In a recent study published in the Research Square * prepress server, researchers found that impaired interferon type I (IFN-I) immunity is associated with an increase in the severity of coronavirus disease 2019 (COVID-19). ).
Study: Defective immunity with type I interferon is associated with increased severity of COVID-19. Image credit: Terelyuk / Shutterstock
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The response to coronavirus 2 (SARS-CoV-2) infection of severe acute respiratory syndrome is highly variable, leading to a variety of clinical outcomes, ranging from asymptomatic infection to severe disease and even death. A better understanding of this heterogeneity in responses to IFN-based COVID-19 treatment could help identify alternative therapeutic strategies.
Studies have shown that while blood type I interferon (IFN-I) responses are critical in early acute infection, they deteriorate before the clinical worsening of COVID-19. Therefore, researchers have observed a dichotomous clinical response to IFN-I-based treatments in the late stage of COVID-19.
Based on these observations, studies have also identified mutations in the genetic loci that govern IFN-I immunity depending on interferon regulatory factor (IRF) 3 and toll-like receptor (TLR). Similarly, autoantibodies to IFNα, IFNω, or IFNβ and the TLR7 pathway are critical for conferring early immunity to SARS-CoV-2 infection. However, treatment with exogenous IFN-I does not improve the clinical outcomes of COVID-19.
Here, it is also important to consider the importance of deploying sensitive immunoassays when studying type I IFNs directly from patient samples. As is well known, IFNα protein levels remain below the detection limits of conventional enzyme-linked enzyme-linked immunosorbent assays (ELISA) and Luminex. More importantly, plasma IFN levels at the time of patient sampling do not represent how patients’ cells respond to viral exposure.
About the study
In the current study, researchers enrolled healthy controls and participants infected with SARS-CoV-2 at St. John’s Hospital. James of Dublin, Ireland, March-June 2020. The control group consisted of 61 healthy individuals who matched the study cohort in age, ± 5 years. years.
At the time of enrollment, the team assigned all study participants degrees of disease severity based on hospital admission and supplemental oxygen requirements. Patients who did not require hospitalization were classified as moderately ill, while those hospitalized and those who received supplemental oxygen through a nasal cannula were considered severe. Those classified as critical required more than six liters of oxygen per minute, delivered by high-flow nasal oxygen or a venturi mask.
The team characterized the 13 subtypes of IFN-alpha, especially IFNα2 proteins by highly sensitive assays, IFN function, interferon-stimulated genes (ISG), and autoantibodies that neutralize IFN-I. The researchers also selected a subset of patients and stimulated their whole blood samples with relevant viral antagonists to better assess the functionality of their immune system to external stimuli. They also obtained plasma samples of 342 and 212 for cytokine and autoantibody analysis, respectively. In addition, they used plasma samples from a small subset of 31 patients for cell phenotyping.
Study results
The authors observed multiple alterations in the response to IFN-I with increasing severity of COVID-19. Late stimulation with exogenous IFN-I did not benefit patients; in addition, it compromised any apparent clinical benefit of viral agonists. In particular, IFNβ secretion was more altered than IFNα, which was not expected due to its low levels in the patient’s plasma. This finding further indicated the challenges in accurately detecting and quantifying IFNβ in the blood.
The Gyros trial identified four male patients as positive anti-IFNα autoantibodies in the hospitalized group, with two moderately ill patients, one severely and one critically ill. Because most patients remained negative for anti-IFN autoantibodies, this factor could not have caused serious illness in patients.
The authors also observed that stimulation of whole blood from COVID-19 patients hospitalized with IFN-I ex vivo induced a non-canonical inflammatory response. In addition, whole-blood TLR gene expression data revealed similar TLR7 expression in all groups, lower TLR3 expression, and higher TLR4 and TLR8 expression in hospitalized patients. In addition, the authors found eight additional cytokines with significant differences in hospitalized patients, mainly after TLR3 stimulation.
The IFN-I response to stimuli, including polyinosinic: polydithymitic acid (Poly: IC), lipopolysaccharide (LPS), and R848 (a TLR7 / 8 agonist) was altered in critically ill patients. In fact, Poly: IC stimulation significantly reduced the IFNβ response in moderate to severe disease groups, but decreased after R848 and LPS stimulation in hospitalized groups.
The attenuation of broad IFN responses in severe patients with COVID-19 is not yet explained. Studies have shown that this phenotype is not attributable to the interference of SARS-CoV-2 with host immunity. Consequently, with increasing severity, pDCs continued to be able to produce IFNα intracellularly. Future work should investigate the functionality of intracellular pathways in cells isolated from severe patients with COVID-19. It could help to better understand this phenotype and provide goals for new treatment strategies.
Conclusions
The study highlighted the critical role of IFN-I-mediated immunity in dictating COVID-19 results. Other studies have implicated IFNβ in long-term COVID-19, emphasizing the need to understand the regulation of IFN-I during SARS-CoV-2 infection.
The current study also identified two main reasons for an impaired IFN-I response in severe COVID-19. They showed a decrease in circulating plasmacytoid dendritic cells (pDC) and deregulated monocytes that secreted less IFNα. Second, leukocyte stimulation with IFN-I promoted an inflammatory response in severe patients with COVID-19, but not in moderately ill patients.
In addition, physiological concentrations of IFNα proteins are usually below pg / mL levels. The results of the study, therefore, highlighted the importance of using sensitive assays to measure circulating IFNα levels in severe patients with COVID-19. The authors also observed differences in plasma IFNα2 protein levels among moderately and severely ill patients with COVID-19.
As new experimental tools become available, they will help researchers fully understand the functions of the 13 IFNα subtypes in patients with COVID-19, which may also be relevant to other viral infections. Most importantly, clinical studies should test IFN-I intervention strategies early, that is, before the symptoms of the disease appear, and target them to patients with known risk factors.
* Important news
Research Square publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guided by clinical practice or health-related behavior, or treated as established information.