2015 Middle East respiratory syndrome coronavirus infection_ virus-host cell interactions and implications on pathogenes

2015·0.44 MB·English

Zhouetal.VirologyJournal (2015) 12:218
DOI10.1186/s12985-015-0446-6
REVIEW Open Access
Middle East respiratory syndrome
coronavirus infection: virus-host cell
interactions and implications on
pathogenesis
Jie Zhou1,2,3, Hin Chu1,2,3, Jasper Fuk-Woo Chan1,2,3,4 and Kwok-Yung Yuen1,2,3,4*
Abstract
Middle-East RespiratorySyndromecoronavirus (MERS-CoV) was identified to cause severe respiratory infection in
humans since 2012.The continuing MERS epidemic with a case-fatality of more than 30 % poses a major threat to
public health worldwide. Currently, the pathogenesis of human MERS-CoV infection remains poorly understood. We
reviewed experimental findings from human primary cells and ex vivo human lung tissues, as well as those from
animal studies, so as to understand the pathogenesis and high case-fatality of MERS. Human respiratory epithelial
cellsare highlysusceptible to MERS-CoV and can supportproductive viral replication. However, theinduction of
antiviral cytokines and proinflammatory cytokines/chemokines are substantially dampened in theinfectedepithelial
cells, due to the antagonistic mechanisms evolved by thevirus. MERS-CoVcan readily infect and robustly replicate
inhumanmacrophagesanddendriticcells,triggeringtheaberrantproductionofproinflammatorycytokines/
chemokines.MERS-CoVcanalsoeffectivelyinfecthumanprimaryTcellsandinducemassiveapoptosisinthesecells.
Althoughdatafromclinical,invitroandexvivostudiessuggestedthepotentialforvirusdissemination,extrapulmonary
involvementinMERSpatientshasnotbeenascertainedduetothelackofautopsystudy.InMERS-CoVpermissive
animalmodels,althoughviralRNAcanbedetectedfrommultipleorgansoftheaffectedanimals,thebrainofhuman
DPP4-transgenicmousewastheonlyextrapulmonaryorganfromwhichtheinfectiousviruscanberecovered.More
researchfindingsonthepathogenesisofMERSandthetissuetropismsofMERS-CoVmayhelptoimprovethe
treatmentandinfectioncontrolofMERS.
Background 555 deaths in over 20 countries worldwide, with a high
GeneraloverviewofMERSandMERS-CoV case-fatality of more than 30 % [3]. The continuing
In September 2012, a novel lineage C betacoronavirus MERS epidemic in the Middle East is believed to be
was identified as the etiological agent to cause severe related to the failure to control the zoonotic sources,
respiratory infection in humans in the Middle East [1]. most probably the dromedary camels, which results in
The novel virus was formally named as Middle East ongoing camel-to-human transmission [4–9]. While all
respiratory syndrome coronavirus (MERS-CoV) by the primary cases of MERShave been epidemiologically linked
Coronavirus Study Group of International Committee to the Middle East, numerous clusters in the community
onTaxonomyofVirusesin2013[2].Asof23September andhealthcaresettingshavealsobeenreported.Thelargest
2015, MERS-CoV has caused 1570 infection cases and healthcare-associated outbreak occurred in the Republic of
Korea in 2015, in which 186 cases including 36 deaths oc-
curred after the index patient returned from the Middle
*Correspondence:[email protected]
1StateKeyLaboratoryofEmergingInfectiousDiseases,TheUniversityof East [10]. The high case-fatality rate of MERS and the
HongKong,HongKongSpecialAdministrativeRegion,China capability of MERS-CoV to cause outbreaks in healthcare
2DepartmentofMicrobiology,TheUniversityofHongKong,QueenMary
facilitiesposesignificantthreattopublichealthworldwide.
Hospital,102PokfulamRoad,HongKongSpecialAdministrativeRegion,
China
Fulllistofauthorinformationisavailableattheendofthearticle
©2015Zhouetal.OpenAccessThisarticleisdistributedunderthetermsoftheCreativeCommonsAttribution4.0
InternationalLicense(http://creativecommons.org/licenses/by/4.0/),whichpermitsunrestricteduse,distribution,and
reproductioninanymedium,providedyougiveappropriatecredittotheoriginalauthor(s)andthesource,providealinkto
theCreativeCommonslicense,andindicateifchangesweremade.TheCreativeCommonsPublicDomainDedicationwaiver
(http://creativecommons.org/publicdomain/zero/1.0/)appliestothedatamadeavailableinthisarticle,unlessotherwisestated.
Zhouetal.VirologyJournal (2015) 12:218 Page2of7
Unlike most other human-pathogenic coronaviruses, replication, as well as the occurrence of infection-
which mainly cause self-limiting upper respiratory tract induced apoptosis in human lung tissue [24]. Moreover,
infections, MERS-CoV is capable of causing severe it was shown that MERS-CoV infection in ex vivo lung
disease with lower respiratory tract involvement and tissues displayed the comparable extent and kinetics to
extrapulmonary manifestations [11, 12]. Patients with the infection of highly pathogenic avian H5N1 influenza
severe MERS often present with pneumonic symptoms virus in lung tissues of the same donors, indicating the
including fever, cough and dyspnea, with some progres- high infectivity of MERS-CoV in human respiratory epi-
sing to respiratory failure and acute respiratory distress thelium [24]. However, in the latter study, MERS-CoV
syndrome [13, 14]. Extrapulmonary manifestations such could also infect ciliated bronchial epithelial cells while
as renal failure, hepatic dysfunction, and diarrhea are these cells were not susceptible to the virus in the
notuncommon[13,15].Additionally,derangedcoagulation former study [23, 24]. Notably, the studies in human ex
profileandhematological changesmay also beobservedin vivo airway tissues invariably revealed that pulmonary
severe MERS[15]. The infectious virus could be recovered endothelial cells were highly susceptible to MERS-CoV
exclusivelyfrompatients’respiratorytract,whilstviralRNA [23, 24], suggesting that MERS-CoV infection in
could be detected extrapulmonary specimens such as respiratory tract could potentially develop into a
blood, urine and stool by nucleic acid amplification tests systematic or disseminated infection. Taken together,
[16,17]. These clinicalandlaboratoryfindingsaresuggest- human respiratory epithelium is highly permissive to
iveofpossiblydisseminatedviralinfection. MERS-CoV. The effective infection results in robust
MERSbearssomeresemblancetosevereacuterespira- viral propagation and massive induction of apoptosis.
tory syndrome (SARS) in terms of clinical manifest- These studies provided pathological basis of the major
ation. The etiological agent of SARS is a lineage B pulmonary features of MERS i.e., pneumonia and
betacoronavirus, SARS coronavirus (SARS-CoV). In acute lung injury.
2002–2003, SARS-CoV infected more than 8000 pa- As the first line of host defense, human epithelial cells
tients with a case-fatality rate of 9.6 %, affecting over 30 are stimulated to produce antiviral and proinflammatory
countries worldwide [18–20]. However, unlike SARS, no cytokines and chemokines to eliminate the invading
autopsy study has been conducted in deceased MERS pathogens. Based on the studies in human primary
patients. Therefore, our understanding of the pathogen- respiratory epithelial cells, respiratory epithelial cell lines
esis of MERS remains largely elusive. In this review, we and ex vivo human lung tissue, there has been a consen-
summarize the current knowledge on MERS-CoVcellu- susrecognitionthattheinductionofantiviralinterferons
lar tropisms and the virus-host interaction observed in (i.e. type I and III IFNs) was basically dampened, al-
in vitro human cells, ex vivo human tissues, and their though type I and type III IFNs treatment can effectively
implications on the pathogenesis of MERS. The relevant inhibit the MERS-CoV replication [21–23]. Additionally,
findings in MERS-CoV infected experimental animals MERS-CoV infection failed to elicit strong proinflamma-
are also reviewed, aiming to recapitulate the human tory cytokines response in human primary respiratory
MERS disease and to better the understanding of patho- epithelial cells and ex vivo respiratory tissues [21, 23, 24].
genesisof humanMERS-CoV infection. The respiratory epithelial cell line Calu-3 cells were used
to study the early and late phase of innate immune
CellulartropismofMERS-CoVinrespiratorysystem response after MERS-CoV infection. It was demonstrated
andinnateimmuneresponseuponinfection that the proinflammatory cytokines/chemokines such as
TheprimaryinfectionsiteofMERSishumanrespiratory IL-1β, IL-8 and IL-6 exhibited a delayed but marked
tract. It was demonstrated that MERS-CoVcould effect- inductionuponMERS-CoVinfection[25].Basedonthese
ively infect and robustly replicate in the human airway observations, antagonistic mechanisms of MERS-CoV to
epithelium [21, 22]. Ex vivo tissues from human respira- attenuate innate immune response have been extensively
tory tract were also examined for the cellular tropism of sought. A number of MERS-CoV proteins, including the
MERS-CoV [23, 24]. It was shown that MERS-CoV papain-like protease, membrane protein, and accessory
infected non-ciliated bronchial epithelial cells, bronchi- proteins4a,4band5,havebeenidentifiedtosuppressthe
olar epithelial cells, alveolar epithelial cells and endothe- interferon production [26–29]. Among them, MERS-CoV
lial cells of pulmonary vessels [23]. Additionally, upon 4a was shown to suppress PACT-induced activation of
MERS-CoV infection in ex vivo lung tissues, the unin- RIG-I and MDA5 and circumvent the innate immune
fected cells underwent massive apoptosis with extensive response[27].Additionally,MERS-CoVpapain-likeprote-
caspase 3 activation, implicating that paracrine mechan- aseexhibitedthedeubiquitinatinganddeISGylatingactiv-
ism may contribute to the induction of apoptosis [23]. ities and suppressed the innate immune response [29].
Another study in human ex vivo lung tissue echoed the Collectively, MERS-CoV may have evolved multiple
discovery of MERS-CoV’s productive infection and antagonisticmechanismstodampenorattenuatethehost
Zhouetal.VirologyJournal (2015) 12:218 Page3of7
defense, which contributed to the high pathogenicity in evidenced by the progressive increase in viral antigen
humans. expression, increase in viral RNA, and increase in virus
Consistent with the responsiveness of MERS-CoV to titer in the culture media of the infected cells [38]. Intri-
interferontreatmentinvitro,combinational treatmentof guingly, in the same study, the authors reported that
IFN-α2b and ribavirin reduced virus replication and im- MERS-CoV induced no IFN-β and marginal IFN-α
proved clinical outcome in MERS-CoV infected rhesus expressionininfected dendritic cells.Onthe otherhand,
macaques [30]. It was further demonstrated that IFN- MERS-CoV triggered substantial expression of IFN-γ,
β1b treatment showed a better outcome in the virus- IL-12, IP-10/CXCL-10 and RANTES/CCL-5, which was
inoculatedcommonmarmosets[31]. significantly higher than that of SARS-CoV-infected
dendritic cells. In addition, the surface expression of
The human immune cells involved in MERS-CoV MHC class II and costimulatory molecule was disturbed
infection in MERS-CoV-infected dendritic cells, which might con-
While the cellular tropism of SARS-CoV in human tribute to the immune dysregulation during MERS-CoV
respiratory tract resembles thatofMERS-CoV [21,22],a infection [38]. Recently, Scheuplein et al. reported the
number of immune cells displayed distinct susceptibility infection of plasmacytoid dendritic cells by MERS-CoV.
toMERS-CoVandSARS-CoV. Remarkably, the author concluded that although MERS-
CoV infection in plasmacytoid dendritic cells was abort-
Macrophages ive, the infection induced the production of large
The novel MERS-CoV has a broad tissue and cellular amounts of type I and type III IFNs exclusively in these
tropism including human monocytic cell line, THP-1 cells [39].
[32]. A subsequent study focused on human macro- In the case of SARS-CoV, a number of studies demon-
phages and demonstrated that MERS-CoV could effi- strated that human dendritic cells were susceptible to
ciently infect and replicate in human monocyte-derived SARS-CoV but were unable to support viral replication
macrophages (MDMs) [33]. Notably, a 2–4-log increase [35, 36, 40]. Nonetheless, SARS-CoV infection led to the
in viral RNA was consistently detected in MERS-CoV phenotypic and functional maturation of dendritic cells,
infected MDMs derived from different donors within with regard to MHC class II and costimulatory molecule
48 h post infection. In addition, MERS-CoVsignificantly expression, T cell-stimulatory capacity, and cytokine/
induced the expression of proinflammatory and chemo- chemokine production including TNF-α, MIP-1α/CCL-
tactic cytokines and chemokines, including IP-10/CXCL- 3, RANTES/CCL-5, IP-10/CXCL-10, and MCP-1/CCL-2
10, MCP-1/CCL-2, MIP-1α/CCL-3, RANTES/CCL-5, [35,40].Importantly, Zhao et al. demonstrated the po-
IL-8, and IL-12,in the infected human macrophages [33]. tential role of dendritic cells in controlling the patho-
In the meantime, MERS-CoV triggered the upregulation genesis of SARS-CoV in a mouse study. In particular,
ofMHCclassI-,MHCclassII-,andcostimulation-related the authors showed that severe outcome of SARS-
genes in MDMs. Furthermore, by utilizing ex vivo organ CoV infection correlated with the slow kinetics of
culture, the authors demonstrated that the alveolar virus clearance and delayed activation of respiratory
macrophages in human lung tissues were susceptible to dendritic cells [41].
MERS-CoV[33]. Collectively, in contrast to the inability to elicit the
The SARS-CoVcan infect human macrophages. How- production of proinflammatory cytokines in human
ever, viral replication of SARS-CoV in human macro- respiratory epithelial cells, MERS-CoV and SARS-CoV
phages was abortive and no infectious virus particles are able to stimulate the induction of proinflammatory
were produced [34–37]. Despite an abortive infection, cytokines/chemokines in human macrophages and den-
the SARS-CoV infection in human macrophages in- dritic cells. However, the question arises whether the
duced the expression of a number of proinflammatory triggered innate immune response is beneficial or detri-
chemokines including IP-10/CXCL10 and MCP-1/CCL2. mental in MERS-CoV and SARS-CoV infected patients
On the other hand, the induction of IFN-α and IFN-β, since the host immune response may act as a two-edged
which are important antiviral cytokines and key compo- sword at different stages of disease [42]. Therefore, fur-
nentsofinnate immunity, waslargely absent [35,37]. ther studies are warranted in experimental animals and
patients to elucidate how the virus-host interaction in
Dendriticcells these immune cells affect the pathogenesis of human
Dendritic cells are essential sentinels of the immune coronavirusinfections.
system, which detect invading pathogens and bridge the
innate immune system with the adaptive immune Tlymphocytes
system. Infection of human monocyte-derived dendritic Although lymphopenia is commonly observed in SARS
cells (mDCs) by MERS-CoV was productive as and MERS patients, the exact cause of lymphopenia
Zhouetal.VirologyJournal (2015) 12:218 Page4of7
currently remains unknown. It has been postulated that MERS-CoV infection in vivo. However, so far, no human
SARS-CoV may directly infect Tcells and lead to Tcell autopsy study has been documented. To address the
depletion [43]. However, alternative models for lympho- possible extrapulmonary involvement, we have to seek
penia upon SARS-CoV infection have also been pro- evidence from MERS-CoV infected experimental animals
posed, including sequestrationoflymphocyteswithin the although none of these animals can fully recapitulate the
inflamed tissues, cytokine-induced cell death, as well as humanMERSdisease.
suppression of hematopoietic progenitor cells in bone
marrow or thymus [37]. As for the infection of MERS- MERS-CoV infection and pathogenesis in non-human
CoV, a recent study demonstrated that the infection of primate model and small animal models
human DPP4-transduced and Tcell-deficient mice with The receptor for MERS-CoV was identified to be an
MERS-CoV resulted in the persistence of MERS-CoV in exopeptidase, dipeptidyl peptidase 4 (DPP4) [47]. The
the lungs while the virus was cleared in control mice role of DPP4 as the main determinant in the host trop-
and B cell-deficient mice. These findings hinted that T ism of MERS-CoV has been elucidated in several studies
cells might play critical roles in controlling the patho- [48–50]. Commonly used laboratory animal species such
genesis of MERS-CoV [44]. Subsequently, a study as Syrian hamster, mice and ferrets are not susceptible
published earlier this year directly addressed the issue of to MERS-CoV since DPP4 orthologs of these animal
MERS-CoV infection in T cells. The authors demon- species are unable to bind MERS-CoVspike protein and
strated that Tcells from human peripheral blood mono- mediate virus entry [49, 51, 52]. The MERS-CoV inocu-
nuclear cells, human lymphoid tissues, and the spleen of lation in rabbits displayed an asymptomatic infection.
common marmosets were highly susceptible to MERS- Neither significant histopathological change nor clinical
CoV. Furthermore, MERS-CoV induced substantial symptom was observed in these rabbits although the
apoptosis in the infected Tcells that involved the activa- virus could be detected from lung tissues [53]. Camels
tion of the intrinsic and extrinsic caspase-dependent are susceptible to the MERS-CoV isolated from human.
apoptosis pathways [45]. The results suggested that the Although the infected camels can shed large amounts of
unusual capacity of MERS-CoV to infect Tcells and in- virus from the upper respiratory tract, the disease signs
duce apoptosis might contribute to the high pathogen- were mild [54]. Among all experimental animals tested
icityofthe virus. for the development of MERS animal models, rhesus
The role of T cells in controlling the pathogenesis of macaques developed a mild to moderate respiratory
SARS-CoVinfectionremainsincompletelyunderstood.In infection[55,56] whereascommon marmosetsdisplayed
a mouse study, it was observed that depletion of CD4+ T amoderatetosevererespiratorydiseaseafterinoculation
cells resulted in enhanced interstitial pneumonitis and using a combination routes of intranasal, intra-tracheal,
delayed clearance of SARS-CoV from the lung tissues, oral and ocular [57]. In marmosets, the MERS-CoV in-
whichwasassociatedwithreducedproductionofneutral- fection was suggested to be a disseminated infection
izing antibody and cytokines as well as reduced pulmon- since viral RNA was detectable in nearly all tested
aryrecruitmentoflymphocytes[46]. tissues in all infected animals, including blood, kidney,
intestine, liver and spleen etc. However, except for the
Possible involvement of extrapulmonary organs samples from the respiratory tract, isolation of infectious
upon MERS-CoV infection virus in other organs was not successful. Interestingly,
MERS-CoV viral RNA could be detected in blood, urine the susceptibility of macrophages to MERS-CoV as
and stool specimens of some MERS patients, suggesting evidenced in the in vitro and ex vivo studies was verified
that the virus dissemination may occur [17]. We and in alveolar macrophages of MERS-CoV infected marmo-
others have shown that endothelial cells of blood vessel set[57].
in human ex vivo lung tissues were permissive to The first MERS mouse model was generated by prior
MERS-CoV [23, 33], which may provide the pathological transduction of adenoviral vector expressing human
basis of the potential virus dissemination. In addition, it DPP4 (hDPP4). These mice displayed a transient viral
has been demonstrated that MERS-CoV can infect pneumonia which resolved within 1–2 weeks after infec-
human monocyte-derived dendritic cells and cause pro- tion [44]. Several lines of human DPP4 transgenic mice
ductive viral replication [38]. Human primary Tcells are have been subsequently reported. MERS-CoV infection
also readily susceptible to MERS-CoV [45]. Dendritic and replication were invariably evidenced in these
cells and Tcells are migrating cells in the human body. hDPP4 transgenic mice [58–60]. However, disease sign
Therefore, the MERS-CoV infected dendritic cells and T and pathology in these mice differed, which appeared to
cells may allow the virus to disseminate systemically depend on the promoters controlling the expression of
beyond the respiratory tract. Collectively, extrapulmon- hDPP4 gene. Pascal etal. replaced themouse DPP4 ORF
ary organs and tissues are very likely to be involved in with human DPP4 so that the knocked-in hDPP4 is
Zhouetal.VirologyJournal (2015) 12:218 Page5of7
under the control of the endogenous mouse DPP4 pro- lung tissues of the immunized hDPP4 transduced mouse
moter [60]. The authors believed that this strategy may model [44]. The same group subsequent examined the
render hDPP4 to be expressed in a physiologically- VRP-S in a more permissive hDPP4 transgenic mouse
relevant context. After virus inoculation in these mice, model [59]. The VRP-S immunized hDPP4 transgenic
MERS-CoV robustly replicated in the mouse lung. How- micewerecompletelyprotectedfromlethalinfection.Pre-
ever, the inoculated mice did not exhibit disease signs, treatmentwithserumofthemouseimmunizedwithVRP-
without any extrapulmonary involvement. On the other Scanalsobeprotectedfromfatalinfection[59].Twofully
hand, two lines of hDPP4 transgenic mice which had the human neutralization antibodies binding to distinct epi-
transgene under the control of chicken β-actin promoter topes of MERS spike protein, which were generated using
[58] and cytokeratin 18 promoter [59] respectively, were the mouse expressing human antibody, displayed the pre-
highly permissive to MERS-CoV infection. The mice and post-exposure protection efficacy from MERS-CoV
developed progressive pneumonia with fatal outcome infectioninhDPP4transgenicmice[61].
after intranasal inoculation. The infectious virus can
constantly and exclusively be recovered from lung and Conclusions
brain tissues [58, 59]. Similar to the marmoset study, The pathogenesis of human MERS-CoV infection
while viral RNAcan also be detected from extrapulmon- remains poorly understood. Human respiratory epithe-
ary organs including the heart, spleen and intestines, liumishighlysusceptibletoMERS-CoVandcansupport
virus isolation from these organs was unsuccessful. The productive viral replication. However, MERS-CoV has
hDPP4 transgenic mouse with cytokeratin 18 (CK18) evolved multiple antagonistic mechanisms to attenuate
promoter was generated in parallel with another trans- the induction of antiviral and proinflammatory cytokines
genic mouse line with surfactant protein C (SPC) pro- in the affected epithelial cells. Additionally, MERS-CoV
moter. SPC promoter confers transgene expression in can readily infect and robustly replicate in human mac-
bronchiolar and alveolar epithelia while CK18 promoter rophages and dendritic cells, which elicits the aberrant
can drive a more universal transgene expression in epi- production of proinflammatory cytokines/chemokines.
thelia of liver, kidney, gastrointestinal tract and some MERS-CoVcan also effectively infect human primary T
cells in the nervous system, apart from respiratory tract. cells and induce massive apoptosis in these cells. Al-
The hDPP4 mice with CK18 promoter developed lethal though clinical presentations as well as in vitro and ex
infection after intranasal inoculation of MERS-CoV. In vivo studies implicated the potential virus dissemination
contrast, the same inoculation in the hDPP4 mice with upon MERS-CoV infection, the extrapulmonary involve-
SPC promoter caused no mortality or body weight loss ment has not been ascertained. In the MERS-CoV per-
[59]. Therefore, the morbidity and mortality in human missive animal models, viral RNA can be detected from
DPP4 transgenic mice may correlate to the tissue/cellular multiple organs of the infected animals. However, recov-
distribution and/or the expression intensity of the trans- ery of the infectious virus was unsuccessful in most
gene. Notably, a common discovery among these MERS- extrapulmonary organs. More studies are warranted to
CoVsusceptible animals was that the gene expression of further characterize the tissue tropisms of MERS-CoV
antiviral cytokines, proinflammatory cytokines and che- for the better understanding towards the pathogenesis of
mokines was elevated [55, 57, 58]. Collectively, the tissue MERS.
tropisms of MERS-CoV in human hosts have not been
fully elucidated although there has been accumulating Competinginterests
Theauthorsdeclarethattheyhavenocompetinginterests.
evidence of possible extrapulmonary involvement in
MERS patients. Undoubtedly, hDPP4 transgenic mouse Authors’contributions
studies are conducive for the development of antivirals or JZ,HC,JFWCandKYYallcontributedtoconceivingthecontentandwriting
vaccines against MERS-CoV. However, in terms of impli- thetext.Allauthorsreadandapprovedthefinalmanuscript.
cation for the pathogenesis in human MERS, findings
Acknowledgements
from these hDPP4 transgenic mice must be interpreted ThestudieswerepartiallysupportedbyTheme-basedResearch(TBR)Scheme
withgreatcaution. Anin-depthinvestigation of the tissue (T11/707/15,ResearchGrantsCounciloftheHongKongSpecialAdministrative
Region),NationalScienceandTechnologyMajorProjectsofInfectiousDisease
tropisms of MERS-CoV in human hosts will facilitate our
(2012ZX10004501-004)andHealthandMedicalResearchFund(HMRF14131392,
understanding towards the transmission route and patho- FoodandHealthBureau,TheGovernmentofHongKongSpecialAdministrative
genesisofMERS. Region).
The MERS-CoV mouse models have been utilized to
Authordetails
test the efficacy of antiviral drug, neutralization antibody 1StateKeyLaboratoryofEmergingInfectiousDiseases,TheUniversityof
and vaccine. AVenezuelanequineencephalitis replication HongKong,HongKongSpecialAdministrativeRegion,China.2Department
ofMicrobiology,TheUniversityofHongKong,QueenMaryHospital,102
particle expressingMERS-CoVspike protein (VRP-S) was
PokfulamRoad,HongKongSpecialAdministrativeRegion,China.3Research
demonstrated to substantially reduce the virus titer in CentreofInfectionandImmunology,TheUniversityofHongKong,Hong
Zhouetal.VirologyJournal (2015) 12:218 Page6of7
KongSpecialAdministrativeRegion,China.4CarolYuCentreforInfection, 20. PeirisJS,LaiST,PoonLL,GuanY,YamLY,LimW,etal.Coronavirusasa
TheUniversityofHongKong,HongKongSpecialAdministrativeRegion, possiblecauseofsevereacuterespiratorysyndrome.Lancet.2003;361:1319–25.
China. 21. KindlerE,JonsdottirHR,MuthD,HammingOJ,HartmannR,RodriguezR,
etal.EfficientreplicationofthenovelhumanbetacoronavirusEMCon
Received:5October2015Accepted:1December2015 primaryhumanepitheliumhighlightsitszoonoticpotential.MBio.2013;4:
e00611–00612.
22. ZieleckiF,WeberM,EickmannM,SpiegelbergL,ZakiAM,MatrosovichM,
etal.Humancelltropismandinnateimmunesysteminteractionsofhuman
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