Human Coronaviruses: A Review of Virus-Host Interactions

Abstract

Human coronaviruses (HCoVs) are known respiratory pathogens associated with a range of respiratory outcomes. In the past 14 years, the onset of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) have thrust HCoVs into spotlight of the research community due to their high pathogenicity in humans. The study of HCoV-host interactions has contributed extensively to our understanding of HCoV pathogenesis. In this review, we discuss some of the recent findings of host cell factors that might be exploited by HCoVs to facilitate their own replication cycle. We also discuss various cellular processes, such as apoptosis, innate immunity, ER stress response, mitogen-activated protein kinase (MAPK) pathway and nuclear factor kappa B (NF-κB) pathway that may be modulated by HCoVs.

Keywords: ER stress; MAPK; NF-κB; apoptosis; human coronavirus; innate immunity; virus–host interactions.

Figure 1

Genome organisation of human coronaviruses (HCoVs). HCoV genomes range from about 26 to 32 kilobases (kb) in size, as indicated by the black lines above the scale. Coronavirus (CoV) genome is typically arranged in the order of 5′-ORF1a-ORF1b-S-E-M-N-3′. The overlapping open reading frames (ORF) ORF1a and ORF1b comprise two-thirds of the coronavirus genome, which encodes for all the viral components required for viral RNA synthesis. The other one-third of the genome at the 3′ end encodes for a set of structural (orange) and non-structural proteins (green).

Figure 2

Coronavirus replication cycle. Coronavirus infection begins with the attachment of the S1 domain of the spike protein (S) with its cognate receptor. This drives the conformational change in the S2 subunit in S, promoting the fusion of the viral and cell plasma membrane. Following the release of the nucleocapsid to the cytoplasm, the viral gRNA is translated through ribosomal frameshifting to produce polyproteins pp1a and pp1ab. pp1a and pp1ab are autoproteolytically processed by host and viral proteases to generate 16 non-structural proteins (NSPs), which will then be assembled to form the replicase-polymerase. The replicase-polymerase is involved in the coronaviral replication, a process in which the genomic RNA are replicated and the subgenomic RNA will be transcribed and translated to form the structural proteins. The viral products produced will be assembled in the ERGIC, and bud out as a smooth-wall vesicle to the plasma membrane to egress via exocytosis. Host factors that promote infection and inhibit infection are highlighted in green and red, respectively. APN, aminopeptidase N; ACE2, Angiotensin converting enzyme 2; DPP4, dipeptidyl peptidase 4; 9-O-Ac Sialic Acid, 9-O-Acetylated Sialic Acid; IFITM, Interferon induced transmembrane protein; ATP1A1, ATPase, Na⁺/K⁺ Transporting, Alpha 1 Polypeptide; HnRNP A1, Heterogeneous nuclear ribonucleoprotein A1; MADP1, Zinc Finger CCHC-Type and RNA Binding Motif 1; DDX1, ATP-dependent RNA Helicase; PCBP1/2, Poly r(C) binding protein 1/2; PABP, Poly A binding protein; COPB2, Coatomer protein complex, subunit beta 2 (beta prime); GAPDH, Glyceraldehyde 3-phosphate dehydrogenase; ERGIC, Endoplasmic reticulum Golgi intermediate compartment; ER, endoplasmic reticulum; VCP, Valosin-Containing Protein.

Figure 3

Regulation of MOMP by Bcl2 family of proteins. (a) The Bcl2 family of proteins is categorized into three main classes according to their functions and number of Bcl2 homology (BH) domains. The pro-survival Bcl2-like family members (Bcl2, B-cell lymphoma-extra-large (Bcl-XL), myeloid cell leukemia (Mcl1)) contain all four BH domains and are anti-apoptotic. A second class, known as Bcl2-associated X (BAX)-like proteins, which includes BAX and Bcl2 homologous antagonist killer (BAK), is pro-apoptotic and lacks the BH4 domain. Finally, the third class, known as BH3-only proteins (Bid, Bcl2-associated death promoter (Bad), and p53-upregulated modulator of apoptosis (PUMA)), contain only BH3 domain and is pro-apoptotic. (b) Two models have been proposed to account for the role of the Bcl2 family proteins in MOMP—the indirect activator model and direct activator–depressor model [11]. In the indirect activator model, the anti-apoptotic Bcl2-like proteins suppress the insertion of Bax-Bak pore complex into the mitochondria to promote MOMP and release of cytochrome c. However, when BH3-only proteins are activated beyond a certain threshold, the inhibitory effects of Bcl2-like proteins can be subverted. In the direct activator–depressor model, BH3-only protein acts as direct activators to induce Bak-Bak insertion into the outer mitochondrial membrane. These BH3-only proteins can be suppressed by Bcl2-like protein, which can in turn be inhibited by another subset of BH3-only proteins. This figure is modified from [12].

Figure 4

Activation of apoptosis by HCoVs. Binding of death ligands to death receptor induces caspase 8 activation, which in turn activates effector caspases 3 and 7 to stimulate apoptosis. On the other hand, intrinsic pathway is regulated by pro-apoptotic and anti-apoptotic Bcl2 family proteins, such as Bcl-XL, Bcl2, Bax and Bak to induce MOMP. Subsequent caspase 9 activation caused by enhanced MOMP stimulates caspases 3 and 7 activation. During HCoV infection, the virus or specific viral proteins (yellow-orange boxes) target at multiple stages of both the extrinsic and intrinsic apoptosis signalling pathways.

Figure 5

HCoV viral proteins on innate immunity. During HCoV infection, PRRs such as TLRs, RIG-I and MDA5 are activated to trigger a series of signalling pathway, including MAPK and NF-κB, for IFN production. These IFNs then act on IFNAR and activate the JAK-STAT signalling pathway to induce ISGs. The yellow-orange boxes show the viral proteins that have been reported to modulate host innate immunity at multiple stages.

Figure 6

HCoVs on ER stress response. During HCoV infections, the ER stress response, which comprises of three signalling pathways, PERK, ATF6 and IRE1, is activated. HCoVs encode many viral proteins (yellow-orange boxes) that target the various signalling pathway of ER stress during viral infections.

Figure 7

HCoVs on MAPK signalling pathways. MAPK pathways comprises of the ERK, JNK and p38 MAPK pathways. During HCoV infections, the signals are transduced by the MAPK pathways by a three-tier protein kinase cascade, with the kinase of each tier being phosphorylated by upstream kinases at the Thr and Tyr residues. HCoVs and their viral proteins (yellow-orange boxes) have been shown to induce these MAPK pathways as shown in the figure.