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.
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