Dendritic Cells and SARS-CoV-2 Infection: Still an Unclarified Connection

Abstract

The ongoing pandemic due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has so far infected about 2.42 × 10⁷ (as at 27 August 2020) subjects with more than 820,000 deaths. It is the third zoonotic coronavirus-dependent outbreak in the last twenty years and represents a major infective threat for public health worldwide. A main aspect of the infection, in analogy to other viral infections, is the so-called "cytokine storm", an inappropriate molecular response to virus spread which plays major roles in tissue and organ damage. Immunological therapies, including vaccines and humanized monoclonal antibodies, have been proposed as major strategies for prevention and treatment of the disease. Accordingly, a detailed mechanistic knowledge of the molecular events with which the virus infects cells and induces an immunological response appears necessary. In this review, we will report details of the initial process of SARS-CoV-2 cellular entry with major emphasis on the maturation of the spike protein. Then, a particular focus will be devoted to describe the possible mechanisms by which dendritic cells, a major cellular component of innate and adaptive immune responses, may play a role in the spread of the virus in the human body and in the clinical evolution of the disease.

Keywords: Covid-19; DC-SIGN; SARS-CoV-2; dendritic cells; spike protein.

Figure 1

Domain organization and cleavage sequences of SARS-CoV-2 spike glycoprotein. (A) The domains of the protein are as the follows. S1 Domain: NTD (N-terminal domain), RBD (receptor binding domain), SD1 and SD2 (subdomain 1 and subdomain 2). S2 Domain: FL (fusion loop), HR1 (heptad repeat 1), CH (central helix), CD (connector domain), HR2 (heptad repeat 2), TM (trans-membrane domain), CP (cytoplasmic tail). The panel also reports the position of the residues at both the ends of the individual segments. (B) Consensus sequences for S1/S2 and S2′ cleavage sites. A comparison among SARS-CoV-2, SARS-CoV, MERS-CoV, Pangolin-CoV, and Bat-CoV is also reported. Red color highlights the polybasic sequence of SARS-CoV-2 and MERS-CoV (see text for details).

Figure 2

Scheme summarizing the possible involvement of dendritic cells in SARS-CoV-2 infection. Pneumocytes are infected by SARS-CoV-2 and, after pyroptosis, release viruses, PAMP (pathogen-associated molecular patterns) and DAMPS (damage-associated molecular patterns). PAMPs and DAMPs might activate dendritic cells. Moreover, DC-SIGN (localized on dendritic cells) might recognize and bind the virus. Then, dendritic cells might move toward lymph nodes. Locally, dendritic cells might affect different populations of T-lymphocytes. SARS-CoV-2 might also increase, through RAAS (renin-angiotensin-aldosterone system), the production of aldosterone (ALDO) that is intracellularly recognized by its receptor (MR) (see the text for more mechanistic details). In turn, this results in an activation of dendritic cells and macrophages. Aldosterone could also affect coagulation enhancing microthrombosis. SARS-CoV-2 also infects endothelial cells, causing hypercoagulation and affecting dendritic cells. The image also shows the cytokine storms that are due to the activation of a plethora of cells, including those of innate immunity response. In the inset, aldosterone stimulation of endothelial cells NADPH oxidases with a concomitant ROS production is shown. ROS might be also involved in the hyperinflammation condition.

Figure 3

Scheme showing the putative dendritic cells involvement in SARS-CoV-2 entry through nasal epithelial cells. The entry of SARS-CoV-2 through epithelial cells is followed by pyroptosis and activation of dendritic cells in a manner similar with that reported in Figure 2. Particularly, the interaction between DC-SIGN and the virus is shown. The binding (and DAMP and PAMP interaction that is not shown) could cause the virus to spread from the nasal epithelial cells to the rest of human body.