2009 Severe acute respiratory syndrome-coronavirus and human coronavirus-NL63_ an updated overview

2009·0.37 MB·English

Severe acute respiratory syndrome-coronavirus and
human coronavirus-NL63: an updated overview
a a,b
Vanessa Ditt and Oliver Schildgen
Severeacuterespiratorysyndrome-coronavirusandhumancoronavirus-NL63,though
bothbelongingtodifferentgroupsofthesamegenus,areinterestingrepresentativesof
theirkind;thefirstoneisofzoonoticorigin,accountedforthepandemicin2002/2003
thatwasdistributedworldwideandhadamortalityrateofabout10%,theotherone
was identified later and probably has been circulating within the population for
centuries and belongs to those viruses that cause the ‘common cold’. A lot of effort
hasbeenmadetoinvestigatebothvirusesandtounderstandtheirdifferencesandtheir
similarities withregardto further zoonotic events. This review gives an overview of
severe acute respiratory syndrome-coronavirus and human coronavirus-NL63, their
historyandthecurrentstateofresearch.
(cid:2)2009WoltersKluwerHealth|LippincottWilliams&Wilkins
Reviews in Medical Microbiology 2009, 20:19–28
Keywords: coronaviruses, NL63, severe acute respiratory syndrome
Introduction andsimilaritiesandtheircharacteristics.Thisreviewwill
mainly focus on SARS-CoVand HCoV-NL63.
Sincethefirsthumanpathogeniccoronaviruses(HCoV)-
229EandHCoV-OC43wereidentifiedinthe1960sand
associated with mild respiratory diseases [1,2], only little
new information had emerged in this field until the
Identification of severe acute respiratory
beginning of this century. Suddenly the focus was
directed towards coronaviruses again as a special, mean- syndrome-coronavirus and human
while well known member of this group appeared in coronavirus-NL63
2002/2003[3–5]intheprovinceofGuangDong(China)
and caused ‘severe acute respiratory syndrome (SARS)’; Several techniques were employed to characterize and
fatal symptoms that were very unusual for coronaviruses identifythecausativeagentofSARS.Patientmaterialwas
astheywereconsideredtobenonhazardousatthistime. inoculated onto rhesus monkey kidney cells (fRhk4) to
Strenuouseffortsweremadetoidentifyand characterize observe for cytopathic effects; tests for other known
this new pandemic threat and to curb it. respiratory viruses were negative. Electron microscopy
revealedthemorphologyandledtocharacterizationofthe
Amongst the heterogeneous family of coronaviridae virusfamily.Histopathologicalexaminationdisplayedmild
coronavirusNL63(HCoV-NL63)wasidentifiedin2004 interstitial inflammation withscatteredalveolar pneumo-
[6]andcoronavirusHKU1(HCoV-HKU1)in2005[7]. cytes. In an immunofluorescence antibody assay, sera
Compared with SARS-coronavirus (CoV), these newly from patients had high titres of antibodies against the
detected coronaviruses led to clinical symptoms more infectedcells. Random reversetranscriptase-PCR assay
similar to those caused by HCoV-229E and HCoV- generatedDNAfragmentsof unknownoriginbutwith
OC43.Alotofresearchworkhasbeenundertakensince homology toviruses of the familyof coronaviridae and
then to learn more about these viruses, their differences confirmedtheresultsofelectronmicroscopy[5].Afew
aInstituteforVirology,UniversityHospitalBonn,Bonn,andbKlinikenderStadtKo¨lngGmbH,Institutfu¨rPathologie,Cologne,
Germany.
CorrespondencetoPDDrrer.nat.OliverSchildgen,c/oKlinikenderStadtKo¨lngGmbH,Institutfu¨rPathologie,OstmerheimerStr.
200,D-51009Cologne,Germany.
E-mail:[email protected]
Received:24June2009; accepted:8August2009.
DOI:10.1097/MRM.0b013e328331ad24
ISSN 0954-139X Q 2009 Wolters Kluwer Health I Lippincott Williams & Wilkins 19
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
20 Review in Medical Microbiology 2009, Vol 20 No 2
days later, these results were confirmed by two other groups were able to identify the same information soon
groups [3,4]. afterwards [13,14].
Sequence of events There are some hints in the previously published
SARS and its causative agent appeared quite unexpect- literature about coronaviruses that HCoV-NL63 was
edly and spread quite explosively. The infection was detected much earlier. Someviruseswere described that
transmitted from palm civets to humans, although it has didnottotallycorrespondwithHCoV-229EandHCoV-
sincebeenconfirmedthatbatsarethenaturalreservoirof OC43.Unfortunately,theseisolateswerelostsoitcannot
SARS-CoV [8,9]. Because of the fast mutation rate of be checked whether one or more were identical to
RNAviruses and their resulting genotypic markers, the HCoV-NL63 [6].
course of infection could be reconstituted very exactly.
In the early phase of the SARS pandemic, the very first
index patient fulfilling the subsequent WHO defini- Taxonomy and genome structure
tion of SARS appeared in Foshan near Guangzhou on
16 November 2002. One month later, the second case Both SARS-CoVand HCoV-NL63 are members of the
occurred in Shenzhen; a man who had regular contact genus Coronavirus, belonging to the family of Corona-
withwildanimalswasaffectedandinfectedhisfamilyand viridae within the order Nidovirales. Both viruses are
several staff members from the hospital towhich he was positive single-strand RNAviruses with a large genome
admitted. Similar cases were reported nearby. of about 30kb in size. Virus particles are enveloped and
possess peculiar spike proteins on their surface leading
InJanuary2003,thesecondphaseoftheSARSoutbreak to their crown-like appearance. Electron microscopy
started in Guangzhou. Several affected people became revealed particles of 80–140nm located either inside
fatally ill and were transferred to the major hospitals infected cells at the rough endoplasmic reticulum in
where they accounted for nosocomial spread to other double-membranevesiclesoroutsidethecellattachedto
patients and healthcare workers. the plasma membrane.
The next and final phase started in mid-February and The genome of both SARS-CoVand HCoV-NL63 can
heraldedthebigpandemic,whenadoctorwasinfectedin be roughly divided into two parts. The 50 two-thirds
GuangdongprovinceandtookthediseasetoHongKong consist of one large polyprotein (ORF1ab) including
where he stayed in a hotel (‘hotel M’). Seventeen other several domains with autocatalytic activities, thus pro-
people were infected by him and were admitted to ducing nonstructural proteins (NSPs) involved in repli-
different hospitals where further nosocomial infections cation and immune evasion. ORF1ab encodes 16 NSPs
occurred. Some of the infected people transferred the in toto in both SARS-CoVand HCoV-NL63.
virus via air travel to Vietnam, Singapore and Toronto
where new sources of infection emerged. The last third at the 30 end of the genome contains the
ORFs coding for the functional proteins: spike (S),
On21March2003,anovelcoronaviruswasidentified[5] envelope (E), membrane (M), nucleocapsid (N) and
and a few days later confirmed [3,4]. The first strain further accessory proteins genes varying in number and
(Tor2)wasfullysequencedon12April2003andSARS- position from species to species.
CoVwasproventobethecausativeagentforSARS[10].
InJuly2003,theepidemicendedafternofurtherhuman- Traditionally, coronaviruses are classified – due to their
to-human transmissions were reported. In September antigenic cross reactivity – into three different groups,
2003, a new case was reported from a laboratory in which were mainly confirmed later by performing
Singaporeandduringthenext2yearsotheraccidentsin sequenceanalysis.GroupIandIIvirusesafflictmammals,
laboratories occurred. whereas viruses from group III infect exclusively birds.
While HCoV-NL63 belongs to the group 1b, SARS-
HCoV-NL63 was discovered in a 7-month-old child CoVaswellasbatcoronavirusesareconsideredgroup2b
with bronchiolitis. Diagnostic tests for all known viruses, although the latter rather represent a new group
respiratory viruses were negative. The sample with the of coronaviruses.
unknown agent was inoculated on cell culture and a
cytopathic effect could be observed on tertiary monkey HCoV-NL63ismostcloselyrelatedtoHCoV-229E,and
kidney (tMK and LLC-MK2) cells. In the supernatant phylogeneticanalysissupportsthefactthatHCoV-NL63
of the latter, a new virus could be identified by using diverged from HCoV229E in the 11th century [15].
the Virus discovery based on cDNA-AFLP (VIDISCA) Furthermore,thereseemtobetwomaingeneticclusters
method[11,12].Sequencecomparisondisplayedthatthe of HCoV-NL63 [16], and there is evidence that the
virus is most closely related to HCoV-229E and belongs genome of HCoV-NL63 is arranged in a mosaic-like
to the subgroup 1b coronaviruses. Two further research manner [15].
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
SARS-CoV and HCoV-NL63: an updated overview Ditt and Schildgen 21
Disease/virology and public transportation. The virus could be detected
not only in the respiratory tract but also in the
PatientsinfectedwithHCoV-NL63generallysufferfrom gastrointestinal tract, liver, kidney and brain as well as
only mild symptoms, including cough, rhinitis, rhinor- other tissues [49].
rhoea and pharyngitis,often together with fever [17]. In
rare cases, pneumonia can occur. Mostly children from The seroprevalence was quite low amongst the general
zero to 3 years and older people as well as immuno- population,rangingfromzeroto1.81%dependingonthe
compromised individuals are afflicted. performed study and slightly higher in asymptomatic
healthcare workers. In contrast, a much higher rate was
In children suffering from severe lower respiratory tract found in asymptomatic animal handlers (up to 40%),
infections, a substantial number had croup compared which is not surprising, as they have probably acquired
withacontrolgroup[18–21].Crouporlaryngotracheo- immunity by less pathogenic SARS-CoV-like strains,
bronchitis is characterized by a loud barking cough, which also emerged by zoonotic recombinations [50].
inspiratory stridor and hoarseness. Also, an association An infection with SARS-CoV can be accompanied by
with Kawasaki disease has been postulated [22] but copathogens such as other respiratory viruses, hMPV, or
couldnotbeconfirmedbyanumberofresearchgroups other coronaviruses [38].
[23–25].
After its detection in the Netherlands and later on in
NewHaven,USA,thepresenceofHCoV-NL63couldbe Viral life cycle
proveninanumberofcountries,suggestingaworldwide
distribution [17,18,21,26–36]. Out with subtropical Viral entry
regions, HCoV-NL63 was mainly detected in winter It is amazing that both viruses use the same receptor for
monthsandoftenturnedupwithothercopathogenssuch cell entry as SARS-CoV and HCoV-NL63 are only
as influenza, respiratory syncitial virus, parainfluenza and distantly related and belong to different groups.
human metapneumovirus (hMPV) [13,18,20,26]. The Angiotensin I converting enzyme 2 (ACE2), a cellular
viral load of HCoV-NL63 is attenuated when accom- metallopeptidase, negatively regulates the conversion of
panied by another pathogen [18]. However, and not angiotensinItoangiotensinIIbyACEandispartofthe
surprising,theinfectionitselfseemstobestrongerwhena renin–angiotensin–aldosterone system that contributes
challenge with two pathogens had occurred [16]. Like to the regulation of the cardiovascular system.
SARS-CoV, HCoV-NL63 is detectable up to 2 months
aftertherecoveryfromthedisease[30,37].Seroprevalence Especially for HCoV-NL63, the use of another receptor
studies showed that virtually every adult encounters would have been more likely as it is closest related to
HCoV-NL63 infection at least once in a lifetime. HCoV-229E, which enters the cell via CD13 [51].
AntibodiesspecificfortheSproteinarepresentandeven Despite of this similarity, there are some different
displaya neutralizing effect [6]. featuresconcerningentryandreplicationasbothSARS-
CoVand HCoV-NL63 cause harm to such a different
People infected with SARS-CoV suffered from fever, extent.
chills,myalgia,rigorandanonproductivecough.Clinical
symptoms such as rhinorrhoea and sore throat could be It could be demonstrated that both viruses engage the
detectedlessoften.IncontrasttoHCoV-NL63,children cellular receptor inadifferentwayasmutationsinACE2
werenotaffected[38–40]butnormalandhealthyadults leadtoanimpairmentofSARS-CoVbinding,butdonot
as well as old people were susceptible. change binding properties between HCoV-NL63 and
ACE2 [52]. The interaction of HCoV-NL63 S-protein
Of8096infectedpeople,774died,whichaccountsfora turnedouttobegenerallyweakerthanbindingofSARS-
mortality rate of almost 10%. SARS-CoV was spread CoVS-proteinasthebindingsitesareindeedsimilarbut
worldwide in more than 30 countries [3–5,10,39,41– not identical [53].
46].Thefirstoutbreakoccurredinlate2002/early2003.
Seasonalityof SARS-CoVinfection isnot knownas the EntryofHCoV-NL63islessdependentonlowpHthanit
pandemic occurred just once, with its peak occurring is for SARS-CoV and does not need the cathepsin L
in winter. function [54].Furthermore,it isknownforSARS-CoV
thatafterbindingtoACE2,boththevirusparticleaswell
It is meanwhile confirmed that SARS-CoV can be astheboundreceptorsareinternalized,thusreducingthe
ascribedtoazoonoticoriginprimarilyfrombats[47,48]. amountofACE2onthecellsurface.ACE2isessentialfor
AlthoughSARS-CoVwasinitiallyspreadformcivetsto cleaving of ACE, a molecule that positively affects lung
humans [41], the actual transmission route was from injuryduring respiratorydisease;therefore,downregula-
human to human most likely by droplets and occurred tion of ACE2 could account for the exacerbation of the
most likely within healthcare facilities, workplaces lung’s state during SARS [55].
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
22 Review in Medical Microbiology 2009, Vol 20 No 2
Nonstructural proteins Accessory proteins
Formostofthe16NSPs,thestructurecouldbeidentified Thepresence of accessoryproteins variestoa bigextent
and a putative function could be predicted or even in SARS-CoVand HCoV-NL63. Whereas SARS-CoV
confirmed. NSP1 is known to playan important role in contains ORF3a and b, 6, 7a and b, 8, 9b and an
immune system evasion [56,57]. The function of NSP2 additionalORFwithintheNgene,thereisonlyORF3
andNSP11hasyettobedetermined.NSP3containstwo existing in HCoV-NL63. It is supposed that they
papain-like proteases (PLPs) that – together with the somehow play a role in replication, but currently, only
mainprotease(Mpro)encodedinNSP5 – areresponsible accessory proteins from SARS-CoV are known to
forprocessingthepp1aandpp1ab.Furthermore,NSP3is interfere with the IFN defence mechanism [74–76].
important for virion assembly and immune evasion.
Interferon and innate and immune response
NSP4andNSP6 – togetherwithNSP3-arethoughtto TheexpressionofIFNisabasicreactionoftheimmune
function indouble-membranevesicle (DMV)formation systemtoinitiatearesponseagainstpathogensinfiltrating
but this assumption has yet to be confirmed. NSP 7– host cells [77–79]. IFN-secreting cells alert their
NSP10allseemtobeessentialinthereplicationprocess, neighbouring cells to produce a subset of antiviral
and in contrast to NSP1 and NSP3, they are highly proteins to inhibit viral amplification. This is accom-
conserved. NSP8 could probably function as a primase plishedbycomponentsoftheinnateimmunesystemthat
[58]. Together with NSP7, it forms a structure with are able to sense typical pathogen patterns inside or
RNA-bindingproperties[59].NSP9issupposedtoplaya outsideof acell.Oncevirusessucceedinenteringahost
certain role in RNA binding as well [60]. NSP12 is cell,therearemoleculessuchasRIG-IandMyD88that
a RNA-dependent RNA polymerase and NSP13 is a are able to recognize uncapped double-stranded (ds)
helicase.NSP8 seemsto playa keyrolein theprocessof RNA. By initiating a signalling cascade via the
replication as it could be demonstrated that there are membrane-bound mitochondrial antiviral signalling
interactions with almost every NSP involved in replica- (MAVS) protein, via TANK-binding kinase 1 (TBK1)
tion[61].NSP14hasa30–50exonucleaseactivity,andlike and IkB kinase e, interferon regulatory factor 3 (IRF3)
NSP16,itfunctionsasamethyltransferaseforRNAcap becomes phosphorylated and dimerizes. After transloca-
formation [62,63]. At last, there is NSP15, a unique tionintothenucleus,expressionofIFNbisactivatedand
proteinamongst all nidovirales and which is essential for thereafter secreted where it stimulates nearby cells and
replication. It is an urydilate-specific endoribonuclease enhances the cells’ own activation. Toll-like receptors
(NendoU), but its role for viral replication remains (TLRs)recognizepathogenstructuresoutsideofthecell.
unclear to date [58,64]. DependingontheTLR,differentpathwaysareactivated
to stimulate IFNb expression.
Structural proteins After binding of IFNb to its appropriate receptor on a
Viral RNA is located within a bilayer containing the hostcell,theexpressionofmorethan100genesencoding
structural proteins S, E and M. The last one is the antiviral proteins is implemented by signalling via the
most abundant protein and plays an important role in Janus kinase 1/tyrosine kinase 2 kinases. After activation
the assembly of new emerging virus particles and the ofbothkinasesbyIFNb,signaltransducerandactivatorof
incorporation of other viral components [65]. The transcription 1 and 2 (STAT1 and STAT2) are activated
S-protein is a glycosylated surface protein that associates leading to the formation of the interferon-stimulated
withthehostcellreceptor,thusallowingtheentryofthe gene factor 3 complex, which in turn has the ability to
virionbyfusionwithACE2.Itisnotimportantforvirus activate expression of those antiviral proteins mentioned
assembly or budding. The envelope protein (E) is an above.
integral membrane protein that does not appear
abundantly on the cell surface and forms ion-like Coronaviruses have developed strategies to undermine
channels on membranes of infected cells [66]. It has the immune response at distinct sites of these signalling
a crucial role in virus morphology and budding [67,68] cascades.Duringthereplicationphase,ahugeamountof
and – for yetunknownreasons – isessentialforgroupI dsRNAisproduced,butdoesnotactivatetheIFNsystem
coronaviruses such as HCoV-NL63 but not for group II [80,81].
coronavirusessuchasSARS-CoV,althoughlackoftheE
proteincouldleadtoattenuationofreplicationinvivoasit Cells make use of both an active and passive evasion
isconfirmedwithmousehepatitisvirus(MHV)[69,70]. system. On one side, theyare able to hide their dsRNA
from the cell, probably in an endoplasmic reticulum–
The N protein is the only structural protein that is not Golgi intermediate compartment as coronaviruses are
present on the cell surface. By self-association and supposedtoreplicateinthoseDMVs[82].Ontheother
interaction with M, it is neededfor the encapsidation of side, there are several proteins involved in blocking the
theRNAgenome.Furthermore,itisknownforbeinga inductionofIFN,namelyN,thereplicaseproteinsNSP1
strong interferon (IFN) antagonist [71–73]. and NSP3 and the two accessory proteins ORF6 and
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
SARS-CoV and HCoV-NL63: an updated overview Ditt and Schildgen 23
ORF3b.Todate,onlyaccessoryproteinsofSARS-CoV donotdemonstrateclinicalsignsofillness;butinthelast
could be associated with antagonizing IFN pathways few years, they were successfully used as a model for
[74,76]. evaluation of vaccinesand antiviral therapies[89,90].
In expression assays, it could be demonstrated that N of The possible use of ferrets as an optimal model for
SARS-CoV inhibits nuclear factor kappa B (NFkB) studying SARS has been controversially discussed
signalling. It is very likely that other components are [91,92], but recent results demonstrate that they
affected by N as well, but studies carried out so far constitute a good model as they display virus replication
were mainly performed with MHV. NSP1 intervenes in intheupperandlower respiratorytractandclinicalsigns
more thanonewayto block IFNinduction. It is able to such as fever, sneezing, lung damage and a similar blood
degrade not only IFN mRNA but also host mRNA as count compared with humans and, therefore, provide a
well, which seems to be important for inhibiting IFN possibility for studying antiviral therapeutics [93–95].
expression[56].Inotherstudies,itcouldbeobservedthat
NSP1affectsthesignallingpathwaysbyblockingSTAT1 Different inbred mouse strains have been tested so far
phosphorylation and IRF3 dimerization [57]. with different results. SARS-CoV is not able to cause
comparable respiratory symptoms of illness in young
NSP3isanotherIFNantagonist.ThePLPseemstocarry BALB/C or C57/BL6 mice, although virus replication
over much of IFN inhibitory function [83]; PLP may peaks at days 2–3 later and slightly elevated levels of
blocktheNFkBpathwayoraffectIRF3[75,83].ORF6 tumour necrosis factor alpha (TNFa) and moderate
makesuseof atotallydifferenteffectnamelybyaffecting interstitial pneumonitis at day 3 could be demonstrated
karyopherin, thus preventing nuclear translocation of [96–98].Pronouncedsigns ofclinicalillnesscanbeseen
IFN-inducing factors such as STAT1 [84]. in 129S6 mice [88,99].
In aged BALB/C mice, the infection with SARS-CoV
leads to a more severe disease than in young BALB/C
Animal models mice, mimicking the age-related course of infection in
humans [100]. This makes the aged BALB/C mouse
In-vivomodelsthatmimicthenaturalcourseofinfection an excellent animal model for studying SARS-CoV
in humans are necessary and essential for carrying out pathogenesisastheynotonlysupportviralreplicationbut
fundamental research and assessing efficacy of antiviral also display clinical signs of illness as well as several
drugsandimmunizationreagents.Unfortunately,thereis histopathological findings [88].
currently no usable animal model available for studying
HCoV-NL63 infection. AsimilareffectwasalsoobservedforC57/BL6and129S6
mice but with less prolonged viral shedding within the
In contrast, a lot of animals were tested for their lungsofthe129S6mice.Earlyhistopathologicalchanges
susceptibilitytoSARS-CoV.Severalnonhumanprimates in the lungs of 129S6 and C57/BL6 mice displayed
wereinfectedwithSARS-CoV;allwereabletoreplicate similar results.
SARS-CoV within their lungs and display clinical
symptoms to avarying extent depending on the species. Fromalltestedmousemodelswithspecificgenedeletions
(knockoutmice),onlytheSTAT1(cid:2)/(cid:2)micewith129S6
Infectedmacaquesdemonstratedclinicalandpathological background displayed a significantly different outcome
features, diffuse alveolar damage, formation of hyaline from wild type strains [88,99].
membranes and pneumocytic type II hyperplasia similar
to those found in humans [42]. Furthermore, it was
observedthattheseanimalsdisplayedasimilar patternof
upregulated chemokines and cytokines compared with Ageing and pathogenesis
infected humans [85].
As seen with many infections and diseases, there is a
On the contrary, African green monkeys did not display clear tendency for enhanced suffering and more severe
anysignificantlungdisorder,althoughtheviruswasableto clinicalsymptomsinchildrenandolder people,withan
replicateintherespiratorytract[86].Consideringthelack increased mortality rate for the latter group. Although
of consistency, the cost and handling of primates, small childrendonotpossessasufficientlydevelopedimmune
animal models are preferred for studying SARS-CoV system,theproblemfortheelderlyiscertainlythattheir
infection. It could be demonstrated that golden Syrian immune system has somehow lost its ability to fight
hamsterscanreplicatedifferentSARS-CoVstrainstohigh pathogens properly. So the elderly represent a high-risk
titresaccompaniedbypathologicalchangesafterinfection group for both viruses. Not much is known on a
with different SARS-CoV strains as Urbani, Frankfurt molecularlevelaboutthisphenomenontermed‘immu-
(FFM)andHongKong(HK)[87,88].Unfortunately,they nosenescense’.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
24 Review in Medical Microbiology 2009, Vol 20 No 2
What has been found out so far is that the effect of thenaturalHR2fortheHR1-bindingpositionsandthus
vaccination with SARS-CoV decreases in mice with preventing fusion and virus entry [102,113].
increasing age. After challenging with SARS-CoV, the
adaptive immune system of old mice does not display Another possibility is the use of specific antibodies
theabilitytogenerateanappropriateresponseagainstthe directed against the HR regions of the S protein. These
virus as is seen in young mice [101]. So far studies with antibodies were able to inhibit viral replication in vitro
other viruses have been performed with controversial [114]. The RNA interference technology is also
results, but further studies on SARS-CoVand HCoV- applicable via inhibition of viral replication at the
NL63 are still outstanding. transcriptional level. Small interfering RNAs (siRNAs)
directed against conserved regions of the spike protein
weretestedfortheirantiviraleffectsanddisplayedastrong
inhibition of virus replication in cell culture. Especially,
Antiviral agents the combination of several siRNAs at the same time
displayed good results with both HCoV-NL63 and
Currently,thereisnoeffectiveantiviraltreatmentagainst SARS-CoV [102,115].
HCoV-NL63 and SARS-CoV available. Several agents
havebeentestedfortheirantiviraleffectinvitro,affecting The usage of nucleoside analogues can also inhibit viral
thereplicationcycleatdifferentstages.Particularlythose replication of HCV-NL63 in cell culture, even though
that affect replication at the early stages of infection themolecular mechanismfor thiseffectisunclear[102].
appearedtobecandidateswithgoodprospects.Amongst The purine nucleoside analogue ribavirin was given to
those promising agents against HCoV-NL63 are immu- patients during the SARS outbreak. The dosages and
noglobulins–obtainedfromhealthyvolunteers–thatare mode of administration were not standardized and was
administered intravenously [102]. In the past, they often accompanied byadverse effects such as haemolytic
displayed good results in treating immune deficiencies, anaemia, hypomagnesaemia, calcaemia or all [116].
autoimmune neuromuscular disorders, respiratory dis- Animalstudieswithribavirinhavenotbeenencouraging
eases and Kawasaki disease [103,104]. Good results were [117],andwhentestedinvitro,theeffectofribavirinwas
demonstrated with neutralizing antibodies, as well from highly dependent on the cell types used. But when
human as from nonhuman origin in different animal ribavirin was combined with type I IFNs, promising
models.Equineantibodieslimitedinfectioninagedmice, results could be demonstrated in vitro [118].
Syrian and Chinese hamsters, in rats and even in
macaques [105–108]. Protease inhibitors turned out to be quite powerful in
suppressing viral replication at a posttranslational level.
Antibodies of human origin have the advantage of not Replication of HCoV-NL63 and SARS-CoV requires
beingdegradedsorapidlyandtoprovideahigherefficacy proteolytic processing of pp1a and pp1ab by the Mpro
than those of nonhuman origins. Apart from the andaPLP.Recently,severalagentshavebeenidentifiedto
possibility to generate human antibodies by immunizing inhibit Mpro, mostly by direct targeting of the catalytic
and by exploiting the hybridoma cell line technique, site of the enzyme [119–125].
phage display is now available. A self-constructed or
commercially available human antibody library can be
screened for antibody fragments that specifically bind to
an antigen of choice. With this technique, an antibody Conclusion
againsttheSproteinofSARS-CoVwasidentified[109],
which turned out to be very successful in cell culture. Itisnow6yearssincethebigSARSpandemicoccurred.
The efficacy of a neutralizing antibody can be further Alotoftimeandefforthasalreadybeeninvestedandwill
enhanced by using several antibodies in parallel, all of beinthefuture.Sothequestionariseswhetherthiseffort
them targeting different epitopes [110]. isworthmaking?IstherereallyachancethatSARS-CoV
will come back?
For SARS-CoV, other immunomodulators corticoster-
oids, pentaglobulin, thymosin, thalidomide and anti- AlthoughSARS-CoVmaynotreemerge,thereisagood
TNF were used for the first time during the epidemic chancethatotherzoonoticcoronaviruseswillappearwith
[111,112]. Another possibility is to disturb the fusion similar devastating potential. Coronaviruses do recom-
process of the viral spike protein and the ACE2 host bineandhavetheabilitytocrossspeciesbarriers,soitmay
receptor with artificial peptides. The heptad repeat bejustaquestionoftimewhenthenextnewcoronavirus
regions1and2(HR1andHR2)ofthespikeS2domain turns up.
undergo a conformational change when binding to the
ACE2 receptor, thus allowing fusion of the viral and Soeffortsthataremadeinthisfieldsofararenotinvain,
cellular membrane. Applied HR2 derivatives are able to and there remains a lot of work to be done. Although
reduce viral replication, presumably by competing with much has been found out about the appearance and
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
SARS-CoV and HCoV-NL63: an updated overview Ditt and Schildgen 25
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