An Overview of Current Knowledge of Deadly CoVs and Their Interface with Innate Immunity

Abstract

Coronaviruses are a large family of zoonotic RNA viruses, whose infection can lead to mild or lethal respiratory tract disease. Severe Acute Respiratory Syndrome-Coronavirus-1 (SARS-CoV-1) first emerged in Guangdong, China in 2002 and spread to 29 countries, infecting 8089 individuals and causing 774 deaths. In 2012, Middle East Respiratory Syndrome-Coronavirus (MERS-CoV) emerged in Saudi Arabia and has spread to 27 countries, with a mortality rate of ~34%. In 2019, SARS-CoV-2 emerged and has spread to 220 countries, infecting over 100,000,000 people and causing more than 2,000,000 deaths to date. These three human coronaviruses cause diseases of varying severity. Most people develop mild, common cold-like symptoms, while some develop acute respiratory distress syndrome (ARDS). The success of all viruses, including coronaviruses, relies on their evolved abilities to evade and modulate the host anti-viral and pro-inflammatory immune responses. However, we still do not fully understand the transmission, phylogeny, epidemiology, and pathogenesis of MERS-CoV and SARS-CoV-1 and -2. Despite the rapid application of a range of therapies for SARS-CoV-2, such as convalescent plasma, remdesivir, hydroxychloroquine and type I interferon, no fully effective treatment has been determined. Remarkably, COVID-19 vaccine research and development have produced several offerings that are now been administered worldwide. Here, we summarise an up-to-date understanding of epidemiology, immunomodulation and ongoing anti-viral and immunosuppressive treatment strategies. Indeed, understanding the interplay between coronaviruses and the anti-viral immune response is crucial to identifying novel targets for therapeutic intervention, which may even prove invaluable for the control of future emerging coronavirus.

Keywords: epidemiology; innate immunity; transmission; treatment; viral life cycle; viral structure.

Figure 1

The transmission patterns and countries with the highest proportion of coronavirus diagnoses. Transmission patterns for (A) SARS-CoV-1, (B) MERS-CoV and (C) SARS-CoV-2 and countries with the largest proportions of confirmed cases are shown separately. (D) The COVID-19 cases and deaths—cumulative total per 100,000 population for countries with the largest proportions of confirmed cases. (The datasets analysed in this figure are available on the WHO website WHO|World Health Organization).

Figure 2

Coronavirus particle, genomes, related family tree and identities of non-structural proteins. The structure of the coronavirus virion (A), the coronavirus family tree (B), genomes of SARS-CoV-1, MERS-CoV and SARS-CoV-2 (C) and timelines for emergence of SARS-CoV-1, MERS-CoV and SARS-CoV-2 (D) (created with BioRender.com).

Figure 2

Coronavirus particle, genomes, related family tree and identities of non-structural proteins. The structure of the coronavirus virion (A), the coronavirus family tree (B), genomes of SARS-CoV-1, MERS-CoV and SARS-CoV-2 (C) and timelines for emergence of SARS-CoV-1, MERS-CoV and SARS-CoV-2 (D) (created with BioRender.com).

Figure 3

Coronavirus lifecycle. After binding to cellular receptors, coronaviruses enter cells and release their RNA genome. The RNA is transcribed and translated into proteins or replicated to form new RNA, which is assembled into viral particles and released from the cell (ERGIC: ER–Golgi intermediate compartment, ER: endoplasmic reticulum, S: Spike, E: envelope, M: membrane, N: nucleocapsid, nsp: non-structural proteins).

Figure 4

The RLR, TLR and JAK-STAT signalling pathways and interference of signalling pathways by structural and non-structural proteins of coronaviruses. Endosomal TLR3 and TLR7 recognise dsRNA and ssRNA, respectively, leading to activation of NF-κB, which can promote the expression of pro-inflammatory cytokines. TLR3 also triggers IRF-3 activation leading to IFN production. In the JAK-STAT pathway, binding of the receptor leads to its autophosphorylation. Then, Tyk2 and JAK1, which are bound to the intracellular domain of IFNAR, are activated and cause subsequent phosphorylation of STAT1 and STAT2. Phosphorylated STAT1 and STAT2 dimerise and associate with a transcriptional regulator IFR9 (IFN regulatory factor 9), forming the heterotrimeric transcriptional factor complex IFN-stimulated gene factor 3 (ISGF3). Then, ISGF3 translocates to the nucleus and binds to the ISRE promoter of target ISGs. Several coronavirus proteins, which evade anti-viral immune response, are also shown.