Type I interferons (IFN-I) are signaling molecules that play a significant role in antiviral immunity. IFN-I receptors, IFNAR1 and IFNAR2, activate interferon-stimulated genes (ISG). ISGs stimulate antiviral functions and promote the recruitment of inflammatory cells to the site of infection.
The IFN-I System Protects Against COVID-19
In patients with severe COVID-19, the IFN-I response is deficient, either due to congenital disorders of the interferon system, neutralizing autoantibodies to IFN-I, or because IFN-I is not produced.
IFN-I linked to hyperinflammation in COVID-19
- Patients with severe COVID-19 show excessive inflammation, associated with an IFN-I response in combination with the pro-inflammatory cytokines TNF/IL-1β.
- High lung IFN-I levels are associated with an increased incidence of COVID-19.
- Long-term IFN signaling in respiratory diseases impedes lung epithelial repair and promotes immunopathology and systemic inflammation, increasing disease severity and susceptibility to bacterial infections.
- Some ISGs help the coronavirus enter cells. Thus, the interferon-stimulated SIGLEC-1 gene encodes a protein that can be a coronavirus attachment receptor. In this case, the coronavirus can bind to both the ACE2 receptor and the SIGLEC-1 protein, facilitating infection with the coronavirus.
Clinical Trials of Interferons for COVID-19 Show Mixed Results
- Clinical trials of IFN administration have shown little to no benefit during acute coronavirus infection, despite IFN being very effective against coronavirus in laboratory tests.
- No beneficial effects were observed in hospitalized patients with COVID-19 with either IFNβ-1a or combined treatment with IFNβ-1a and remdesivir. Combining IFNβ-1a and remdesivir resulted in worse outcomes than remdesivir alone.
- In patients with moderate COVID-19, pegylated IFN-α2b, on the other hand, accelerated the clearance time of the virus.
- Pegylated IFN-λ reduced the risk of COVID-19-related hospitalizations by 50% and reduced the number of emergency room visits in people at high risk for severe COVID-19.
Modified IFN-α2 is a Potential New Treatment for COVID-19
During treatment that affects the IFN system, it is essential to determine the optimal balance of stimulation of the antiviral response while avoiding excessive inflammation and supporting tissue repair.
Modified IFNα2 (IFNmod) could be a new treatment for COVID-19. yIFNmod binds to the IFNAR2 receptor but much worse to the IFNAR1 receptor, reducing the signaling of all forms of endogenous IFN-I. Studies on cancer cells showed that IFNmod weakly stimulates antiviral genes and does not stimulate inflammatory ones. Moreover, studies in rhesus monkeys infected with immunodeficiency virus showed that IFNmod limits the expression of both antiviral and pro-inflammatory ISGs.
When infected with coronavirus, rhesus monkeys develop a mild to moderate disease that can progress to severe illness. After infection with coronavirus, macaques show a rapid and sustained IFN-I response, with numerous ISGs activated as early as one day after infection.
American scientists investigated how IFNmod affects ISG, replication, and pathology of coronavirus in rhesus monkeys.
IFNmod reduces the Viral Load in the Airways
The scientists administered IFNmod to uninfected rhesus monkeys at 1 mg/day intramuscularly for four consecutive days. After the introduction of IFNmod, ISG moderately increased both in the blood and the bronchi, but the signaling and inflammatory genes of IL-6 remained unchanged. The administration of IFNmod to uninfected macaques did not affect signaling molecules associated with inflammation and recruitment of inflammatory cells—the levels of IL-1β, IL-6, IL-8, IL-12p40, TNFβ, IFNγ, MIP1α, and MIP1β remained the same.
Upon stimulation with IFNα, IFNmod suppressed the expression of both antiviral ISG (ISG15, OAS1) and the pro-inflammatory chemokine CXCL10.
Conclusion. Without endogenous IFNα, IFNmod stimulates a weak IFN-I antiviral response. However, when IFNα is added, IFNmod inhibits both the antiviral and pro-inflammatory properties of IFN-I.
Next, the scientists experimented on cells treated with IFNmod and then infected with a coronavirus. IFNmod inhibited coronavirus replication in a dose-dependent manner. The viral RNA copy number was reduced by up to 80% at the highest dose tested.
The scientists then administered IFNmod to rhesus monkeys at a dose of 1 mg/day intramuscularly for four days: the day before infection with coronavirus, on the day of infection, and within two days after infection. Most animals showed no clinical signs of the disease. IFNmod was well tolerated, with no signs of clinical pathology or adverse effects on the kidneys and liver. The introduction of IFNmod within two days after infection dramatically reduced the level of viral load:
- in bronchial samples – more than 3000 times;
- in nasal swabs – more than 1500 times;
- in throat swabs – 12 times on the first day and 570 times on the second.
After the cessation of IFNmod administration, the viral load remained stable until seven days post-challenge.
Conclusion. IFNmod treatment rapidly and drastically reduced the viral load in the respiratory tract of rhesus monkeys infected with the coronavirus.
IFNmod Reduces Lung Pathology and Reduces Inflammation Markers in Coronavirus
Macaques treated with IFNmod had 1,500 and 500 times lower viral loads in the upper and lower lung segments, respectively, two days after being infected with coronavirus, compared to untreated macaques.
Both untreated and IFNmod-treated macaques showed no lung pathology two days after infection. However, 4 and 7 days after infection, the pathology appeared much more extraordinary in untreated macaques. The total score of lung pathology in IFN-mod and untreated monkeys was 3.8 and 10.0, respectively. The average lung pathology score per share in the IFNmod and untreated group is 1.2 and 2.5.
A key feature of COVID-19 is the production of multiple inflammatory mediators and the recruitment of inflammatory cells to the site of infection. In untreated macaques, 2 days after infection with coronavirus, the level of inflammatory signaling molecules in bronchial samples was significantly increased. The same signaling molecules remained at normal levels in the IFNmod-treated monkeys. Inflammatory mediators in the IFNmod and untreated group, respectively:
- IL-1β: 0.81 vs 8.1;
- IL-6: 2.92 vs 196.9;
- TNFβ: 0.99 vs 1.77;
- IFNγ: 0.86 vs 2.15.
IFNmod Lowers Inflammatory Monocyte Levels and Downregulates SIGLEC-1 Expression
Increased levels of inflammatory monocytes in the blood of patients with severe COVID-19. In macaques infected with coronavirus, the percentage of inflammatory monocytes from total blood monocytes rose from 11% to 31% two days after infection. However, in monkeys treated with IFNmod, the rate of inflammatory monocytes increased from only 14% to 18%. This difference between the IFNmod and untreated groups persisted until four days post-challenge, when untreated monkeys had 19% inflammatory monocytes and 10% in the IFNmod group. Thus, IFNmod reduced the likelihood of systemic and lower respiratory tract inflammation.
The interferon-sensitive protein SIGLEC-1 is on the monocyte membrane and functions as a coronavirus attachment receptor. Activation of SIGLEC-1 on human blood monocytes is an early marker of coronavirus infection and severe disease. Intense and rapid activation of SIGLEC-1 on blood monocytes was observed in untreated macaques infected with coronavirus. Two days after the coronavirus infection, the percentage of monocytes expressing SIGLEC-1 increased from 0.5 to 91.7%. SIGLEC-1 expression was significantly lower in IFNmod-treated monkeys, 80.6%. Thus, IFNmod attenuated antiviral and pro-inflammatory ISGs.
IFNmod Reduces Systemic and Lower Airway Inflammation
The coronavirus caused the activation of genes associated with the response to heat stress and programmed cell death in lung cells of untreated macaques. In contrast, in the IFNmod group, the activation of these genes was attenuated.
IFNmod almost completely suppressed inflammation during acute coronavirus infection, significantly reducing the recruitment and activation of myeloid cells and neutrophils in the lower airways. IFNmod effectively inhibited the IFN-I system in the lower airways.
IFNmod Protects Lung Cells from Death
The coronavirus caused the activation of genes associated with the response to heat stress and programmed cell death in lung cells of untreated macaques. In contrast, in the IFNmod group, the activation of these genes was attenuated.
Conclusion
Modified IFNα2 can bind to the interferon receptor IFNAR2 but binds to IFNAR1 much less, leading to receptor occupancy and blocking the binding and signaling of all forms of endogenous IFN-I produced in response to a viral infection.
In rhesus monkeys, the coronavirus causes a strong IFN-I response, leading to inflammation and lung damage. The introduction of IFNmod markedly reduces the viral load in the upper and lower respiratory tract, inflammation, and lung pathology. Thus, IFNmod suppresses both coronavirus replication and coronavirus-induced inflammation.
Administration of IFNmod before coronavirus infection results in subtle activation of antiviral ISGs while significantly attenuating endogenous IFN-I signaling and protecting against IFN-I-related immunopathology during coronavirus infection.
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