Molecular Pathogenesis of Middle East Respiratory Syndrome (MERS) Coronavirus

Abstract

Purpose of review: Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012 and is listed in the World Health Organization's blueprint of priority diseases that need immediate research. Camels are reservoirs of this virus, and the virus spills over into humans through direct contact with camels. Human-to-human transmission and travel-associated cases have been identified as well. Limited studies have characterized the molecular pathogenesis of MERS-CoV. Most studies have used ectopic expression of viral proteins to characterize MERS-CoV and its ability to modulate antiviral responses in human cells. Studies with live virus are limited, largely due to the requirement of high containment laboratories. In this review, we have summarized current studies on MERS-CoV molecular pathogenesis and have mentioned some recent strategies that are being developed to control MERS-CoV infection.

Recent findings: Multiple antiviral molecules with the potential to inhibit MERS-CoV infection by disrupting virus-receptor interactions are being developed and tested. Although human vaccine candidates are still being developed, a candidate camel vaccine is being tested for efficacy. Combination of supportive treatment with interferon and antivirals is also being explored.

Summary: New antiviral molecules that inhibit MERS-CoV and host cell receptor interaction may become available in the future. Additional studies are required to identify and characterize the pathogenesis of MERS-CoV EMC/2012 and other circulating strains. An effective MERS-CoV vaccine, for humans and/or camels, along with an efficient combination antiviral therapy may help us prevent future MERS cases.

Keywords: Coronavirus; MERS; Pathogenesis; Therapeutics.

Fig. 1

MERS-CoV replication. MERS-CoV interacts with cellular DPP4 receptor to enter permissive cells. Inside the cell, the virus capsid disintegrates in endosomal compartments to release the positive (+) sense genome in the cytoplasm. The 5′ end of the (+) sense genome is translated to make replicase proteins, which enable transcription and replication of the genome. The (+) sense genome is transcribed to make (−) sense full-length genome, which acts as a template for the synthesis of full-length (+) sense genome. (−) sense full-length genome is also used as a template to make sub-genomic (+) sense RNAs of varying lengths, which are transcribed to (+) sense mRNAs. These mRNAs are translated to make several structural and accessory proteins in the endoplasmic reticulum. The genomic (+) sense RNA and the proteins come together to form a new virion in the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC). The new virions are released through secretory vesicles

Fig. 2

MERS-CoV inhibits innate antiviral signaling. Mammalian cells have evolved conserved pathogen sensing molecules called pattern recognition receptors (PRRs). When a coronavirus, such as MERS-CoV, infects a human cell, the virus produces dsRNA as replication and transcription intermediates. dsRNA stimulates cellular sensors of viral nucleic acid such as TLR3, RIGI, and MDA5. These sensors, through adaptor proteins and cellular kinases (TBK1 and IKKε), activate interferon regulatory factor 3 (IRF3). Activated IRF3 molecules form homodimers and translocate to the nucleus of the infected cell to induce the expression of type I IFNs (IFNα and IFNβ). IFNs then bind to IFN α/β receptor (IFNAR) to stimulate the Jak/Stat pathway, which in turn induces the expression of antiviral interferon-stimulated genes (ISGs). ISGs protect cells from subsequent virus replication and associated cell damage. MERS-CoV proteins M and ORFs 4a, 4b, and 5 (depicted in italics) have evolved different strategies to inhibit the expression of interferon and ISGs. ER = endoplasmic reticulum

Fig. 3

Therapeutic approaches to disrupt MERS-CoV spike (S) protein and DPP4 interaction. MERS-CoV binds to its cellular receptor, dipeptidyl peptidase 4 (DPP4), via the receptor-binding domain (RBD) in the S1 subunit of the S protein. Following these interactions, the S2 subunit facilitates the fusion of viral and cellular membranes to release the virus particle inside the cell. Monoclonal antibodies and small molecules directed against the RBD of the S1 subunit are being developed to disrupt the interaction between DPP4 and MERS-CoV S protein. In addition, small peptides are being developed to inhibit the membrane fusion activity of the S2 subunit of MERS-CoV S protein