SARS-CoV-2: A Glance at the Innate Immune Response Elicited by Infection and Vaccination

Abstract

The COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to almost seven million deaths worldwide. SARS-CoV-2 causes infection through respiratory transmission and can occur either without any symptoms or with clinical manifestations which can be mild, severe or, in some cases, even fatal. Innate immunity provides the initial defense against the virus by sensing pathogen-associated molecular patterns and triggering signaling pathways that activate the antiviral and inflammatory responses, which limit viral replication and help the identification and removal of infected cells. However, temporally dysregulated and excessive activation of the innate immune response is deleterious for the host and associates with severe COVID-19. In addition to its defensive role, innate immunity is pivotal in priming the adaptive immune response and polarizing its effector function. This capacity is relevant in the context of both SARS-CoV-2 natural infection and COVID-19 vaccination. Here, we provide an overview of the current knowledge of the innate immune responses to SARS-CoV-2 infection and vaccination.

Keywords: COVID-19; SARS-CoV-2; human immunology; immune response; innate immunity; vaccines.

Figure 1

Schematic representation of signaling pathways and immune responses induced by SARS-CoV-2 infection. Before entering the host cell, SARS-CoV-2 is detected on the cell surface by specific TLRs capable of recognizing the E and S proteins (namely TLR2/6 and TLR4). Following host cell entry, the SARS-CoV-2 virus is recognized by RNA sensors present in both the cytosol and endosomes (RLRs and TLRs). Intracellular TLRs can detect endosomal ssRNA (TLR7/8) or dsRNA (TLR3), while RIG-I and MDA5 play a role in sensing viral RNAs within the cytoplasm. Upon recognition, these sensors recruit the signal adapter molecules MyD88 and TRIF, inducing downstream signaling. This leads to the activation of NF-κB and IRF transcription factors and the production of pro-inflammatory cytokines (e.g., IL6 and TNF-α) and type I IFNs (IFN-α and IFN-β). Viral protein antigens are also processed and presented on MHCs to T cells in the presence of co-stimulatory molecules. Cytokines and chemokines released by infected cells modulate the cellular innate response, favoring the infiltration of monocytes and neutrophils. Activated dendritic cells, instead, present the antigens to CD4⁺ T cells, which secrete cytokines favoring the production of immunoglobulins by mature B cells, and CD8⁺ T cells that directly kill infected cells. (This figure was created with BioRender.com). RLRs: retinoic acid-inducible gene I (RIG-I)-like receptors; TLRs: oll-like receptors; NF-κB: Nuclear Factor kappa B; MAPKs: mitogen-activated protein kinases; IRFs: interferon regulatory factors; MDA5: melanoma differentiation-associated gene 5.

Figure 2

COVID-19 vaccines: processing by dendritic cells and innate immune response activation. Schematic representation of the mechanisms of action of the three major vaccine platforms against SARS-CoV-2: (1) mRNA-based vaccines, in which an mRNA molecule encoding for the SARS-CoV-2 S protein is encapsulated in lipid nanoparticles; (2) AdV vaccines, in which the SARS-CoV-2 S protein is encoded by a DNA molecule embedded in an AdV capsid; and (3) recombinant protein-based vaccines in which SARS-CoV-2 S proteins are assembled around nanoparticles to resemble the actual virus structure.