune response. As noted above, SARS-CoV and SARS-CoV-2 both seem to use the ACE2 as a cell entry receptor. This hypothetical receptor for SARS-CoV-2 is mainly expressed in alveolar type II cells in the lungs.20–22 Angiotensin-converting enzyme 2 receptors are also found in monocytes, macrophages or endothelial cells, and there is also evidence of neurotropism in SARS-CoV-2.23 Upon infection, macrophages present antigens to T cells. This process, added to the presence of virus-derived PAMPs, leads to T cell activation and differentiation, including the synthesis and release of cytokines associated with different T cell subsets.6,9

One salient feature of both SARS-CoV and MERS-CoV is their ability to suppress the host response to viral infection. Both of these coronaviruses implement multiple strategies to interfere with the signalling pathways leading to IFN production. These dampening strategies are strongly associated with the severity of disease. Severe or lethal cases of SARS-CoV or MERS-CoV manifested with a greater accumulation of neutrophils and monocytes-macrophages in the lungs. In both viral infections, this was the main mechanism involved in lung damage. It was hypothesised that in infection by SARS-CoV or MERS-CoV, the delay in the type I IFN response compromised the control of viral replication. This would in turn lead to the increased influx of neutrophils and monocytes-macrophages just described.9 The increased accumulation and persistent activation of these cells would cause lung damage, with potential manifestations including pneumonia or acute respiratory distress syndrome. It would be reasonable to assume a similar scenario in infection by SARS-CoV-2, with a variable degree of interference with the immune response. This delay in the immune response could be what makes asymptomatic transmission possible.18

As noted above, T cells play a key role in the immune response to coronavirus. This became evident in the investigation of the pathogenesis of MERS-CoV. In infections caused by this virus, CD4+ cells proved more susceptible to infection and their damage was associated with poorer outcomes. This susceptibility was also observed in infection by SARS-CoV.9 In the latter case, CD4+ depletion resulted in a reduction in pulmonary lymphocyte recruitment, leading to severe interstitial pneumonitis and reduced viral clearance.24 As a result from this dysregulation, the presence of CD4+ T cells in the region resulted in increased levels of proinflammatory cytokines that attracted an accumulation of monocytes and neutrophils that in turn activated other inflammatory cascades through the release of additional cytokines (IL-1, LL-6, IL-8, IL-21, TNF-β and MCP-1).7

Coronaviruses have developed specific adaptations to evade detection by the immune system. This phenomenon has been studied extensively during the various SARS-CoV and MERS-CoV epidemics. Interference with type I interferon recognition and signalling, with intercellular signalling cross-talk and with intracellular signalling are the 3 main immune evasion mechanisms.6

When it comes to white blood cells, coronaviruses primarily infect macrophages. These cells present antigens to T cells, triggering their activation and the synthesis of cytokines associated with each T cell subtype (especially Th17). These cytokines then amplify the immune response.9

As noted above, the production of type I IFN is important to the end of optimising the release of antiviral proteins, promote phagocytosis by macrophages and facilitate the protection of uninfected cells. Coronavirus accessory proteins can interfere with PAMP-mediated toll-like receptor (TLR) signalling during viral replication, preventing activation of these pathways.9

This interference has 2 results. On one hand, it facilitates persistence of the virus. On the other, it has a negative effect on natural killer (NK) cell, macrophage and CD8+ T cell activation. The innate immune response is thus dysregulated. These 2 phenomena can be associated with dysregulated cytokine production, producing a proinflammatory state.18 Thus, the synthesis of IL-1, IL-6, IL-8, IL-21, tumour necrosis factor-beta (TNF-β) and monocyte chemoattractant protein-1 (MCP-1) causes lymphocyte and white blood cell recruitment at the site of infection, which could exacerbate respiratory manifestations.3,9,25,26

The use of both antivirals has been proposed for COVID-19 based on their previous performance against SARS-CoV and MERS-CoV. At present, there is no evidence supporting their use, and the early data on the subject suggest that they may not have an impact on mortality in these patients.31

This drug has exhibited antiviral activity against a broad spectrum of RNA viruses, including SARS-CoV and MERS-CoV.6,9,32 Its effectiveness for treatment of Ebola is currently under investigation, as is its effectiveness and usefulness against SARS-CoV-2.32

The potential efficacy of hydroxychloroquine (HQ) against coronavirus was already described in the SARS-CoV epidemic. This molecule increases the pH of the environment, hindering the activity of the viral phagolysosome and therefore slowing down or inhibiting the replication of coronavirus. In vitro studies have recently demonstrated activity against SARS-CoV-2.33 There is no evidence from clinical trials supporting its efficacy in patients, and therefore it continues to be an empiric therapy.34 It is important to watch for the potential development of adverse effects when HQ is used either alone or in combination with other drugs.33,35

Macrolides have been shown to have certain immunomodulatory properties. Thus, they seem to have an effect on neutrophil activity or the release of cytokines such as IL-8. There is evidence that they can be useful for treatment of viral pneumonias and therefore have been proposed for adjuvant treatment in patients with COVID-19. There is still no evidence confirming that their use alone or in combination with HQ improves patient outcomes.35

The main goal of administering interferon in the context of infection by coronavirus is to mitigate the potential disruption of this innate immune response pathway by the virus. This rationale was applied in previous epidemics by coronaviruses with controversial outcomes.

The use of steroid therapy in patients with COVID-19 is controversial. On one hand, it may have an immunosuppressant effect that could be useful in case of proinflammatory immune dysregulation.29,36 On the other hand, these drugs exacerbate and prolong lymphopenia, and therefore could interfere in the response needed for viral clearance. In patients with respiratory illness caused by SARS-CoV, their use was not beneficial and was even associated with a longer duration of detectable viral loads (Table 1).

The recommendations made for steroid therapy by clinicians that managed patients with COVID-19 in Wuhan rested on 5 key points: (1) The risks and benefits of its use must be weighed carefully. (2) Its use should be considered mainly in critically ill patients. (3) Its use should be considered in patients with hypoxaemia due to underlying disease or previously receiving long-term steroid therapy. (4) It should be given at a low-to-medium dose (≤0.5–1mg/kg/day of methylprednisolone or equivalent agent), and (5) the duration of treatment should be short (≤7 days).37

As discussed above, the synthesis of IL-6 by macrophages and T cells is part of the immune response against SARS-CoV-2. In cases of COVID-19 with a prolonged course or clinical worsening, there is frequently evidence of high serum levels of this cytokine. Tocilizumab is a humanised monoclonal antibody that inhibits ligand binding to the IL-6 receptor. It could be used to halt the underlying immune cell activation, and therefore could be a therapeutic option in patients with severe or progressing disease. If methods for quantification of this molecule were not available, ferritin could be used as a biomarker.12,18,30,36 At present, ferritin offers an adequate sensitivity and specificity to guide the diagnosis and followup of macrophage activation syndrome.28

The use of convalescent plasma was proposed in previous epidemics caused by SARS-CoV and MERS-CoV, and at present there are few data on its benefits. Only 1 study conducted in 5 patients suggested positive outcomes. Its use must be considered with caution, as it is not free of risks.38

In conclusion, SARS-CoV-2 may share some characteristics with previously known coronaviruses and have a similar effect on the immune response. Given its activity on the interferon signalling pathways and the way it dysregulates innate immunity, the use of treatments aimed at modulating or containing the innate immune response may be of interest. A better understanding of the underlying pathophysiological mechanisms or the identification of specific biomarkers (lymphocytes or IL-6 levels) could be useful in predicting the course of disease and developing individualised treatment plans with use of targeted therapies.