Interferon deficiency as a hallmark of COVID-19
Researchers have found that critical and severe COVID-19 patients have a highly impaired interferon response, which encourages a persistent blood viral load and heightened inflammatory response. This phenotype is now said to be associated with a poor prognosis.
COVID-19 is a hard nut to crack. Characterised by multiple, distinct patterns of disease progression, each person who encounters the virus is likely to react differently to the previous patient. Whilst we know that age and pre-existing conditions influence the likelihood of developing symptoms, researchers are still trying to establish the cause of a more severe response at a cellular level.
The body’s response to a viral infection trigger the production of proteins known as ‘interferons’. These proteins stimulate internal and external cellular networks which regulate innate and acquired immune responses and demonstrate antitumour properties. The networks rely on the stimulation of genes which engage in different anti-viral functions depending on the type of interferon which induced its expression.
There are two main types of interferon – Type I and Type II. They act on similar receptors but produce distinct effects. Type I interferons are expressed in multiple cell types and can induce damaging proinflammatory responses if not regulated properly. Type II interferons are found mainly on mucosal surfaces and are unlikely to result in immunopathology.
Early clinical descriptions of COVID-19 infections suggested a two-step disease progression, starting with mild/moderate symptoms followed by a sudden respiratory worsening 9 to 12 days after the onset of symptoms. Researchers have found that patients with a severe COVID-19 infection have a dysregulated inflammatory response which leads to the accumulation of immune cells and fluid in the lung alveoli. This has the potential to lead to acute respiratory distress syndrome (ARDS) and subsequent death.
The cause of a dysregulated inflammatory response in severe COVID cases was investigated by a team of researchers in Paris who analysed the blood of patients to see the amount, type and state of activation of immune cells. They found that with disease progression, the state of activation of T cell and natural killer (NK) cells declined and there was a surge in apoptosis-related genes. This suggests that in severe and critical patients, there is a likelihood of lymphocytopenia resulting from exacerbated T cell death.
Next, they investigated the transcription level of immune-related genes in the white blood cells. They found that, in addition to increased T-cell apoptosis, there was a significant decrease in interferon-stimulated genes in patients with severe COVID compared to those with mild/moderate infections. Specifically, a low Type I interferon response was associated with clinical deterioration and poor prognosis due to an increased plasma viral load. This is a marker of uncontrolled lung infection.
The increased inflammation was accounted for by an increase in cytokine and chemokine-related genes with more severe disease progression. High levels of interleukin-6 protein and tumour necrosis factor-α (TNF-α) can lead to an increase in inflammation and was found in the blood of critical and severe patients. This increase in inflammatory response encourages the influx of innate immune cells into the lung tissue which can cause damage and scarring, exacerbating the effects of COVID-19.
This complex study identifies 3 key cellular effects which have the potential to explain why some patients experience a more severe response to COVID-19. The lack of interferon production and signalling, in addition to a persistent blood viral load, encourages the production of pro-inflammatory mediators which can damage lung tissue. It is important to note that it is not the virus itself which is causing lung injury, but the immune system dysregulation which occurs when the virus enters the body. Now that scientists have identified a decline in interferon production as an exacerbator COVID-19, they may be able to use exogenous interferons in the treatment of the disease.
Hadjadj, J. et al. (2020) Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science 369(6504), pp. 718-724. Available from: DOI: 10.1126/science.abc6027