diseases Review Human Coronaviruses: A Review of Virus–Host Interactions Yvonne Xinyi Lim, Yan Ling Ng, James P. Tam and Ding Xiang Liu * School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore; [email protected] (Y.X.L.); [email protected] (Y.L.N.); [email protected] (J.P.T.) * Correspondence: [email protected]; Tel.: +65-6316-2861 Academic Editor: Maurizio Battino Received: 8 June 2016; Accepted: 18 July 2016; Published: 25 July 2016 Abstract: Human coronaviruses (HCoVs) are known respiratory pathogens associated with a range of respiratory outcomes. In the past 14 years, the onset of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) have thrust HCoVs into spotlight of the research community due to their high pathogenicity in humans. The study of HCoV-host interactions has contributed extensively to our understanding of HCoV pathogenesis. In this review, we discuss some of the recent findings of host cell factors that might be exploited by HCoVs to facilitate their own replication cycle. We also discuss various cellular processes, such as apoptosis, innate immunity, ER stress response, mitogen-activated protein kinase (MAPK) pathway and nuclear factor kappa B (NF-κB) pathway that may be modulated by HCoVs. Keywords: human coronavirus; virus–host interactions; apoptosis; innate immunity; ER stress; MAPK; NF-κB 1. Introduction Human coronaviruses (HCoVs) represent a major group of coronaviruses (CoVs) associated with multiple respiratory diseases of varying severity, including common cold, pneumonia and bronchilitis [1]. Today, HCoVs are recognised as one of the most rapidly evolving viruses owing to its high genomic nucleotide substitution rates and recombination [2]. In recent years, evolution of HCoVs has also been expedited by factors such as urbanization and poultry farming. These have permitted the frequent mixing of species and facilitated the crossing of species barrier and genomic recombination of these viruses [3]. To date, six known HCoVs have been identified, namely HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV); of which, four HCoVs (HCoV-229E, HCoV-NL63, HCoV-OC43 and HCoV-HKU1) are globally circulated in the human population and contribute to approximately one-third of common cold infections in humans [4]. In severe cases, these four HCoVs can cause life-threatening pneumonia and bronchiolitis especially in elderly, children and immunocompromised patients [1,5,6]. Besides respiratory illnesses, they may also cause enteric and neurological diseases [7–11]. SARS-CoV first emerged in 2002–2003 in Guangdong, China as an atypical pneumonia marked by fever, headache and subsequent onset of respiratory symptoms such as cough and pneumonia, which may later develop into life-threatening respiratory failure and acute respiratory distress syndrome [12]. Being highly transmissible among humans, it quickly spread across 29 countries, infecting more than 8000 individuals with a mortality rate of about 10% [13,14]. Originally, palm civets were thought to be the natural reservoir for the virus [15]. However, subsequent phylogenetic studies pointed to the bat origin of SARS-CoV based on sequences of SARS-like virus found in bats [16]. The MERS-CoV epidemic surfaced in Saudi Arabia in 2012 with similar clinical symptoms as SARS-CoV Diseases 2016, 4, 26; doi:10.3390/diseases4030026 www.mdpi.com/journal/diseases Diseases 2016, 4, 26 2 of 28 Diseases 2016, 4, 26 2 of 27 butSARS-CoV with a much but higher with mortality a much ratehigher of about mortality 35% [rate17]. Unlikeof about SARS-CoV, 35% [17]. which Unlike exhibits SARS-CoV, super-spreader which events,exhibits transmission super-spreader of MERS-CoV events, transmission is geographically of MERS-CoV limited [12 is]. geographically In fact, reported limited cases of[12]. MERS-CoV In fact, oftenreported stem from cases outbreaks of MERS-CoV within often the Middlestem from Eastern outbre countriesaks within or the recent Middle travel Eastern to the countries region [18 or,19 recent]. travel to the region [18,19]. Taxonomy, Genomic Structure and Morphology Taxonomy,CoVs are Genomic a group Structure of large and enveloped Morphology RNA viruses under the Coronaviridae family. Together with ArtierivirdaeCoVs are a group and Roniviridae, of large enveloped Coronaviridae RNA viruses is classified under the under Coronaviridae the Nidovirale family. orderTogether [20 ]. As proposedwith Artierivirdae by the International and Roniviridae, Committee Coronaviridae for Taxonomy is classified of Viruses, under the CoVs Nidovirale are further order categorized [20]. As intoproposed four main by genera, the InternationalAlpha-, Beta- Committee, Gamma -for and TaxonomyDeltacoronaviruses of Viruses,based CoVs onare sequence further categorized comparisons into of entirefour viral main genomes genera, [Alpha-21,22]., Beta- These, Gamma CoVs- canand infect Deltacoronaviruses a wide variety based of hosts,on sequence including comparisons avian, swine of andentire humans. viral HCoVsgenomes are [21,22]. identified These toCoVs be eithercan infect in the a wideAlpha- varietyor Betacoronavirus of hosts, includinggenera, avian, including swine Alphacoronavirusesand humans. HCoVs, HCoV-229E are identified and HCoV-NL63, to be either in and theBetacoronaviruses Alpha- or Betacoronavirus, HCoV-HKU1, genera, SARS-CoV,including MERS-CoVAlphacoronaviruses and HCoV-OC43, HCoV-229E (Table and1). HCoV-NL63, and Betacoronaviruses, HCoV-HKU1, SARS-CoV, MERS-CoVUnder the and electron HCoV-OC43 microscope, (Table the 1). CoV virions appear to be roughly spherical or moderately pleomorphic,Under with the electron distinct microscope, “club-like” projectionsthe CoV virions formed appear by the to be spike roughly (S) protein spherical [23 ,or24 ].moderately Within the virionpleomorphic, interior lies with a helically distinct “club-li symmetricalke” projections nucleocapsid formed that by enclosesthe spike a (S) single-stranded protein [23,24]. and Within positive the sensevirion RNA interior viral genomelies a helically of an extraordinarilysymmetrical nucleocapsid large size ofthat about encloses 26 to a 32 single-stranded kilobases [20]. and The positive positive sense RNA viral genome of an extraordinarily large size of about 26 to 32 kilobases [20]. The positive sense viral genomic RNA acts as a messenger RNA (mRNA), comprising a 51 terminal cap structure sense viral genomic RNA acts as a messenger RNA (mRNA), comprising a 5′ terminal cap structure and a 31 poly A tail. This genomic RNA acts in three capacities during the viral life cycle: (1) as an initial and a 3′ poly A tail. This genomic RNA acts in three capacities during the viral life cycle: (1) as an RNA of the infectious cycle; (2) as a template for replication and transcription; and (3) as a substrate for initial RNA of the infectious cycle; (2) as a template for replication and transcription; and (3) as a packaging into the progeny virus. The replicase-transcriptase is the only protein translated from the substrate for packaging into the progeny virus. The replicase-transcriptase is the only protein genome,translated while from the viralthe genome, products while of all the downstream viral products open of reading all downstream frames are open derived reading from subgenomicframes are 1 mRNAs.derived In from all CoVs, subgenomic the replicase mRNAs. gene In makesall CoVs, up the approximately replicase gene 5 makestwo-thirds up approximately of the genome 5′ andtwo- is comprisedthirds of of the two genome overlapping and is comprised open reading of two frames overlapping (ORFs), open ORF1a reading and frames ORF1b, (ORFs), which ORF1a encodes and 16 non-structuralORF1b, which proteins. encodes The 16 finalnon-stru one-thirdctural ofproteins. the CoV The genomic final one-third RNA encodes of the CoV canonicalgenomic RNA set of fourencodes structural CoV protein canonical genes, set inof thefour order structural of spike protein (S), envelope genes, in (E),the membraneorder of spike (M) (S), and envelope nucleocapsid (E), (N).membrane In addition, (M) several and nucleocapsid accessory ORFs(N). In are addition, also interspersed several accessory along ORFs the structural are also interspersed protein genes along and thethe number structural and locationprotein genes varies and among the number CoV species and lo [cation25] (Figure varies1 ).among CoV species [25] (Figure 1). Figure 1. Genome organisation of human coronaviruses (HCoVs). HCoV genomes range from about 26 Figure 1. Genome organisation of human coronaviruses (HCoVs). HCoV genomes range from about to 32 kilobases (kb) in size, as indicated by the black lines above the scale. Coronavirus (CoV) genome is 26 to 32 kilobases (kb) in size, as indicated by the black lines above the scale. Coronavirus (CoV) typically arranged in the order of 51-ORF1a-ORF1b-S-E-M-N-31. The overlapping open reading frames genome is typically arranged in the order of 5′-ORF1a-ORF1b-S-E-M-N-3′. The overlapping open (ORF) ORF1a and ORF1b comprise two-thirds of the coronavirus genome, which encodes for all the reading frames (ORF) ORF1a and ORF1b comprise two-thirds of the coronavirus genome, which viral components required for viral RNA synthesis. The other one-third of the genome at the 31 end encodes for all the viral components required for viral RNA synthesis. The