Recent Aspects on the Pathogenesis Mechanism, Animal Models and Novel Therapeutic Interventions for Middle East Respiratory Syndrome Coronavirus Infections

Abstract

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an emerging zoonotic virus considered as one of the major public threat with a total number of 2 298 laboratory-confirmed cases and 811 associated deaths reported by World Health Organization as of January 2019. The transmission of the virus was expected to be from the camels found in Middle Eastern countries via the animal and human interaction. The genome structure provided information about the pathogenicity and associated virulent factors present in the virus. Recent studies suggested that there were limited insight available on the development of novel therapeutic strategies to induce immunity against the virus. The severities of MERS-CoV infection highlight the necessity of effective approaches for the development of various therapeutic remedies. Thus, the present review comprehensively and critically illustrates the recent aspects on the epidemiology of the virus, the structural and functional features of the viral genome, viral entry and transmission, major mechanisms of pathogenesis and associated virulent factors, current animal models, detection methods and novel strategies for the development of vaccines against MERS-CoV. The review further illustrates the molecular and computational virtual screening platforms which provide insights for the identification of putative drug targets and novel lead molecules toward the development of therapeutic remedies.

Keywords: MERS-CoV; animal models; emerging zoonotic virus; mechanisms of pathogenesis; probable drug targets; vaccine development.

FIGURE 1

(A) Graphical representation of the structure of the MERS-CoV. The schematic representation shows that the structure of Middle East Respiratory Syndrome Coronavirus, which contains the RNA enclosed in the nucleocapsid within the envelope that is embedded with spike proteins, glycoproteins and membrane proteins (van den Brand et al., 2015). (B) Genome organization of MERS CoV. The genomic organization of MERS-CoV displays the viral genes S, 3, 4a, 4b, 5, E, M, 8b, and N. The genome encodes for five unique accessory proteins such as 3, 4a, 4b, 5 and 8b and four major structural proteins which are illustrated in the genome scheme (Gao et al., 2016). (C) Experimental structure of MERS-CoV complexes with human DPP4 (PDB ID: 4L72). DPP4 is an extracellular RBD domain, which comprises of both N- and C-terminal. The N-terminal is the β-propeller domain and C-terminal is the α/β hydrolase domain (Wang et al., 2013). (D) Genome organization of receptor binding domain (RBD) that illustrates the S1 and S2 sub-domains (Zhang et al., 2015).

FIGURE 2

Life cycle of MERS-CoV displaying fusion with plasma membrane. The fusion of S protein to the plasma membrane of host cell, formation of a double membrane vesicle in the host cell, eventually releasing the RNA enclosed in the nucleocapsid followed by genome transcription. The viral RNA undergoes replication and transcription followed by the 4, 5, and 6 RNA synthesis and translation; the endoplasmic reticulum aids the assembly and packaging of virus particle forming a complete double membrane vesicle and lastly through exocytosis and MERS-CoV is released out of the host cell (Du et al., 2009).

FIGURE 3

Transmission of MERS-CoV and symptoms possessed by infected human. The figure shows the path by which the virus is transmitted from the infected camel to the human and camel to various animals (Kandeil et al., 2019); further, this virus is transmitted to other human population via human to human transmissions (Shehata et al., 2016).

FIGURE 4

The molecular mechanism of pathogenesis by MERS-CoV in human and animals. The pathogenesis mechanism is mainly occurred by DPP4, papian like protease PLpro, and accessory proteins such as p4a and membrane M protein (Durai et al., 2015).