Could Antigen Presenting Cells Represent a Protective Element during SARS-CoV-2 Infection in Children?

Abstract

Antigen Presenting Cells (APC) are immune cells that recognize, process, and present antigens to lymphocytes. APCs are among the earliest immune responders against an antigen. Thus, in patients with COVID-19, a disease caused by the newly reported SARS-CoV-2 virus, the role of APCs becomes increasingly important. In this paper, we dissect the role of these cells in the fight against SARS-CoV-2. Interestingly, this virus appears to cause a higher mortality among adults than children. This may suggest that the immune system, particularly APCs, of children may be different from that of adults, which may then explain differences in immune responses between these two populations, evident as different pathological outcome. However, the underlying molecular mechanisms that differentiate juvenile from other APCs are not well understood. Whether juvenile APCs are one reason why children are less susceptible to SARS-CoV-2 requires much attention. The goal of this review is to examine the role of APCs, both in adults and children. The molecular mechanisms governing APCs, especially against SARS-CoV-2, may explain the differential immune responsiveness in the two populations.

Keywords: Antigen Presenting Cells (APC); COVID-19; IFN-signaling; SARS-CoV-2; cytokine storm; juvenile immunity.

Figure 1

Host cell entry mechanism of SARS-CoV-2. Angiotensin-converting Enzyme 2 (ACE2) and Transmembrane Protease/Serine subfamily 2 (TMRPSS2) are proteins in the host cell surface that are exploited by SARS-CoV-2 viral spike (S) protein for its entry. Once inside the host cell, the viral genome of SARS-CoV-2 is released, uncoated, and translated to form the viral replication and transcription complex. The SARS-CoV-2 structural proteins—namely, spike (S), envelope (E), and membrane (M)—are translocated to the Endoplasmic Reticulum (ER) and then to the Endoplasmic Reticulum-to-Golgi Intermediate Compartment (ERGIC), while the nucleocapsid (N) protein is released into the cytoplasm once translated and interacts with the newly produced genomic viral RNA. Passing through the ERGIC, S, E, and M proteins combine with the nucleocapsid, assembling a mature virion that is secreted from the cell via exocytosis.

Figure 2

SARS-CoV-2 and host interactions and viral evasion strategies. Pattern Recognition Receptors (PRRs), localized in the host cell membrane and cytoplasm, sense the viral RNA, triggering the Interferon (IFN) and NF-κB pathways that lead to the expression of type I IFN (IFN-α and IFN-β) and pro-inflammatory mediators, like the pro-inflammatory cytokines. However, several components of SARS-CoV-2 can interfere with these mechanisms: N and M proteins impairs the TLRs activation through the inhibition of the recruitment of TRIF to the TLR and the inhibition of the nuclear translocation of NF-κB. They also interfere with the IFN-signaling, along with several viral ORFs and Nsp3. This leads to the reduced expression of Interferon Stimulated Genes (ISGs). Nsp1, Nsp6, Nsp13, ORF7a, M proteins, ORF7b and ORF6 can also inhibit the IFN signaling interfering respectively with the activity of the transcription factor STAT1 and its nuclear translocation.

Figure 3

Schematic representation of the activity of Antigen Presenting Cells (APCs) infected with SARS-CoV-2. A macrophage (A), a Dendritic Cell (B) and a B cell (C) are represented, as well as the effects that SARS-CoV-2 induces in their activity. (A) In Macrophages, the entry of SARS-CoV-2 can also be mediated DC-specific intercellular adhesion molecule 3-grabbing-non-integrin (DC-SIGN) or Liver/Lymph node-specific intercellular adhesion molecule 3-grabbing integrin (L-SIGN). The viral ORF6 inactivates the transcription factor IRF3, suppressing IFN-mediated responses and inducing an altered secretion of pro-inflammatory mediators. This results in an excessive release of chemokines, which attracts pro-inflammatory cells and other monocytes, also promoting other cells infection. Nsp5, instead, acts against an epigenetic regulator which regulates the expression of Major Histocompatibility Complexes II (MHC II), limiting antigen presentation. Moreover, the ORF8 induces pyroptosis through the activation of the inflammasome. (B) In Dendritic Cells, the inhibition of the activity of STAT1 reduces the expression of ISGs and increases the expression of the chemokine IP-10. This leads to the recruitment of inflammatory cells, and also alters their capacity to activate T cells. (C) B cells release proteins against N and S proteins.