Overview of lethal human coronaviruses

Abstract

Coronavirus infections of multiple origins have spread to date worldwide, causing severe respiratory diseases. Seven coronaviruses that infect humans have been identified: HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, and SARS-CoV-2. Among them, SARS-CoV and MERS-CoV caused outbreaks in 2002 and 2012, respectively. SARS-CoV-2 (COVID-19) is the most recently discovered. It has created a severe worldwide outbreak beginning in late 2019, leading to date to over 4 million cases globally. Viruses are genetically simple, yet highly diverse. However, the recent outbreaks of SARS-CoV and MERS-CoV, and the ongoing outbreak of SARS-CoV-2, indicate that there remains a long way to go to identify and develop specific therapeutic treatments. Only after gaining a better understanding of their pathogenic mechanisms can we minimize viral pandemics. This paper mainly focuses on SARS-CoV, MERS-CoV, and SARS-CoV-2. Here, recent studies are summarized and reviewed, with a focus on virus-host interactions, vaccine-based and drug-targeted therapies, and the development of new approaches for clinical diagnosis and treatment.

Fig. 1

Phylogenetic tree of coronaviruses based on full-length genome sequences. All complete genome sequences of coronavirus were downloaded from the NCBI reference sequence database, RefSeq. The tree was constructed using maximum likelihood estimation (MLE) by MEGA X, with Clustal Omega as the multiple sequence alignment method, and 1000 bootstrap replicates. Only bootstraps ≥50% values are shown. The seven known human-infecting coronaviruses are indicated with a red star

Fig. 2

Common transmission methods and symptoms of coronavirus infection. The main modes of transmission include droplet transmission, contact transmission, and fecal–oral transmission. Fever, cough, fatigue, muscle soreness, and abdominal pain are common symptoms of the three coronavirus infections

Fig. 3

Clustering of the spike protein of each coronavirus. Fifty-four spike protein sequences filtered from each coronavirus coding sequences were clustered using the CLANS (CLuster ANalysis of Sequences) program on the website of MPI Bioinformatics Toolkit. Each colored dot represents the spike protein sequence of each coronavirus. Dots in the same color mean they are of the same genus, and each line shows the similarity of two sequences, with darker lines indicating higher similarity (lower E values). The Coronaviridae family includes the following genera: Alphacoronavirus (colored in green); Betacoronavirus (red); Gammacoronavirus (orange), and Deltacoronavirus (blue). The indicated SARS-CoV, MERS-CoV, and SARS-CoV-2 belong to the genus of Betacoronavirus

Fig. 4

Pathogenesis of SARS-CoV, MERS-CoV, and SARS-CoV-2. SARS-CoV and SARS-CoV-2 play a pathogenic role by inhibiting ACE2. Under the influence of renin and ACE, angiotensinogen is converted into Ang II. Through the AT1 receptor, Ang II acts as a lung injury-promoting factor, and in some cases, may cause vascular constriction, an inflammatory response, cell proliferation, fibrosis, and apoptosis of alveolar epithelial cells, resulting in diseases such as pulmonary hypertension, pulmonary fibrosis, and acute lung injury. ACE2 converts Ang II into Ang (1–7), and through the MAS receptor, Ang (1–7) play roles in vasodilation, antiproliferative activity, and antioxidant activity. SARS-CoV downregulates the activity of ACE2 and causes an increase in the amount of Ang II and lung injury. MERS-CoV infection of dendritic cells and macrophages can lead to the continuous production of pro-inflammatory cytokines and chemokines, leading to a large number of immune cells infiltrating a patient’s lower respiratory tract, causing severe inflammation and tissue damage. MERS-CoV can infect T-cells from human lymphoid organs and causes the peripheral blood inducing apoptosis by intrinsic and extrinsic pathways, thus avoiding host immune response

Fig. 5

The targets of the different drug candidates against the three coronaviruses. Common targets against the three coronaviruses are mainly the S protein and the S1/S2 subunits, PL protein, RdRp, 3CL protein, and Helicase. The figure shows drug candidates (in black) and vaccines (in red). Among them, Remdesivir has been trending in the news recently. It inhibits the RdRp, is in phase III for SARS-CoV-2, and may have an effect on the three viruses. Ribavirin in combination with a pegylated interferon may also have an effect against the three viruses. Ritonavir and Lopinavir, which inhibit the 3CLpro and are in phase III for SARS-CoV-2, have an effect on both SARS-CoV-2 and MERS-CoV. DNA vaccines and vaccines based on the S protein or subunits of the S protein are in development