Immune dysregulation and immunopathology induced by SARS-CoV-2 and related coronaviruses - are we our own worst enemy?

Abstract

Human coronaviruses cause a wide spectrum of disease, ranging from mild common colds to acute respiratory distress syndrome and death. Three highly pathogenic human coronaviruses - severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus and SARS-CoV-2 - have illustrated the epidemic and pandemic potential of human coronaviruses, and a better understanding of their disease-causing mechanisms is urgently needed for the rational design of therapeutics. Analyses of patients have revealed marked dysregulation of the immune system in severe cases of human coronavirus infection, and there is ample evidence that aberrant immune responses to human coronaviruses are typified by impaired induction of interferons, exuberant inflammatory responses and delayed adaptive immune responses. In addition, various viral proteins have been shown to impair interferon induction and signalling and to induce inflammasome activation. This suggests that severe disease associated with human coronaviruses is mediated by both dysregulated host immune responses and active viral interference. Here we discuss our current understanding of the mechanisms involved in each of these scenarios.

Fig. 1. Genomic organization of SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes three types of viral proteins. Sixteen non-structural proteins are encoded by open reading frame 1a (ORF1a) and ORF1b, which make up more than two-thirds of the genome. Non-structural protein 1 (nsp1)–nsp11 are encoded by polyprotein 1a (pp1a). nsp12–nsp16 are expressed in pp1ab only when a ribosomal frameshift occurs at the junction of nsp11 and nsp12, which occurs approximately 25% of the time. Genes encoding the structural proteins (spike (S), envelope (E), membrane (M) and nucleoprotein (N) proteins) and accessory proteins (ORF3a, ORF3b, ORF6, ORF7a, ORF7b, ORF8 and ORF9b proteins) are located downstream of ORF1a/1b. The S protein is responsible for viral entry by interacting with the host cell-expressed receptor angiotensin-converting enzyme 2 (ACE2). The S1 subunit of the S protein binds ACE2, while the S2 subunit triggers fusion. The S1 and S2 subunits are separated by a furin cleavage site, which is not found in SARS-CoV. The accessory proteins of SARS-CoV-2 are dispensable for replication but are crucial in mediating immune evasion. CT, cytoplasmic tail; FP, fusion peptide; HR, heptad repeat; L, leader sequence; NTD, amino-terminal domain; RBD, receptor-binding domain; TM, transmembrane domain.

Fig. 2. Antagonism of interferon signalling by SARS-CoV-2 and related coronaviruses.

Coronavirus RNA in the cytoplasm is sensed by the cytoplasmic RNA sensors RIG-I and MDA5. Sensing of viral RNA triggers conformational changes in these sensors and results in the recruitment of downstream effector proteins. MAVS interacts with RIG-I or MDA5 through CARD domains to recruit the downstream kinases TBK1 and IKKε for phosphorylation of interferon-regulatory factor 3 (IRF3) and IRF7. MAVS activation also recruits TNF receptor-associated factor 6 (TRAF6), which serves as an adaptor for the IKK complex (NEMO, IKKα and IKKβ). The IKK complex phosphorylates NF-κB canonical inhibitor, IκB, which results in IκB degradation and activation of NF-κB. IRF3, IRF7 and NF-κB translocate to the nucleus and interact with the corresponding positive regulatory domain (PRD). IRF3 and IRF7 bind PRD I/PRD III, NF-κB binds PRD II, and AP-1 (a heterodimer of JUN and ATF2) binds PRD IV on the interferon-β (IFNβ) promoter to form the interferon enhanceosome for induction of IFNβ expression. IFNβ is secreted and interacts with the IFNα/β receptor (IFNAR; comprising the IFNAR1 and IFNAR2 subunits) in an autocrine or a paracrine manner. Binding of interferon to IFNAR activates the signal transducer and activator of transcription 1 (STAT1) and STAT2 kinases, Janus kinase 1 (JAK1) and the tyrosine kinase TYK2. Phosphorylated STAT1 and STAT2 associate with IRF9 to form ISGF3, which translocates to the nucleus and interacts with the interferon-stimulated response element (ISRE) promoter to drive the expression of downstream interferon-stimulated genes (ISGs). ISGs perform different antiviral functions. The example depicted in the figure is the 2′-5′-oligoadenylate synthetase (OAS)–RNase L pathway. OAS interacts with viral RNA and catalyses the formation of 2′-5′-oligoadenylate (2-5A) from ATP. 2-5A is a secondary messenger that activates RNase L to drive viral RNA degradation. Viral proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and related coronaviruses shown in the figure interfere with interferon production and signalling at different steps. Viral proteins (depicted in red) are from SARS-CoV-2 unless otherwise specified. MERS-CoV, Middle East respiratory syndrome coronavirus; N, nucleocapsid protein; nsp, non-structural protein; ORF, open reading frame protein.

Fig. 3. Migration of respiratory dendritic cells from infected lung epithelia to draining lymph nodes.

Airway epithelial cells are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or related coronaviruses. Respiratory dendritic cells (rDCs) acquire viral antigens from infected epithelial cells and process antigens into peptides for MHC loading. Activated rDCs with MHC–peptide complexes present on the cell surface migrate to the lung-draining lymph nodes and present these MHC–peptide complexes to naive T cells. Together with other necessary co-stimulatory signals, T cells are activated upon T cell receptor engagement with the MHC–peptide complexes presented by rDCs. Activated T cells undergo rapid proliferation and migrate to the site of infection for virus clearance. Initial migration of rDCs from the site of infection to the draining lymph nodes (DLNs) is impaired by elevated prostaglandin D₂ (PGD₂)–PGD₂ receptor 1 (DP1) signalling mediated by increased expression of a phospholipase (PLA2G2D) in rDCs in an age-dependent manner^,. Impaired rDC migration to the draining lymph nodes results in suboptimal T cell activation and poor clinical outcomes in experimentally infected animals.