SARS-CoV-2 and the host-immune response

Abstract

The SARS-CoV-2 pandemic and the COVID-19 disease have affected everyone globally, leading to one of recorded history's most significant research surges. As our knowledge evolves, our approaches to the virus and treatments must also evolve. The evaluation of future research approaches to SARS-CoV-2 will necessitate reviewing the host immune response and viral antagonism of that response. This review provides an overview of the current knowledge on SARS-CoV-2 by summarizing the virus and human response. The focuses are on the viral genome, replication cycle, host immune activation, response, signaling, and antagonism. To effectively fight the pandemic, efforts must focus on the current state of research to help develop treatments and prepare for future outbreaks.

Keywords: COVID-19; adaptive immunity; immune response; innate immunity; viral immune evasion.

Figure 1

(A) Genomic Organization of SARS-CoV-2 and SARS-CoV-2 Viral Entry and Replication Cycle. This figure demonstrates the genome of SARS-CoV-2, a positive-sense RNA virus, and the proteins produced from each genome segment. The 29.903 kilobase genome was first identified in Wuhan, China, in December 2019. From 5’ to 3’, the genome is organized as 5’-cap structure, 5’ UTR, ORF1ab, spike (S), ORF3a-d, envelope (E), membrane (M), ORF6, ORF7a-b, ORF8, ORF9b-c, nucleocapsid (N), ORF10, 3’ UTR, and 3’-poly-A tail. Nsps 1-16 are translated from ORF1ab. Structural and accessory proteins are translated from their corresponding segment. Nucleotide annotations acquired from GenBank Accession NC_045512. (B) This figure represents the overview of SARS-CoV-2 viral entry and the replication cycle. aSARS-CoV-2 entry begins after binding the S protein S1 domain to the ACE2. The S1/S2 site on the S protein will then be cleaved by TMPRSS2, resulting in the removal of S1. bFollowing, the S2’ site is cleaved by TMPRSS2, furin, and cathepsins, priming the S protein by allowing S2 to form a pre-hairpin in the cellular membrane. cThe pre-hairpin forms a six-hairpin bundle that pulls the viral membrane and cellular membranes together, fusing them and allowing the viral RNA to release into the cytosol. dUpon release into the cytosol, translation of the viral RNA will begin to be translated. eThe non-structural proteins (nsps) polyproteins pp1a and pp1ab will be translated from ORF1ab. Autoproteolysis and post-translational processing will form the replication transcription complex (RTC) and the RNA-dependent-RNA-polymerase (RdRp) within the endoplasmic reticulum (ER). fWithin the ER, in specialized double-membrane vesicles (DMV), the RTC will synthesize the complementary negative-strand genomes and negative-strand subgenomic RNAs. gThe negative strands will serve as the template for progeny genomes and subgenomic RNAs. hThe subgenomic RNAs are translated as structural and accessory proteins. The structural proteins S, E, and M are translated into the ER membrane and the N into the cytoplasm to encapsulate the viral genome. iThe N-coated viral genome will bud into the ERGIC complex containing S, E, and M proteins. jThe virion will be budded into a vesicle bound to the cellular membrane. kThe vesicle will fuse with the cellular membrane, and exocytosis will release the fully-formed virus into extracellular space.

Figure 2

Host Immune Response to SARS-CoV-2 Infection. SARS-CoV-2 activates and antagonizes several arms of the immune response to infection. In total, SARS-CoV-2 will activate and proliferate an immune response (red arrows) through cellular damage (dysfunctional mitochondria), single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), cytosolic DNA, open-reading frame 8 (ORF8), the envelope (E) protein, the spike (S) glycoprotein, and the nucleocapsid (N) protein (shown in red). These parts of the virus initiate the response to induce the production of type I interferons (IFN), type III IFN, and inflammasomes (red lines). These cytokine responses will act in autocrine and paracrine manners to activate IFN receptors (IFNAR, IFNLR) to induce interferon-stimulated genes (ISGs), interferon regulatory factor 1 (IRF1), and NOD-like receptor family CARD domain-containing five (NLRC5) (black lines). IRF1 and NLRC5 induce major histocompatibility complex (MHC) class I expression. ISGs will inhibit viral replication as well as activate RNase L, which will cleave all cellular and viral ssRNA and induce cell death (black lines). The cytokine responses will also recruit dendritic cells, CD8+ killer T cells, and initiate the adaptive immune response. The adaptive immune response to SARS-CoV-2 includes CD8+ T cells, CD4+ T cells, and B cells (plasma cells) to produce antibodies. At least 26 SARS-CoV-2 proteins (shown in blue with blue lines) antagonize some part of the immune response.