Plasmacytoid dendritic cells during COVID-19: Ally or adversary?

Abstract

Plasmacytoid dendritic cells (pDCs) are specialized cells of the immune system that are thought to be the main cellular source of type I interferon alpha (IFNα) in response to viral infections. IFNs are powerful antivirals, whereas defects in their function or induction lead to impaired resistance to virus infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. IFN production needs to be controlled, because sustained IFN production can also have detrimental effects on disease outcome. As such, pDCs are likely important for acute antiviral protection against SARS-CoV-2 infection but could potentially also contribute to chronic IFN levels. Here, we provide a historical overview of pDC biology and summarize existing literature addressing their involvement and importance during viral infections of the airways. Furthermore, we outline recent reports focused on the potential role of pDCs during SARS-CoV-2 infection, as well as the potential for this cellular subset to impact COVID-19 disease outcome.

Keywords: COVID-19; CP: Immunology; CP: Microbiology; SARS-CoV-2; antiviral responses; inflammation; plasmacytoid dendritic cells.

Figure 1

Sensing of SARS-CoV-2 SARS-CoV-2 genomic RNA can be sensed by different RNA-driven pattern recognition receptors. Which RNA sensor is activated is determined by the mechanisms of viral entry: membrane fusion (indicated for the epithelial cell on the left) or viral particle uptake (indicated for the pDC on the right). Fusion of the SARS-CoV-2 membrane with the cellular membrane of epithelial cells requires the cellular receptors ACE2, TMRPSS2, and in some cases, NRP1/CD304. This allows the viral RNA to be detected by cytosolic RNA sensors RIG-I/MDA5, which will activate transcription factors IRF3 and nuclear factor κB (NF-κB), leading to production of type I IFNα, type III IFNλ1, and various pro-inflammatory cytokines and chemokines. SARS-CoV-2 utilizes several mechanisms to counter sensing via the RIG-I/MDA5 pathway and subsequent IFN production, which is reviewed in detail elsewhere (Min et al., 2021). Uptake of viral particles, for example, by endocytosis, does not require the receptors that mediate fusion of the viral and cellular membranes. Instead, the virus is engulfed into a cellular vesicle, where it triggers TLR7, starting a signaling cascade that includes MyD88 and IRAK4, ultimately activating the transcription factors IRF7 and NF-κB that will facilitate production of type I IFNα, type III IFNλ1, CXCL10, and other cytokines and chemokines. The interaction of SARS-CoV-2 with NRP1/CD304 can inhibit IFNα production by pDCs, but the molecular mechanisms are currently unknown. pDCs can also sense SARS-CoV-2’s glycosylated envelope protein via TLR2, and this leads specifically to IL-6 production in pDCs. Figure was created with BioRender.com.

Figure 2

Fate of pDCs during COVID-19 and the pDC desert phenomenon During a mild/moderate infection with SARS-CoV-2 (blue panel), the early acute phase of viral infection is characterized by the decline of pDCs from peripheral blood (orange/yellow line), as they migrate to the lungs (green line) to aid in the respiratory tract’s antiviral mechanisms to inhibit virus replication and reduce viral loads (red line). After mounting adaptive immunity and antibody production (blue line), the virus will be cleared and the recovery phase begins. This includes disappearance of pDCs from the lungs, by unknown mechanisms, and increased peripheral numbers facilitated by replenishment from the bone marrow. With a severe SARS-CoV-2 infection (red panel), pDC numbers decline in peripheral blood to lower levels, as compared with a mild/moderate infection. At the same time, pDCs seem to be absent from the lungs (green dotted line). During this time of severe disease, pDC numbers remain low, akin to a “pDC desert” (gray rectangle), until the recovery phase begins and peripheral pDC numbers increase. Figure was created with BioRender.com.