Interferon Therapy and NK Cells
The importance of the interferon pathway is underscored by the fact that many viruses actively interfere with host interferon responses, for which coronaviruses are a prime example. As described above, CoVs utilize numerous tactics to avoid elimination by disrupting the host type I IFN response (174). Therefore, since the majority of CoVs fail to induce any detectable type I IFN response, eliciting a type I IFN response is a very attractive therapeutic strategy (118, 175).
Given the robust immunomodulatory nature of type I IFNs, uninfected or early symptomatic patients would benefit the most from this therapy to prevent exacerbating immunopathology at later stages of disease. Numerous clinical trials have been initiated investigating type I IFNs (Table 1). A large study (NCT04320238) of ~3,000 medical staff allocated participants to two trial arms: (i) low-risk (non-isolated wards or laboratories) or (ii) high-risk (isolated wards in direct contact with COVID-19 patients). In addition to the IFN-α-1b nasal drops, high-risk medical staff will also receive the immune-modulating TLR activator, thymosin α1, which indirectly activates NK cells through pDCs (176, 177). Interestingly, reports in SARS-CoV-1 studies showed that IFN-β therapy had a 50-fold greater anti-viral activity in Vero cells than IFN-α treatment (178). Promising results have been published from a Phase II study (NCT04276688) (179), showing that complementing lopinavir-ritonavir and ribavirin with subcutaneous IFN-β-1b in mild-to-moderate COVID-19 patients is safe with no serious adverse events reported in the triple combination therapy group, and highly effective, with significant and clinically meaningful reductions in time to complete alleviation of symptoms, hospital length of stay, and time to negative viral load (179).
Despite our best efforts in timing type I IFN therapy to mitigate immunopathology, these treatments still increase the risk of excessive activation of proinflammatory signals, which could damage host tissues and perpetuate immunopathology (180, 181). For this reason, alternative therapeutic avenues to direct type I IFN administration are being explored.
Type III IFNs can be a valid alternative to type I IFNs, because they maintain antiviral functions yet are less toxic and less prone to mediate immunopathology (182). The type III IFN, IFN-λ, activates NK cells indirectly (compared to type I IFNs which directly act on NK cells), resulting in a less potent and slower immune response (183, 184). IFN-λ activates NK cells by stimulating macrophages to produce IL-12 which in turn induce NK cells to produce IFN-γ (185). Pegylated IFN-λ is being tested in COVID-19 positive patients with mild symptoms in the absence of respiratory distress (NCT04331899). While IFN-λ can lead to the eventual activation of NK cells, its primary utility is in preventing the tissue damaging potential of neutrophils at mucosal surfaces, such as the lungs. However, IFN-λ also has been shown to reduce the rate of tissue repair, which in the context of COVID-19 which has a long disease course, could mean greater risk of secondary infections. Since exogenous administration of any IFN therapy poses the risk of tipping the balance toward severe COVID-19 immunopathology, Broggi et al. assessed the levels of IFNs in upper and lower respiratory samples from healthy and COVID-19 patients. In this preprint, they report that while the upper airway swabs showed similar mRNA expression levels of type I and III IFN compared to healthy controls, the BALF samples of severe COVID-19 patients had significantly elevated type I and III IFN levels (186). Therefore, as with all of the therapies discussed in this review, careful consideration about safe and effective timing should guide our design of clinical trials.