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PATHOGENICCORONAVIRUSESOF HUMANSANDANIMALS Thispageintentionallyleftblank
PATHOGENIC CORONAVIRUSES OFHUMANSAND ANIMALS SARS,MERS,COVID-19,andAnimal CoronaviruseswithZoonoticPotential
LISA A.BELTZ,Ph.D. MicrobiologyandPublicHealth
AcademicPressisanimprintofElsevier
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Dedication ThisbookisdedicatedtoallofthosewholosttheirlivestoSARS,MERS,or COVID-19.
Thispageintentionallyleftblank
Contents Listoffiguresxiii
Listoftablesxv
Acknowledgmentsxvii
1.Introduction1
1.1Ofvirusesandmen1
1.1.1Coronavirusesofhumans2
1.1.2Factorsaffectingzoonotictransmissionof coronaviruses3
1.2Abriefintroductiontoviruses5
1.2.1Characteristicsofviruses5
1.2.2Overviewofmutationsand recombinationinviruses6
1.2.3Virusesandtheirhostreceptors7
1.2.4BaltimoreclassIVviruses7
1.2.5Viruses,diseases,andpandemics— victoriesandfailures7
1.2.6Vaccination—thenandnow11
1.2.7Comparisonofviruses,bacteria,and eukaryoticcells12
1.3Abriefintroductiontotheimmunesystem13
1.3.1Introductiontotheinnateimmune system14
1.3.2Thecellsoftheinnateimmune system14
1.3.3Introductiontotheadaptiveimmune system15
1.3.4Thecellsoftheadaptiveimmune system16
1.3.5Cytokinesandchemokines17
1.3.6Antibodies20
1.4Introductiontocoronaviruses22
1.4.1Coronavirusgenomicandsubgenomic RNA23
1.4.2Increasinggeneticdiversitybymutation andrecombinationincoronaviruses23
1.4.3Productionofrecombinant,chimeric coronaviruses25
1.4.4Coronaviruses’structuralproteins25
1.4.5Coronaviruses’nonstructural proteins28
1.4.6Abriefsummaryofthecoronaviruslife cycle29
1.4.7Viraltransmission31
1.5Coronavirusesanddisease34
1.5.1Coronavirusesandrespiratory disease34
1.5.2Coronavirusesandcentralnervous systemdisease34
1.5.3Othercoronavirusdisease manifestations37
1.6Categoriesofcoronaviruses37
1.6.1Coronavirusgenera37
1.6.2Coronavirusesofanimalsandzoonotic diseasepotential38
1.7Treatmentofcoronavirusdiseases40
1.7.1Chloroquine40
1.7.2Nucleicacidanalogs41
1.7.3Traditionalmedicinalcompounds41
1.8Preventionofcoronavirusinfection44 References45
2.Severeacuterespiratorysyndrome (SARS)53
2.1Introduction53
2.1.1Abriefoverviewofthe2002 2003 severeacuterespiratorysyndromecoronavirusoutbreak53
2.1.2Phasesofthe2002 2003outbreak53
2.1.3“WetMarkets”andwildcatsand dogs54
2.1.4Thesevereacuterespiratorysyndromecoronavirusspikeproteinandits angiotensin-convertingenzyme2 receptor54
2.2Thehistoryofsevereacuterespiratory syndrome56
2.3Severeacuterespiratorysyndrome—the disease58
2.3.1Anoverviewofsevereacuterespiratory syndrome58
2.3.2Severeacuterespiratorysyndromeand therespiratorysystem61
2.3.3Severeacuterespiratorysyndromeand thecardiovascularsystem67
2.3.4Severeacuterespiratorysyndromeand theskeletalsystem68
2.3.5Severeacuterespiratorysyndromeand thedigestivesystem68
2.3.6Severeacuterespiratorysyndromeand theurinarysystem69
2.3.7Severeacuterespiratorysyndromeand nervoussystem69
2.3.8Severeacuterespiratorysyndromeand theendocrinesystem71
2.3.9Severeacuterespiratorysyndrome,the reproductivesystem,andsex-related diseaseseverity72
2.4Thecausativevirus73
2.4.1Anoverviewofsevereacuterespiratory syndrome-coronavirus73
2.4.2Entryofsevereacuterespiratory syndrome-coronavirusintocells75
2.4.3Viralpolyproteinsandproteases75
2.4.4Severeacuterespiratorysyndromecoronavirusandtheubiquitinpathway76
2.4.5Severeacuterespiratorysyndromecoronavirusandtheunfoldedprotein response77
2.4.6Severeacuterespiratorysyndromecoronavirusopenreading frame878
2.4.7Severeacuterespiratorysyndromeand smallnon-codingRNAs79
2.4.8Severeacuterespiratorysyndromecoronavirusandbats80
2.4.9Transmissionofsevereacute respiratorysyndromebetween humans82
2.4.10Severeacuterespiratorysyndromecoronavirusintheexternal environment83
2.5Theimmuneresponse84
2.5.1Introductiontosevereacuterespiratory syndrome-coronavirusandtheimmune system84
2.5.2Severeacuterespiratorysyndromecoronavirusandtheadaptiveimmune response85
2.5.3Severeacuterespiratorysyndromecoronavirus,cytokines,and chemokines87
2.5.4Severeacuterespiratorysyndromeand interferons89
2.5.5ThesevereacuterespiratorysyndromecoronavirusEproteinandtheimmune response90
2.5.6Severeacuterespiratorysyndromecoronavirusandtheinnateimmune response90
2.5.7Animalmodelsandtheimmune responsetosevereacuterespiratory syndrome93
2.5.8Severeacuterespiratorysyndromecoronavirusandescapefromtheimmune response100
2.5.9Severeacuterespiratorysyndrome immunopathology100
2.6Treatmentoptions101
2.7Diagnosis103
2.8Prevention105
2.8.1Physicalmeansofprevention105
2.8.2Immunization107
2.8.3Activeimmunization108
2.9Surveillance112
References113
3.MiddleEasternrespiratory syndrome125 3.1IntroductiontoMiddleEasternrespiratory syndromeandMiddleEasternrespiratory syndromecoronavirus125
3.1.1AbriefintroductiontoMiddleEastern respiratorysyndrome125
3.1.2AbriefIntroductiontoMiddleEastern respiratorysyndrome-coronavirus125
3.1.3TransmissionofMiddleEastern respiratorysyndrome-coronavirusto humans126
3.2Thehistory128
3.3Thedisease129
3.3.1IntroductiontoMiddleEastern respiratorysyndromeinhumans129
3.3.2ThemortalityrateofMiddleEastern respiratorysyndrome130
3.3.3MiddleEasternrespiratorysyndrome andtherespiratorysystem131
3.3.4MiddleEasternrespiratorysyndrome andthekidneys132
3.3.5MiddleEasternrespiratorysyndrome andthecardiovascularsystem132
3.3.6MiddleEasternrespiratorysyndrome andthenervoussystem133
3.3.7RiskfactorsforMiddleEastern respiratorysyndromeinhumans133
3.4Thecausativevirus136
3.4.1MiddleEasternrespiratorysyndromecoronavirusclassification136
3.4.2GeneticvariationinMiddleEastern respiratorysyndrome-coronavirus137
3.4.3DPP4andtheviralSproteininMiddle EasternrespiratorysyndromecoronavirusandMiddleEastern respiratorysyndrome-coronavirus-like virusesofhumansandanimals137
3.4.4OthermoleculesinvolvedinMiddle Easternrespiratorysyndromecoronavirusentryintoitstarget cells139
3.5AnimalhostsofMiddleEasternrespiratory syndrome-coronavirus140
3.5.1MiddleEasternrespiratorysyndromecoronavirusandbatsasreservoir hosts140
3.5.2MiddleEasternrespiratorysyndromecoronavirusanddromedary camels142
3.5.3MiddleEasternrespiratorysyndrome andBactriancamels146
3.5.4MiddleEasternrespiratorysyndromecoronavirusandothercamelids146
3.5.5MiddleEasternrespiratorysyndromecoronavirusinotheragricultural animals147
3.5.6MiddleEasternrespiratorysyndromecoronavirusandotheranimals148
3.5.7AnimalmodelsofMiddleEastern respiratorysyndrome148
3.6Theimmuneresponse150
3.6.1MiddleEasternrespiratorysyndrome andTlymphocytes150
3.6.2MiddleEasternrespiratorysyndrome,B lymphocytes,andAntibodies151
3.6.3MiddleEasternrespiratorysyndrome, dendriticcells,monocytes/macrophages, andneutrophils151
3.6.4MiddleEasternrespiratorysyndrome, cytokines,andchemokines152
3.6.5MiddleEasternrespiratorysyndrome andinterferons153
3.6.6MiddleEasternrespiratorysyndromecoronavirusescapemechanisms153
3.7Diagnosis154
3.8Treatment154
3.8.1Generalized,physicaltreatments154
3.8.2IntroductiontoMiddleEastern respiratorysyndromedrugtreatment options155
3.9Traditionalmedicinalcompounds158
3.10Prevention159
3.10.1Decontaminationofenvironmental surfaces159
3.10.2Vaccination160 References163
4.COVID-19173 4.1Introduction173
4.1.1Severeacuterespiratorysyndrome coronavirusandotherhuman coronaviruses173
4.1.2Numberofcases,deaths,and vaccinations173
4.1.3Spreadofsevereacuterespiratory coronavirus-2175
4.1.4Factorsaffectingdeterminationof COVID-19cases176
4.1.5Unprepared177
4.1.6Severeacuterespiratorysyndrome coronavirus-2andanimalhosts177
4.2History178
4.3Thedisease180
4.3.1IntroductiontoCOVID-19180
4.3.2COVID-19andtherespiratory system181
4.3.3COVID-19,smoking,andnicotine use182
4.3.4COVID-19andthecardiovascular system183
4.3.5COVID-19,endothelialdysfunction, complement,andcoagulation184
4.3.6COVID-19andneurological disease187
4.3.7COVIDandpsychiatricdisease188
4.3.8COVID-19andspecialsenses190
4.3.9COVID-19andtheendocrine system192
4.3.10COVID-19andtheurinary system195
4.3.11COVID-19andthedigestive system198
4.3.12COVID-19andtheintegumentary system199
4.3.13COVID-19andbiologicalsex202
4.3.14COVID-19casenumberandseverityin childrenandadults205
4.3.15Multisysteminflammatorysyndromein children206
4.3.16LongCOVIDsyndrome(chronicor post-COVID-19syndrome)207
4.3.17Theroleofgeneticfactorsin COVID-19208
4.4Thecausativevirus209
4.4.1Introductiontosevereacuterespiratory syndromecoronavirus-2209
4.4.2Thequestionofthereservoirand intermediatehostsofsevereacute respiratorysyndromecoronavirus-2210
4.4.3Comparisonofsevereacuterespiratory syndromecoronavirusandsevere acuterespiratorysyndrome coronavirus-2212
4.4.4Transmissionofsevereacuterespiratory syndromecoronavirus-2213
4.4.5Severeacuterespiratorysyndrome coronavirus-2mutations213
4.5Theimmuneresponse214
4.5.1COVID-19andtheadaptiveimmune response215
4.5.2COVID-19immunopathology—IL-17 andthecytokinestorm219
4.5.3COVID-19andtheinnateimmune response219
4.5.4COVID-19andautoimmune disorders223
4.6Diagnosisandsurveillance224
4.6.1RNA-based(genetic)tests225
4.6.2Antibody-based(serological)testsfor severeacuterespiratorysyndrome coronavirus-2infection228
4.6.3Viralneutralizationtests232
4.6.4Surveillance232
4.7Treatment233
4.7.1Medicationsandmonoclonal antibodies233
4.7.2Traditionalmedicinalcompounds237
4.8COVID-19,micronutrients,andvitamin D238
4.8.1COVID-19andzinc238
4.8.2COVID-19andcopper239
4.8.3COVID-19andselenium240
4.8.4COVID-19andiron240
4.8.5COVID-19andvitaminD241
4.9Prevention243
4.9.1Rapid,massscanningmeasures243
4.9.2Personalprotectiveequipmentandsocial distancing243
4.9.3Handhygiene243
4.9.4Decontaminationofinfected surfaces244
4.9.5COVID-19,quarantine,andclosureof businesses,schools,andrecreational areas245
4.9.6Naturalimmunity246
4.9.7Vaccinesagainstsevereacuterespiratory syndromecoronavirus-2infection248 References251 Furtherreading273
5.Coronavirusesofwildand semidomesticatedanimalswiththe potentialforzoonotictransmission275
5.1Introduction275
5.2Transmissionofcoronaviruses275
5.2.1Geneticrecombinationbetween coronavirusanimalhosts277
5.2.2Theviralspikeproteinandhost coronavirusreceptors278
5.2.3Introductiontocoronavirusesand intracellularsignalingpathways279
5.2.4Coronavirusvaccines279
5.2.5Severeacuterespiratorysyndromevirus2anditsanimalhosts280
5.3Coronavirusesofbats281
5.3.1Introductiontobatcoronaviruses281
5.3.2WIV1,WIV16,SARS-CoV,and adaptationtodifferenthostspecies282
5.3.3Chimericbatcoronavirusesandsevere acuterespiratorysyndromevirus283
5.3.4Thespikeproteinofbatandhuman coronavirusesandangiotensinconvertingenzyme2286
5.3.5BatCoronaviruses,MERS-CoV,and dipeptidylpeptidaseIV288
5.3.6Characteristicsofcoronavirusspeciesof bats290
5.3.7Preventionagainstbatcoronavirus infection292
5.4Coronavirusesofrodents292
5.4.1Introductiontocoronavirusesof rodents292
5.4.2Mousehepatitisvirus294
5.5Ratcoronavirus312
5.5.1Introductiontoratcoronavirus312
5.5.2Ratcoronavirusanddisease312
5.5.3Ratcoronavirusandtheimmune response312
5.5.4Othercoronavirusesofrodents313
5.6Coronavirusesofnonhumanprimates315
5.6.1Introductiontocoronavirusesof nonhumanprimates315
5.6.2Pathologyofcoronavirusesofnonhuman primates316
5.7Coronavirusesofferretsandminks318
5.7.1Introductiontocoronavirusesofferrets andminks318
5.7.2Ferretentericcoronavirus319
5.7.3Ferretsystemiccoronavirus320
5.7.4Treatmentoptionsandprotection againstferretcoronavirus-induced diseases322
5.7.5Ferretsandfelineinfectiousperitonitis virusofcats323
5.7.6Coronavirusesofminks323
5.7.7Coronaviruseofothermusteloidea324
5.8Coronavirusesofrabbits324
5.8.1Rabbitentericcoronavirus324
5.8.2Rabbitcoronavirus325
5.8.3Otherrabbitcoronaviruses326
5.9Coronavirusesofotherwildor semidomesticatedmammals327 References327
6.Coronavirusesofagriculturaland companionanimalswiththepotentialfor zoonotictransmission341
6.1Introduction341
6.1.1Coronavirusgeneraandspecies341
6.1.2Severeacuterespiratorysyndrome coronaviruses,severeacuterespiratory syndromecoronaviruses-2,and domesticatedanimals343
6.1.3MERS-CoVanddomesticated animals343
6.1.4Diagnosisofcoronavirusesof domesticatedanimals344
6.2Bovinecoronavirusanditsentericand respiratoryforms345
6.2.1Introductiontobovine coronaviruses345
6.2.2Pathologyofbovinecoronaviruses diseasesandtheirunderlying causes346
6.2.3Bovinecoronaviruses—theviruses347
6.2.4Bovineentericcoronavirus349
6.2.5Bovinerespiratorycoronavirus350
6.2.6Bovinecoronaviruses-likecoronaviruses ofotheranimals353
6.3Coronavirusesofdromedaries,llamas,and alpacas355
6.3.1Coronavirusesofdromedary camels355
6.3.2Coronavirusesofalpacasand llamas358
6.4Coronavirusesofswine359
6.4.1Introductiontoswine coronaviruses359
6.4.2Pathologyduetoswinecoronavirusesin general361
6.4.3Theimmuneresponsetoswine coronavirusesingeneral362
6.4.4Viralinhibitionoftheimmune responsetoswinecoronavirusesin general364
6.4.5Porcineepidemicdiarrheavirus366
6.4.6Porcinedeltacoronavirus374
6.4.7Porcinehemagglutinating encephalomyelitisvirus376
6.4.8Swineacutediarrheasyndrome coronavirus378
6.4.9Transmissiblegastroenteritisvirusand porcinerespiratorycoronavirus380
6.5Coronavirusofhorses384
6.5.1Introductiontocoronavirusesof horses384
6.5.2Pathologyduetocoronavirusof horses384
6.5.3Coronavirusesofhorses—thevirus385
6.6Coronavirusesofsheep386
6.7Coronavirusesofcompanionanimals386
6.7.1Coronavirusesofcats386
6.7.2Caninecoronaviruses395
6.7.3Caninerespiratorycoronavirus397
6.8Briefoverviewofdomesticavian coronaviruses401
References401
7.Pullingitalltogether:wheredowego
fromhere?417 7.1Coronaviruses—friendsandfamily417
7.1.1BaltimoreclassIVviruses (coronaviruses’friends)417
7.1.2Coronaviridae(coronaviruses family)418
7.2Zoonotictransmissionofcoronaviruses421
7.2.1Coronavirusesproposedreservoirand intermediatehosts421
7.2.2Comparisonbetweenthehostsand geographicallocationsofsevereacute respiratorysyndromecoronavirus-and severeacuterespiratorysyndrome coronavirus-2-likeviruses428
7.2.3Otheranimalsaspotentialcoronavirus reservoirhosts429
7.3Possiblewaystopredictandpreventfuture epidemicsandpandemics431
7.3.1TheOneHealthapproach431
7.3.2SpillOver432
7.3.3Museumsandemergingpathogensinthe Americas(MEPA)433
7.4Factorsdrivingzoonotictransmission433
7.4.1Viralfactorsdrivingzoonotic transmission434
7.4.2Host-relatedfactorsdrivingzoonotic transmission434
7.4.3Environmentalfactorsdrivingzoonotic transmission435
7.4.4The“humanfactor”andmodeling436
7.4.5Theemergenceanddiseaseseverityof severeacuterespiratorysystem coronavirus-2variants436
7.5Thecontinuingthreatofemerginginfectious diseases437
7.5.1Changesininfectiousdiseasepatterns overthelasttenyears438
7.5.2Thenextpandemics—thinkingoutside ofthebox442
7.6Infectiousdiseasesandthedeveloping world444
7.7Author’snote(March2022)445 References446
AppendixI:Coronavirusdisease overviews455
AppendixII:Glossary463 Index503
Listoffigures Figure1.1Photomicrographofacoronavirus.Thisfiguredepictsaparticleofacoronavirus.The prominentspikesgivethevirusacrown-likeimage.
Figure1.2Illustrationofacoronavirus.Thisimageofacoronavirusshowsseveralstructuralproteins studdingthecell.Thelargestandmostabundantprojectionsaretrimersofthespikeprotein. Thesmallerprojectionsaretheenvelopeandmembraneproteins.
Figure1.3Coronavirusexitinginfectedcell.Thisisaphotomicrographofcoronavirusesbuddingoffof aninfectedcell’smembraneasitexiststhecell.Duringthisprocess,thevirusremovespartof themembrane,whichsubsequentlyisusedintheviralenvelope.
Figure1.4Personalprotectiveequipment(PPE).CoronavirusresearcherwearingPPEconsistingofa disposablefull-bodygarment,afacemask,andlatexgloves.DuringtheSARS-CoV-2 pandemic,thegeneralpublicwasoftenrequiredtowearonetotwomaskswhileindoors. Somepeopleworefaceshields.
Figure2.1Civetcatsinanimalmeatmarket.Civetcats,raccoondogs,andChineseferretbadgersfrom liveanimalmeatmarketsarebelievedtoserveasintermediatehoststhattransmittedSARSCoVtohumans.ThismarketislocatedinGuangzhou,China.Batsarealsosoldinthese markets.PaulHilton.UniversityofEastAnglia.FreeunderCreativeCommons. 55
Figure2.2SARS-CoV-induceddiffusealveolardamageDADinthelungs.Thisphotomicrographshows DADinthelungsofaSARS-CoVinfectedperson.Thecenteroftheimagecontainsa multinucleatedgiantcell.
Figure3.1SamplingthebloodofadromedarycamelsforMERS.CDC/AwadhMohammedBaSaleh, Yemen.
Figure4.1CountrieswiththeHighestCumulativeNumbersofCOVID-19CasesandDeaths.a CountrieswiththeHighestCumulativeNumbersofCOVID-19Cases.The10countries reportingthehighestnumberofCOVID-19cases.bCountrieswiththeHighestCumulative NumbersofCOVID-19Deaths.The10countriesreportingthehighestnumberofCOVID-19 deaths.cCountrieswiththeHighestCumulativeNumbersofCOVID-19CasesasaFunction ofPopulation.The10countriesreportingthehighestpercentageofCOVID-19cases.d CountrieswiththeHighestCumulativeNumbersofCOVID-19DeathsasaFunctionof Population.The10countriesreportingthehighestpercentageofCOVID-19deaths. TablesproducedbytheauthorbasedupondatafromtheWorldHealthOrganization.
Figure4.2ID#24477CDC/JamesGathany,2020PublicDomain.ThisCentersforDiseaseControland Prevention(CDC)scientistispreparingsamplesforReal-TimeReverseTranscriptase(RT) PCRanalysisofSARS-CoV-2specimens.Millionsofthesetestkitshavebeenprocessedinthe UnitedStatessincethebeginningoftheCOVID-19pandemic.
Figure4.3ID#2448CDC/JamesGathany,2020PublicDomain.ThisisacloseviewofaSARS-CoV-2 serologicaltest,usedforthedetectionofIgM.Serologicaltestsareusedtoidentifythe presenceofantibodies,whichcanbefoundinpersonswhohavepreviouslybeeninfected withSARS-CoV-2.
62
174
227
Figure4.4ID#24613CDCPublicDomain.Personalprotectiveequipment(PPE).PPEisusedtoprevent thespreadofSARS-CoV-2.Thisworkerisusedafaceshield,mask,andgown.
Figure4.5ID#15484CDC/DeboraCartagena,2013PublicDomain.TwoN95-typeandaN1000-type facemasks.N95masksareair-purifyingrespiratorcertifiedbytheNationalInstitutefor OccupationalSafetyandHealth.Theyprotectagainstparticulatematterandbiological particles,includingviruses.
Figure5.1Coronavirusesofwildandsemi-domesticanimals.Anoverviewofthebeststudiedand namedcoronavirusesofbats,rodents,ferrets,minks,rabbits,andhedgehogs.Batandrodent coronavirusesarebelievedtohavehostedtheancestorsofthegreatmajorityofcoronaviruses currentlyfoundinothermammalianhostspecies.
Figure5.2Greaterhorseshoebat.Thegreaterhorseshoebat(Rhinolophusferrumequinum)hasalarge rangethroughoutsouthernEuropeandAsiaandNorthernAfrica.Theyarebelievedtohave hostedtheancestortomanypathogenicanimalandhumancoronavirusesandcontinueto serveasareservoirformanyothercoronavirusesofunknownpathogenicity.
Figure5.3Intestinesofamouseinfectedwithmousehepatitsvirus.#16467PublicHealthImageLibrary (PHIL).Thisinfantmousewasinfectedwiththemousehepatitiscoronaviruswhichcauses lethalenteritis.Onlytheintestinesshowedanyhistopathologicchanges.Intestinesofhealthy infantmicehaveapinkcoloration.
Figure5.4Enlargedsalivaryglandscausedwithsialodacryoadenitisvirus.#18683PublicHealthImage Library(PHIL).Thisimagedepictsswellingofthesalivaryglandsintheneckofaratinfected withsialodacryoadenitisvirus.
Figure6.1ThisphotographshowscollectionofbloodfromadromedarycamelfromYemenbeingtested foranti-MERSantibodies.Imagenumber19622Contentprovider:CDC/AwadhMohammed BaSaleh.
Listoftables Table1.1Coronavirusesofhumans.2
Table1.2Baltimoreclassificationsystem.8
Table1.3Humanpandemicsinmoderntimes.12
Table1.4Eukaryotes,bacteria,andviruses.13
Table1.5Typesofimmunecellsandtheirfunctions.17
Table1.6CytokineFunctions. 18
Table1.7ChemokineFunctions. 19
Table1.8Antibodyclasses. 21
Table1.9CoronavirusStructuralProteins.26
Table1.10Generaandlineagesofhumancoronaviruses.37
Table2.1CellsinfectedbySARS-CoVandthepresenceorabsenceofACE-2.56
Table2.2SARSeffectsonthecirculatory,skeletal,digestive,urinary,nervous,endocrine,and reproductivesystems. 60
Table2.3SARSandtheinnateimmunesystem.91
Table2.4ComparisonofseveralSARS-CoVtreatmentoptions.104
Table3.1BathostsofMERS-CoV-likeviruses.142
Table4.1TheEffectsofCOVID-19onHormones.192
Table4.2TheEffectsofCOVID-19onReproductiveSystemHormones.193
Table4.3AccuracyofRNAandSerologicMeansofSARS-CoV-2Detection.226
Table4.4ComparisonofMeasurestoPreventAgainstSARS-CoVandSARS-CoV-2Infection.245
Table5.1Characteristicsofspecificcoronavirusesandtheinfectedbats.291
Table5.2RodentCoronaviruses. 315
Table5.3Ferretentericcoronavirus,ferretsystemiccoronavirus,andminkcoronavirus.324
Table5.4Rabbitcoronavirusandrabbitentericcoronavirus.326
Table6.1Alpha-andbeta-coronavirusesofagriculturalandcompanionanimals.342
Table6.2Comparisonofcalfdiarrhea,winterdysentery,andshippingfever.346
Table6.3Comparisonofcoronavirusesofcamelsandalpacas.355
Table6.4Comparisonofthecoronavirusesofswine.360
Table6.5Comparisonoffelineentericcoronavirusandfelineinfectiousperitonitisvirus.360
Table6.6Comparisonbetweencaninecoronavirusandcaninerespiratorycoronavirus.398
Table7.1BatsInfectedwithSARS-CoV-LikeViruses.423
Table7.2BatsInfectedwithSARS-CoV-2-LikeViruses.426
Table7.3EmergingInfectiousDiseaseAgents—Viruses.439
Table7.4EmergingInfectiousDiseaseAgents—Bacteria,Prions,Protists,Fungi,Helminths,and Insects. 440
Acknowledgments Iwishtoacknowledgethewonderful teamofpeopleatElsevierandAcademic Presswhohelpedmeintheproductionof thiswork.Mythanksgooutto RajaganapathyEssakiPandyan,JaiMarie Jose,MicaEllaOrtega,andKattie Washingtonfortheirgreatpatiencewith me.I’mfortunatetohaveworkedwiththis finegroupofpeople.Ialsowishtothank alltheunnamedpeopleatElsevierwho madetheproductionofthisbookpossible.
IwouldalsoliketothankthegreatpeopleatMassillonWashingtonHighSchool, wholitthesparkofmyloveofbiology, mathematics,writing,andFrench.(You havenoidea,Madame,howmuchIuse myknowledgeofaromancelanguageto deciphertheLatintermswhichaboundin thesciences!)
ThefacultyofMaloneUniversity(then, MaloneCollege)inCanton,Ohio,fanned theflameandstartedmeontheroadto moreintensivelearningand,moreimportantly,increasedmyloveoflearningina fantasticChristianenvironment.Thanksto myformerprofessors,thestaffbehindthe scenes,andmyformercolleagues/friends. Aspecialthanksgoestomytrioofbiology professors,youleftanindeliblemarkon mylife.
Ialsowishtothankmyprofessorsand mygraduateschoolfriendsfromMichigan StateUniversity,especiallymyadvisorand mentor,Dr.FelipeKierszenbaum,who installedinmealoveofparasitologyand immunology.Withoutyourhelp,Iwould nothavebeenabletoachievemytwin lovesofresearchandwriting.Ialsowishto
thankallmyformerlabcolleagues,with whomIenjoyedworking,particularlyDrs. MariadeFatimaLimaandFernando Villalta.Wespentdays,nights,andweekendstogetherdoingandtalkingresearch, drinkinggreatBraziliancoffee,laughing, bemoaningthehardshipsinherentinscience,andthenlaughingsomemoreonour waytosuccess.
Ialsowishtothankmymentors,Drs. AlbertDonnenbergandCharlesRinaldo, frommypostdoctoraldaysatJohns HopkinsUniversityandtheUniversityof Pittsburgh.Thanksalsotomyfriends,formercolleagues,andstudentsatthe UniversityofNorthernIowa,KentState University,andMaloneUniversity.This bookwillbetoolongifImentionallof you!However,IdowanttothankDrs. RobertSeagerandVirginiaBergforallthe greatdiscussions.You,too,weremymentorsandemotionalsupportteamwhenI beganmyworkasaneducatorandan independentresearcher.
Myformercolleagueandcurrentpublic healthcollaborator,Dr.CatherineZeman, deservesaspecialwordofthanks.Ihave lovedkeepingmyfinger“zoomed”intothe researchthatsheandherformergraduate students,Drs.JunuShresthaandNoha Fadl,havebeendoingit.TheCOVID-19 conversationsthatCatherineandIhave hadwerealsoveryhelpfulsincetheygave meanew,morepublichealth-centered viewofthiscrisis.Imighthavereadabout COVID-19,beenhospitalizedwithit,and writtenaboutit,butyourworkduringthis pandemictouchedpeople’slives.Thatisa
hugeresponsibilityandonethatisshared bymycousin,Dr.LeeFinley,another leaderatthelocalpublichealthlevel, wherethelivesthataretouchedinclude thoseoffriends,family,oldschoolmates, andfellowchurchmembers.
Iamalsogratefulforconversationsover coffeewithmyoldhighschoolfriend, SteveBorton,andtothestaffatDunkin’ DonutsinMassillon,Ohio.I’vegainednew insightsintotheviewsofother,nonacademic,nonpublichealthpeopleandhow thepandemicaffectedandcontinuesto affecttheirlives.Sometimes,inacademia andwriting,wecanlosesightofourtrue goalofhelpingpeople.
Mydeepestthanksarealsoduetomy currentemotionalsupportteamandmy family,particularlyMrs.JudithBeltzand Mr.JohnBeltz;mysister-in-law,Stephanie; myniece,Hollie;andmynephew,William. Youkeptsupportingmeasdeadlines loomed.Youcan’tknowhowgratefulIam foryourlove,encouragement,andforall thecoffeethatyoubroughtme.Iknowthat Icancountonyouduringmynextwriting venture.
LisaA.Beltz
MicrobiologyandPublicHealth
March27,2022
1 Introduction 1.1Ofvirusesandmen Thebest-laidschemesofmiceandmenofttogoaskew —RobertBurns(1785)
Manyspeciesofcoronavirusesinfecthumansandanimals,includinglivestock(pigs,cattle, dromedarycamels,alpacas,llamas,horses,sheep,goats),wildandsemi-domesticatedanimals (bats,rodents,ferrets,minks),andcompanion animals(catsanddogs).Someofthesecoronaviruses,includingfelineentericcoronavirus,ferretentericcoronavirus,canineentericcoronavirus,andalpacaentericcoronavirus,primarilycausediseaseinthedigestivesystem.Other coronaviruses,suchassevereacuterespiratorysyndromevirus(SARS-CoV),caninerespiratorycoronavirus,andporcinerespiratorycoronavirus,primarilycauserespiratorydisease. Additionally,severalcoronaviruses,includingferretsystemiccoronavirusandfelineinfectious peritonitisvirus(FIPV),causelethal,immune-mediated,inflammatorysystemicdisease. Furthermore,manycoronavirusescancauseseverecentralnervoussystem(CNS)diseases. Sincehumanshaveclosercontactwithcompanionandagriculturalanimalsthanwithbatsor rodents,itwouldbewisetoinvestgreaterresourcesintoinvestigatingthepotentialof microbesinfectingtheseanimalstoundergozoonotictransmissionthatresultsinpathologyin humans.
Theancestorialcoronavirus(es)isbelievedtohavearisenandmutatedprimarilyinbats. Batshostagreaterandmorediverserangeofcoronavirusesthanotheranimalspecies.1 SuchnaturalreservoirhostsofRNAvirusesusuallyhavethegreatestviralgeneticdiversity amongthepossiblehostspeciesandinfectionofthereservoirhostisasymptomaticinmost circumstances.2 Datingofvariouscoronaviruslineagesindicatesthatbatcoronavirusesare alsoolderthanthoseofotheranimals.1 Additionally,thepopulationsizeofbatcoronavirusesisstablebutisundergoingexponentialgrowthinotheranimalgroups.1 Changing viruspopulationsizefromastabletoanexponentialgrowthstateisindicativeofinterspeciestransmissionofvirusesfromtheirnaturalreservoirhosttoalternatehosts.3 Ithasbeen suggestedbyWooetal.4 thatbatcoronavirusesaretheancestorsofmostalpha-andbetacoronaviruses,includingthehumancoronavirusesHCoV-NL63,HCoV-229E,MERS-CoV, andSARS-CoVandSARS-CoV-2.TheancestorsofHCoV-OC43andHCoV-KHU1,however, mayhaveoriginallybeenpresentinrodents.4,5 Birdcoronavirusesaretheancestorsof gamma-anddelta-coronaviruses.4
PathogenicCoronavirusesofHumansandAnimals DOI: https://doi.org/10.1016/B978-0-323-98809-4.00005-X
1.1.1Coronavirusesofhumans Sevencoronavirusesareknowntoinfecthumans(Table1.1).Thesecoronaviruses, includingSARS-CoV-2,maycausemildtosevere,life-threateningrespiratoryillness. Whilesomeofthemmayalsocauseliver,intestinal,cardiovascular,andneurologicaldiseases,theyoftenproducenodetectableillness(asymptomatic).HCoV-229E,HCoV-OC43, HCoV-HKU1,andHCoV-NL63typicallyproducemildrespiratorydisease,however,they areresponsibleforabout10%ofallhospitalizationsofchildrenwithrespiratorytract infections.6,7 HCoV-NL63infectionsaregenerallymoreseverethanthosecausedby HCoV-OC43andHCoV-229E.8
ThefirsttwoknownhumancoronavirusesareHCoV-229E,discoveredin1966,and HCoV-OC43,discoveredin1967.Theytypically causemildupperrespiratorytractillnessesand cause10% 30%ofthecasesofthecommoncold.9 Co-infectionoccursbetweenHCOV-229E andotherrespiratorydiseaseviruses,suchashumanmetapneumovirusorrespiratorysyncytial virus,andthecombinationofvirusesmayincreasetheextentoflungdamage.10 Itshouldbe notedthatthese“respiratorysystemdisease”virusesinfectanddamagethehumanCNStoa greaterorlesserextent.Forexample,HCoV-229EmayactasanautoimmunetriggerforCNS diseases,includingmultiplesclerosis(MS).11,12 AminopeptidaseN(APN),thehostcellreceptor usedbyHCoV-229E,isexpressedonnervesynapsemembranesandmayprovideameansfor thisvirustoentertheCNS.
Twootherhumancoronaviruses,HCoV-NL63andHCoV-HKU1,discoveredin2004 and2005,respectively,generallyarealsoresponsibleformildrespiratoryillness. Occasionally,however,thesehumancoronavirusesmaycauseseriousdiseases,especially inimmunosuppressedpatientsandinfants.Additionally,HCoV-NL63isamajorcauseof croup inchildrenandHCoV-OC43maycontributetotheproductionofpneumonia13 and
TABLE1.1 Coronavirusesofhumans.
CoronavirusTypeofcoronavirusHostcellreceptorDisease
HCoV-229EAlphacoronavirusAPNa
HCoV-OC43Betacoronavirus LineageA
HCoV-HKU1Betacoronavirus LinageA
N-acetyl-9-O-acetylneuraminic acidreceptor
N-acetyl-9-O-acetylneuaminicacid receptor
Commoncold
Commoncold Rarelyneurologicaldisease
Commoncold Rarelypneumonia
HCoV-NK63AlphacoronavirusACE2b Croup
SARS-CoVBetacoronavirus LinageB ACE2Severeacuterespiratory syndrome(SARS)
MERS-CoVBetacoronavirus LineageC DPP4c
MiddleEastrespiratory syndrome(MERS)
SARS-CoV-2Betacoronavirus LinageB ACE2COVID aAminopeptidaseN. bAngiotensin-convertingenzyme2. cDipeptidylpeptidase4.
severeneurologicaldiseases,suchas chronicdemyelinatingdisease and acuteencephalomyelitis. 14 HCoV-HKU1isalsoabletocauseinflammationofthebronchialtubesofthe lungsandpneumonia.15 Thesecoronavirusesappeartobespreadbythehuman-to-human respiratoryroute.
Theotherthreeknownhumancoronavirusesaremorelikelytocauseseveretofatalrespiratorysystemdiseaseaswellasattackotherorgansystems.SARS-CoVcausedamajoroutbreakofsevereacuterespiratorysyndrome(SARS)in2002 2003.16 Theoutbreakbeganin Chinaandthenspreadworldwidebeforedisappearingentirelyin2004.Someofthefinal caseswerelaboratory-associated.MiddleEastrespiratorysystemcoronavirus(MERS-CoV) wasfirstreportedinSaudiArabiain2012.17 ItiscurrentlyendemicintheMiddleEastand partsofAfricaandEurope.SARS-CoV-2isthecausativeagentofCOVID-19.Itappearsto havefirstemergedinChinainlate2019andremains,atthetimeofthiswritingin September2021,apandemicthathaskilledmillionsofpeoplethroughouttheworld. COVID-19wasdesignatedbytheWorldHealthOrganizationtobeapublichealthemergencyofinternationalconcernonJanuary30,2020,andasa pandemic onMarch11,2020.18
Whilehumancoronavirusesaretransmittedprimarilyviarespiratorysecretions,some ofthesevirusesappeartobecurrentlytransmittedsolelybetweenhumans.Coronaviruses enteredhumanpopulationsviazoonotictransmissionfromanimalintermediatehostspecies,includingseveralspeciesofwildcats,wilddogs,dromedarycamelsintheArabian Peninsula,andperhapspangolinsinChina.Amoredetailed,comparativedescriptionof humanandanimalcoronavirusesisfoundin AppendixI
1.1.2Factorsaffectingzoonotictransmissionofcoronaviruses Thenumbersofknownhumanandanimalcoronavirushavebeenincreasingrecently, suchasSARS-CoV-2,withrapidincreasesinthenumbersofthosetestingpositiveforviral antibodiesanddeaths.Thisincreaseispartiallyduetoincreasedconcern,testing,and detectionofzoonotictransferofanimalvirusesintopeople,andpartiallyduetoincreased human-to-animalcontactinmanyregionsoftheworldthathavebeentransformedfrom foresttocropproduction.Whiletheriskofzoonotictransmissionaffectscountries throughouttheworld,itisaparticularlygreatconcernforpeoplelivingincrowdedconditionsinlow-incomeregionsthatlackpropersanitationandcleanwatersupplies.19 Some coronavirusesareshedinthefecesorurineofinfectedanimalsthatthenenterthefood anddrinkingwaterofpeoplewhomayalreadybeillormalnourished.Manyofthose livinginlow-incomeareasdonothavethefueltocooktheirfoodortreatorpasteurize theirwaterormilk.Thesepopulationsarealsoatmuchgreaterriskofexposuretorodents andthevirusesthattheymaycarry.
Infectionsarealsotransmittedbyconsumptionoffoodandliquidsasnutrientsources orformedicinalpurposes.InAsia,liveanimalmarkets(“wetmarkets”)sellmanydifferentspeciesofanimalsinsmallandoftennonhygienicplacesthatmayallowexposureof peopleandmanyspeciesofanimalstoinfectedanimalsbytherespiratoryrouteviadropletsandaerosolsaswellasbyinhalationofdustcontainingdriedfecal,salivary,orurinarymaterial.Thelatterrouteofinfectionisalsofoundinthetransmissionofpulmonary hantaviruses,anothertypeofrespiratoryvirusfoundintheAmericas.19
Manypeopleliveinlow-incomeorremoteareaswhicharenotreadilyaccessibleto outsidehelp,especiallyduringthewetseason,andmaylackaccesstovaccines,medications,healthcareproviders,andmedicalequipment,includingventilators.Masksand glovesarealsoinshortsupply.Thisisnotonlyaproblemin developingcountries butis alsoathreattothosewholiveintheseunsanitaryconditionsintheinner-citiesandtentcitiesofdevelopedcountries,includingthoseinNorthAmericaandEurope.19 Somepopulationsworldwidearesubjectedtodiscriminationandinadequatehealthcare,including peoplelivinginpartsofAppalachiaintheUnitedStatesandtheRoma(“gypsies”)in Europe.Thoselivinginrefugeecampsarealsoatrisk,notonlyduetotherelativelackof doctorsandmedicinesbutalsofromtheinfluxofinfectedpeopledisplacedbywarorcivil unrest.19
Someculturalpracticesalsomayincreasetheriskofzoonotictransmission.Thesepracticesincludeshoppingforfoodinliveanimalmarkets,drinkingrawcamelmilk,orusing camelurinetowashthehairandskin.20 Manypeoplearedrawntoculturaltraditional medicinesorhealersthatoftenareineffective.Manypeopleinthe developedworld also usesupplementalvitaminsoralternativemedicinalcompoundsofunknownefficacyand whosecontentsvaryamongbatchesratherthanmedicationsthathavebeentestedfor safetyandefficacyandwhosecomponentsareconsistentbetweenbatches.Largegatheringsofpeopleatweddingsandfuneralsaswellastraditionalmeansofpreparingthe deadforburialalsoincreasetheriskofperson-to-personcontactandthespreadofinfectionastheparticipantstravelbacktotheirhomes.21 Someincreasinglypopularpractices inthedevelopedworld,includingdrinkingunpasteurizedmilkandjuices,alsoplacepeopleatriskofacquiringinfectiousdiseaseagents.
Inthedevelopedworld,peoplelivingincrowdedmetropolitanareas,suchasHong KongandNewYorkCity,aremorelikelytobeexposedtoinfectedpeople.Thiswasseen inHongKongduringtheSARSepidemicandpresentlyinNewYorkCity,withitshigh numbersofCOVID-19casesanddeaths.Publictransportation,suchasbuses,airplanes, andsubways,mayalsoincreasetheriskoftransmissionduetoprolongedcontactwith respiratoryemissionsoftheirfellowpassengersandindirectcontact,asexemplifiedby peopleholdingontothepolesinbusesandsubwayswhoseseatsarefull.Itisimpractical tosterilizethesepointsofpotentialinfectionateachstop.Cruiseshipsarepotentialincubatorsforinfectiousagents,includingSARS-CoV-2andothergroupsofvirusessuchas the“cruiseship”norovirus.Manypoorerareasoftheworldareexperiencingincreasesin workerswhoareemployedinurbancenters,followedbyregularweekendreturnstotheir villages,bringingnovelmicrobesalongwiththem.Thiswasamajorfactorinthetransmissionofhumanimmunodeficiencyvirus-1(HIV-1)inpartsofsub-SaharanAfrica.22
Peoplelivinginagriculturalregionsarealsoatriskofinfectionduetotheirproximity topestanimals,suchasrodentsandmonkeysinthefieldsthateatthecrops,aswellas rodentsandinsectsinhabitinghumandwellingsandreleasingtheirexcreta(feces,urine, andsaliva)orbitingtheinhabitants.respectively.Driedsalivamaybecomeaerosolizedby sweepingthefloorsandthenbeinginhaledbythehumanresidents.Thisisnotonlyaconcerninruralareaswherethedwellingshavedirtfloorsbutalsoinvacationhomesin wealthierregionsandpeoplecampingintrailshelters.23
Dwellingsinlow-incomeareasof the developingworld mayalsohavethatchroofsthatareinhabitedbyrodentsorinsects andmaylackdoorsorintactscreenedwindows.Evenpeopleindevelopedregionsmay
alsochoosetoleavetheirdoorsorwindowsopen,asisseeninrestaurantsinpartsofthe southernandcoastalUnitedStates.Rodentsmaystillbefoundinkitchensofrestaurants orhomesthatdocloseintactwindowsanddoors.(Installacheapandeffectiverodent controlsystem—buyacat,they’llenjoythehunt!)
IthasbeenpostulatedthatSARS-CoV-2maydisplayseasonality,sincemanyrespiratoryinfectionsoccurduringthewinter,declineduringwarmerseasons,andthenrepeatedlyreappearduringthefollowingwinter(s)formultipleyears.Thiswasnotthecasefor theothertwohighlypathogenichumancoronaviruses.Duringthe2002 2003SARSepidemic,manydiseasecaseswithahighfatalityratewereseenthatwinter,butonlyfour mildcasesofSARSwerereportedin2004andnocaseshavebeenreportedsincethat time.21 TheseasonalepidemicpatternisalsonotapplicabletotheongoingMERSepidemic whichcontinuesthroughouttheyearandisnormallyfoundinthearid,hotregionofthe ArabianPeninsula.Othernotableexceptionsamongnoncoronavirusepidemicsinclude the2012ZikaoutbreakinBrazil,whichinfectedlargenumbersofpeople,causingtragic neurologicaldiseasesinbothfetusesduringpregnancyand Guillain-Barre ´ syndrome in someadults.Zikavirus-associatedillnessdidnotreturninlargenumbersthefollowing yearorafterward.24 Eventhe1918Spanishinfluenza,whichkilledtensofmillionsofpeopleworldwide,didnotreturnin1919.
1.2Abriefintroductiontoviruses 1.2.1Characteristicsofviruses Almostallvirusesareextremelysmall—smallenoughtopassthrough0.2 μmpore-size filtersthatremovebacteriaandothermicrobes.Unlikebacteriaandallotherformsoflife, theyarenotcomposedofcellsandlack plasmamembranes.Someviruses,includingcoronaviruses,aresurroundedbyan envelope.Drugsthatkillbacteria,theantibiotics,donot killorinactivateviruses.Asmallnumberofantiviraldrugshavebeenproduced,butthey areoftentoxictohumancells.Virusesthatmutatequicklyarealsoabletochangetheir propertiesenoughsothatagivenantiviraldrugorvaccineisnolongereffective,asdiscussedbelow.
Thegeneticinformationof prokaryotes (suchasbacteria)andthe eukaryotes is deoxyribonucleicacid(DNA).Virusesbelongtoneitheroftheabovegroupsandsomecategories ofviruses,includingcoronaviruses,HIV,andhepatitisCvirus,use ribonucleicacid (RNA) astheirgeneticmaterial.Anotherdifferencebetweenprokaryotesandeukaryotes isinthelocationofDNA,whichisfoundinthenucleusofeukaryotesandthenucleoid regionofcytoplasminbacteria.DNAineukaryotesandsomevirusestaketheformofa “double-helix”whosetwostrandsresembleaspiralstaircase.Thenucleusofeukaryotes containsthevastmajorityofcellulargenes.Thegenesarecomposedofthe nucleotides adenine,thymine,guanine,andcytosine.Duringtheprocessof transcription,eukaryotic andprokaryoticgenesserveasblueprintsfortheproductionofseveraltypesofRNAand occurwithinthenucleusorthenucleoidregion,respectively.ThevarioustypesofRNA formsinglestrandsthatfoldintohighlycomplexstructures.RNAiscomposedofthe nucleosides adenosine,uracil,guanosine,andcytosine,whichareverysimilartothe
nucleotidesofDNA.Aftertheirproduction,sometypesofRNAtravelintothe cytoplasm ofthecellwhere,inassociationwith ribosomes,theyproduceproteinsbytheprocessof translation.Proteinsprovidemuchofthestructureofcellsand,via enzymes and hormones,directmostofthecells’functions.Bycontrast,thegeneticinformationofviruses maybesingle-ordouble-strandedDNAorsingle-ordouble-strandedRNAandexist withinaviralnucleocapsid.ViralDNAorRNAcontainonlyasmallnumberofgenesnecessaryforthemtoinfectcellsand replicate (reproduce).
ThecoronavirusesRNAgenomeencodesavariablenumberofstructuralandnonstructuralproteins(Nsp’s).Mostofthe50 terminaloftheirgenomicRNAencodestheRNApolymeraseproteinandtheremainderofthegenomicRNAencodesfourtofivestructural proteins,theS(spike),E(envelope),M(membrane),andN(nucleocapsid)proteins,together withseveralnonstructuralandaccessoryproteinswhichvaryinnumberamongvariousviral speciesandevenwithinthelineagesofindividualvirusspecies.25 Somebeta-coronaviruses havethefifthstructuralprotein,haemagglutininesterase(HE).26
1.2.2Overviewofmutationsandrecombinationinviruses Tobeabletosuccessfullyfunctionandreplicate,virusesmustfindwaystoevadethe immunecells,antibodies,drugs,andvaccines.OftenmutationsoftheviralDNAorRNA allowthisevasiontooccur.Mutations,ingeneral,aredetrimentaltoeukaryoticcells,either resultingintheirdeathoralteringtheirfunctions.However,inthecaseofRNAviruses,mutationsmaybebeneficialsincetheydecreasetheabilityofthehost’sadaptiveimmuneresponse torecognizethem.Additionally,mutationsmayreducetheeffectivenessofdrugtherapy.This highmutationrateispossiblesincevirusesmultiplyveryrapidly.Duetothelargedegreeof diversityinthegenomeofsomeRNAviruses,individualpeoplemaynotbeinfectedbyonly onevariantofaviralspeciesbutbya“swarm”ofcloselyrelatedvariants,manyofwhichare nonfunctionalorarerapidlykilledbythehostimmuneresponse.Asmallminorityofthese mutatedviruses,however,arebettersuitedforsurvivalandcanbemorepathogenictotheir hosts.ThisappearstobethecaseforHIVandmaybetrueforotherrapidlymutatingRNA virusesaswell,includingcoronaviruses.
RNAviruses,ingeneral,mutateatagreaterratethanDNAviruses,partiallyduetothe higherrorrateofthe RNA-dependentRNA-polymerase(RdRp) enzymeusedduringreplication.ExamplesofRNAvirusesthatmutaterapidlyincludeHIV,influenzaviruses, and,toasomewhatlesserextent,coronaviruses.Nucleosidesubstitutionsaretypically fourtimesmorecommonthaninsertionsordeletions.28
Relativetoothersingle-strandedRNAviruses,coronavirusmutationratesaremoderate tohigh(1errorper1000 10,000nucleosidesreplicated),eventhoughcoronavirusesare theonlyknowncategoryofRNAvirusesthathaveamechanismforproofreadingtheir genomesandcorrectingmistakesmadeduringreplication.Thispermitscoronavirusesto escapeproducingexcessivenumbersofgeneticerrorsthatwouldotherwiserendertheir progenynonviable.29,30
Partofthereasonthatcoronaviruseshaverelativelyhighmutationratesisthatthey containunusuallylargeRNAstrandswhoselengthincreasesthechancethatmutations mayoccur.Coronavirusesalsoundergoahighdegreeofgeneticrecombinationeventsin
whichtheyswappiecesoftheirgenomicRNAwiththatofothervirusesofthesameor differentspecies.4,31,32 Thehighdegreeofgeneticrecombination33 mayresultfroma uniquerandom templateswitching processduringgenomicreplication.Alterationintheir geneticmaterialbycoronavirusesisdescribedingreaterdetaillaterinthischapter.
1.2.3Virusesandtheirhostreceptors Virusesare obligateintracellularparasites thatmustinfectcellstofunction.Viruseshave proteinsontheirsurfacesthatbindto receptors,specificmoleculesonthesurfaceofthevirus’ targetcells.Differentspeciesofvirusesusedifferentmoleculesthatbindtodifferentreceptors presentonlyonspecificcelltypes.SARS-CoVusesitsSproteintobindtoitscellularreceptor, angiotensin-convertingenzyme2(ACE2),foundonasubsetofhumancells,especiallyseveralcelltypesfoundintheterminalairsacsofthelungs(alveoli),cellsliningtheairways, andcellsliningthebloodvessels(endothelialcells).MERS-CoVusesitsSproteintobindto itsreceptor, dipeptidylpeptidaseIV(DPP4),onadifferentsubsetofhumanoranimalcells.
Viralbindingtotheirtargetcellreceptorsisvitalforthevirustoenterthecelland directittoproducemorevirusesthatarethenreleasedtoinfectanothercellinaprocess thatisrepeatedmultipletimes.Mutationsofthegenesthatcodefortheviruses’binding moleculesorthetargetcells’receptorsaffecttheabilityofthevirustoenterthecell.If virusescannotentercells,theyarerendered inactive andcannotfunctionorreplicate. Somedrugsand neutralizingantibodies reducethebindingofvirusestotheirtargetcells andthusinactivatetheviruses,reducingtheseverityofthediseaseandmaycurean infectedperson.Otherdrugsinactivatevirusesbyattackingothervitalviralfunctionsor bykillinginfectedcellsbeforethevirusescontainedwithinthemcanreproduce.
1.2.4BaltimoreclassIVviruses The BaltimoreClassificationSystem dividesvirusesintosevenclassesbasedontheirtype ofDNAorRNAgeneticinformation(Table1.2).Coronavirusesare ClassIV viruses.34 Class IVvirusesusepositivesingle-strandedRNAastheirgeneticmaterial.Toreproduce,ClassIV virusesusethevirus-encodedenzymeRdRpto producenegativesingle-strandedRNAand thenmorepositivesingle-strandedRNAtoserveeitherasthegeneticinformationforprogeny virusesorintheproductionofproteins.Other relatedvirusesinClassIVinclude:(1)German measlesvirus,whichoftenkillsfetusesifthemotherbecomesinfectedwhilepregnant,(2) polioviruses,whichaffectmuscularactivity,cripplingpeopleormakingthemunableto breatheontheirown,(3)denguevirus,whichcausesexcruciatingbonepainordeadly hemorrhagicfever,(4)WestNilevirus,whichmaycause encephalitis or meningitis,(5)Zikavirus, whichcausesdeformitiesinfetusesifthemotherisinfectedwhilepregnant,and(6)hepatitis Cvirus,whichmaycausechronicliverdiseaseorlivercancer.
1.2.5Viruses,diseases,andpandemics—victoriesandfailures Throughoutmostofhumanhistory,smallpoxwasamongtheleadingcausesofdeath anddisfigurement.Thecausativevirus, variola,causedamultitudeofdeepskinlesions
