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Functional comparison of MERS-coronavirus lineages reveals increased replicative fitness of the recombinant lineage 5.

ABSTRACT: Middle East respiratory syndrome coronavirus (MERS-CoV) is enzootic in dromedary camels across the Middle East and Africa. Virus-induced pneumonia in humans results from animal contact, with a potential for limited onward transmission. Phenotypic changes have been suspected after a novel recombinant clade (lineage 5) caused large nosocomial outbreaks in Saudi Arabia and South Korea in 2016. However, there has been no functional assessment. Here we perform a comprehensive in vitro and ex vivo comparison of viruses from parental and recombinant virus lineages (lineage 3, n = 7; lineage 4, n = 8; lineage 5, n = 9 viruses) from Saudi Arabia, isolated immediately before and after the shift toward lineage 5. Replication of lineage 5 viruses is significantly increased. Transcriptional profiling finds reduced induction of immune genes IFNB1, CCL5, and IFNL1 in lung cells infected with lineage 5 strains. Phenotypic differences may be determined by IFN antagonism based on experiments using IFN receptor knock out and signaling inhibition. Additionally, lineage 5 is more resilient against IFN pre-treatment of Calu-3 cells (ca. 10-fold difference in replication). This phenotypic change associated with lineage 5 has remained undiscovered by viral sequence surveillance, but may be a relevant indicator of pandemic potential.

SUBMITTER: Schroeder S

PROVIDER: S-EPMC8423819 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The first known cases of Middle East respiratory syndrome (MERS), associated with infection by a novel coronavirus (CoV), occurred in 2012 in Jordan but were reported retrospectively. The case first to be publicly reported was from Jeddah, in the Kingdom of Saudi Arabia (KSA). Since then, MERS-CoV sequences have been found in a bat and in many dromedary camels (DC). MERS-CoV is enzootic in DC across the Arabian Peninsula and in parts of Africa, causing mild upper respiratory tract illness in its camel reservoir and sporadic, but relatively rare human infections. Precisely how virus transmits to humans remains unknown but close and lengthy exposure appears to be a requirement. The KSA is the focal point of MERS, with the majority of human cases. In humans, MERS is mostly known as a lower respiratory tract (LRT) disease involving fever, cough, breathing difficulties and pneumonia that may progress to acute respiratory distress syndrome, multiorgan failure and death in 20% to 40% of those infected. However, MERS-CoV has also been detected in mild and influenza-like illnesses and in those with no signs or symptoms. Older males most obviously suffer severe disease and MERS patients often have comorbidities. Compared to severe acute respiratory syndrome (SARS), another sometimes- fatal zoonotic coronavirus disease that has since disappeared, MERS progresses more rapidly to respiratory failure and acute kidney injury (it also has an affinity for growth in kidney cells under laboratory conditions), is more frequently reported in patients with underlying disease and is more often fatal. Most human cases of MERS have been linked to lapses in infection prevention and control (IPC) in healthcare settings, with approximately 20% of all virus detections reported among healthcare workers (HCWs) and higher exposures in those with occupations that bring them into close contact with camels. Sero-surveys have found widespread evidence of past infection in adult camels and limited past exposure among humans. Sensitive, validated reverse transcriptase real-time polymerase chain reaction (RT-rtPCR)-based diagnostics have been available almost from the start of the emergence of MERS. While the basic virology of MERS-CoV has advanced over the past three years, understanding of the interplay between camel, environment, and human remains limited.

Project description:The SARS coronavirus (SARS-CoV) replicase gene encodes 16 nonstructural proteins (nsps) with multiple enzymatic activities. Several of these enzymes are common components of replication complexes of other plus-strand RNA viruses, such as picornavirus 3C-like protease, papain-like protease, RNA-dependent RNA polymerase, RNA helicase, and ribose 2′-O-methyltransferase activities, while others such as exoribonuclease, endoribonuclease, and adenosine diphosphate-ribose 1″-phosphatase activities, are rarely or not conserved in viruses outside the order Nidovirales. The latter enzymes are believed to be involved in unique metabolic pathways used by coronaviruses to (1) replicate and transcribe their extremely large RNA genomes, and (2) interfere with cellular functions and antiviral host responses. Since the global outbreak of SARS in 2003, major efforts have been made to elucidate the structures of the protein components of the SARS-CoV replication/transcription complex. Thus, in less than 5 years, the structures of as many as 16 SARS-CoV proteins or functional domains have been determined. Remarkably, eight of these 16 structures had novel folds, illustrating the uniqueness of the coronavirus replicative machinery. Furthermore, several new protein functions and potential drug targets have been identified in these studies. Current structural studies mainly focus on the few remaining proteins for which no structural information is available and larger protein complexes comprised of different nsps. The studies aim at obtaining detailed information on the functions and macromolecular assembly of the coronavirus replication/transcription machinery which, over a long period of time, may be used to develop selective antiviral drugs. This chapter reviews structural information on the SARS-CoV macro domain (ADRP) as well as nsps 7, 8, 9, and 15 and summarizes our current knowledge of active-site residues and intermolecular interactions of these proteins.

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Functional comparison of MERS-coronavirus lineages reveals increased replicative fitness of the recombinant lineage 5.

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