Correlation between Type I Interferon Associated Factors and COVID-19 Severity

Abstract

Antiviral type I interferons (IFN) produced in the early phase of viral infections effectively inhibit viral replication, prevent virus-mediated tissue damages and promote innate and adaptive immune responses that are all essential to the successful elimination of viruses. As professional type I IFN producing cells, plasmacytoid dendritic cells (pDC) have the ability to rapidly produce waste amounts of type I IFNs. Therefore, their low frequency, dysfunction or decreased capacity to produce type I IFNs might increase the risk of severe viral infections. In accordance with that, declined pDC numbers and delayed or inadequate type I IFN responses could be observed in patients with severe coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as compared to individuals with mild or no symptoms. Thus, besides chronic diseases, all those conditions, which negatively affect the antiviral IFN responses lengthen the list of risk factors for severe COVID-19. In the current review, we would like to briefly discuss the role and dysregulation of pDC/type I IFN axis in COVID-19, and introduce those type I IFN-dependent factors, which account for an increased risk of COVID-19 severity and thus are responsible for the different magnitude of individual immune responses to SARS-CoV-2.

Keywords: COVID-19; IFN signature; SARS-CoV-2; antiviral response; plasmacytoid dendritic cell 1; risk factor; type I interferon.

Figure 1

Beneficial effects of pDC-derived type I IFNs help to overcome SARS-CoV-2 infection. When the SARS-CoV-2 viruses break through the first line of defense ensured by the epithelial cells, viral particles or cell debris derived from virus-infected cells are delivered to the draining lymph nodes, where pDCs are stimulated to migrate to the entry site of the viruses. Here, the pDC-derived type I IFNs initiate an antiviral state in the host cells, which effectively blocks viral replication, and also promotes the activation and function of both innate and adaptive immune cells thereby creating an effective antiviral response. APRIL: A proliferation-inducing ligand; BAFF: B-cell activating factor; IL: interleukin; IDO: Indoleamine 2, 3-dioxygenase; IFN: interferon; NK: natural killer; pDC: plasmacytoid dendritic cell; TGF: Transforming Growth Factor; Th: T helper; Treg: T regulatory; CTL: cytotoxic T cell.

Figure 2

The inflammatory microenvironment in severe COVID-19 leads to the exhaustion and decreased antiviral potential of pDCs. The overactivation of immune cells in severe COVID-19 leads to an excessive production of pro-inflammatory cytokines and eventually cascades into a cytokine storm. This inflammatory environment drives pDC exhaustion that is characterized by high hypoxia and functional abnormalities of pDCs. However, the inflammatory environment has an inhibitory effect on the virus sensing ability and type I IFN production of pDCs, and their pro-inflammatory cytokine production comes to the fore that can further fuel the detrimental inflammatory circuit. The excessive inflammatory milieu also causes T cell exhaustion and leads to increased T cell death. Consequently, the levels of T cell-derived IL-3, which is an essential survival factor for pDCs, also drop and that leads to pDCs apoptosis. Thus, severe COVID-19 is associated with a reduced number of pDCs. G-CSF: granulocyte colony stimulating factor; GM-CSF: granulocyte-macrophage colony stimulating factor; IFN: interferon; IP: interferon gamma-induced protein, MCP: monocyte chemoattractant protein; pDC: plasmacytoid dendritic cell; TNF: tumor necrosis factor.

Figure 3

Type I IFN related risk factors in COVID-19. A low IFN signature predicts a more severe COVID-19 outcome. Thus, those conditions, which are associated with impaired type I IFN response or decreased pDC number may be risk factors for severe COVID-19. IFN: interferon; pDC: plasmacytoid dendritic cell, IRF: interferon regulatory factor; IFNAR: interferon-α/β receptor.