Depletion and Dysfunction of Dendritic Cells: Understanding SARS-CoV-2 Infection

Abstract

Uncontrolled severe acute respiratory syndrome-coronavirus (SARS-CoV)-2 infection is closely related to disorders of the innate immune and delayed adaptive immune systems. Dendritic cells (DCs) "bridge" innate immunity and adaptive immunity. DCs have important roles in defending against SARS-CoV-2 infection. In this review, we summarize the latest research concerning the role of DCs in SARS-CoV-2 infection. We focus on the complex interplay between DCs and SARS-CoV-2: pyroptosis-induced activation; activation of the renin-angiotensin-aldosterone system; and activation of dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin. We also discuss the decline in DC number, the impaired antigen-presentation capability, and the reduced production of type-I interferon of DCs in severe SARS-CoV-2 infection. In addition, we discuss the potential mechanisms for pathological activation of DCs to understand the pattern of SARS-CoV-2 infection. Lastly, we provide a brief overview of novel vaccination and immunotherapy strategies based on DC targeting to overcome SARS-CoV-2 infection.

Keywords: COVID-19; SARS-CoV-2; dendritic cells; immunopathogenesis; severe acute respiratory syndrome coronavirus 2.

Figure 1

Interaction between SARS-CoV-2 and DCs (schematic). The three pathways affected by SARS-CoV-2 are pyroptosis (black lines), imbalanced RAAS (blue lines), and DC-SIGN (red lines). The adaptive immune system is induced by pyroptosis, which is activated by SARS-CoV-2. In addition, SARS-CoV-2 combines with the ACE2 receptor through its spike protein (S), which is activated by TMPRSS2. This process causes an imbalance in the RAAS through the shedding of ACE2 and releases excessive amounts of aldosterone, which promotes the release of proinflammatory cytokines in DCs through MRs. SARS-CoV-2 impacts DCs directly by DC-SIGN, a receptor which has critical roles in the recognition of viruses (e.g., HIV, Ebola, dengue, cytomegalovirus) and other pathogens (e.g., Leishmania species, Candida albicans, Mycobacterium tuberculosis, Streptococcus pneumoniae, Aspergillus fumigatus). Although SARS-CoV-2 replication in lung cells is well-documented, a similar process has not been confirmed in alveolar DCs. Some researchers have suggested such a replication based on triggering aberrant production of proinflammatory cytokines/chemokines and inducing the spread of SARS-CoV-2 infection, as is the case with SARS-CoV and MERS-CoV, but other scholars have ruled out SARS-CoV replication in human DCs. RAAS, renin–angiotensin–aldosterone system; DCs, dendritic cells; TMPRSS2, transmembrane serine protease 2; MRs, mineralocorticoid receptors; DC-SIGN, dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin.

Figure 2

Multiple suppressive mechanisms in SARS-CoV-2-infected DCs from patients with severe COVID-19. The number of DCs in patients decreases after SARS-CoV-2 infection. Increased apoptosis, alterations in distribution of DCs, and inhibition of MDSCs may be associated with a decrease in DC number. IFN-I secretion is inhibited by various viral proteins that have been shown to be effective against IFN-I signaling in SARS-CoV infection (104). In addition to the effects of viral proteins, anti-IFN antibody and reduced expression of TLR7 have been observed in some patients with severe COVID-19. The capability of antigen presentation is impaired in cDC1 and cDC2. Inhibition of the mTOR signaling pathway, activated DC-SIGN pathway, and activated Wnt5 pathway could contribute to downregulation of MHC-II and co-stimulatory molecules. IFN, interferon; IFNAR, interferon alpha and beta receptor; mTOR, mammalian target of rapamycin; IκB, inhibitor of nuclear factor κB; IRF, IFN regulatory factor; ISG, IFN-stimulated gene; JAK, Janus kinase; IKKϵ, IκB kinase-ϵ; M, membrane; MAVs, mitochondrial antiviral signaling proteins; N, nucleocapsid; Nsp, non-structural protein; ORF, open reading frame; P, phosphate; DC-SIGN, dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin; PLP, papain-like protease; RIG-I, retinoic acid-inducible gene-I; MDA5, melanoma differentiation-associated gene 5; SARS-CoV-2, severe acute respiratory syndrome-coronavirus 2; TANK, TRAF family member-associated NF-κB activator; TBK1, TANK-binding kinase 1; TRAF3, tumor necrosis factor receptor-associated factor 3; STAT, signal transducer and activator of transcription; TYK2, tyrosine kinase 2; Wnt5, Wnt oncogene analog 5.