VIRAL DISEASES

VIRALDISEASES
TARGETCELLS,VIRALPATHOGENICITY,AND
VIRALREPLICATIONCYCLE.
Ligand (viralenvelopeorcapsidproteins)receptor
(host cell membrane proteins) interactions
(hostcellmembraneproteins)interactions
commontoallcellsareusedbyvirusestoattach
to and infect specific target cells.
toandinfectspecifictargetcells.
Enveloped,nonenvelopedvirus
DNAVs.RNAvirusinreplicationcycle
DNA V RNA i i
li ti
l

Fig.430Ligandreceptorinteractions.Ligand(viralenvelopeorcapsidproteins)receptor
g
g
p
g
(
p
p p
)
p
(hostcellmembraneproteins)interactionscommontoallcellsareusedbyvirusestoattach
toandinfectspecifictargetcells.
2

Fig.432A Morphologyofviruses.A, Nonenveloped viruses.Theyattachtohostcellsusinga

proteincoat(viralcoat,capsid,capsomeres)andusuallykillinfectedcellstoreleasenewly
formedvirus.B, Envelopedviruses.Theyattachtohostcellsusingaviralenvelopeandusually
donotkillinfectedcellstoreleasenewlyformedvirus.(FromGoeringR,Dockrell H,Roitt I,etal:
Mimsmedicalmicrobiology, ed 4,St.Louis,2008,Mosby.)
3

Fig.432B Morphologyofviruses.A, Nonenveloped viruses.Theyattachtohostcellsusingaproteincoat

(viral coat capsid capsomeres) and usually kill infected cells to release newly formed virus B Enveloped
(viralcoat,capsid,capsomeres)andusuallykillinfectedcellstoreleasenewlyformedvirus.B,
Enveloped
viruses.Theyattachtohostcellsusingaviralenvelopeandusuallydonotkillinfectedcellstoreleasenewly
formedvirus.(FromGoeringR,Dockrell H,Roitt I,etal:Mimsmedicalmicrobiology, ed 4,St.Louis,2008,
4
Mosby.)

Fig.431 Virusreplicationcycle. Stagesinthe

infection,replication,andegressofavirusina
targetcell.Severalthousandvirusparticles
maybeformedwithineachinfectedcell.(From
RosenthalKS,TanJS:Rapidreview
microbiologyandimmunology, ed 2,St.Louis,
2007,Mosby.)
5

Fig.433A ReplicationofDNAandRNA
viruses. (FromGoeringR,Dockrell H,Roitt I,et
al:Mimsmedicalmicrobiology, ed 4,St.Louis,
2008,Mosby.)

Fig.433B ReplicationofDNAandRNA
viruses. (FromGoeringR,Dockrell H,Roitt I,et
al:Mimsmedicalmicrobiology, ed 4,St.Louis,
2008,Mosby.)

Fig.434 Actionsofviralproteins.
Proteins synthesized by viruses can
Proteinssynthesizedbyvirusescan
affectnormalcellfunctionthrough
mechanismsillustratedhere.(From
Kumar V, Abbas A, Fausto N,etal:
KumarV,AbbasA,Fausto
N, et al:
Robbins&Cotran pathologicbasisof
disease, ed 8,Philadelphia,2009,
Saunders.))
8

Viral Diseases
ViralDiseases
Virulencedeterminates
Vi l
d t
i t
Controltheprocessinvolvedin
Replication,includingattachmentto,replicationin,andreleaseofvirusfrom
host cells
hostcells
Escaping,modulating,orsuppressingthehostinnateandadaptiveimmune
response
Purpose?

Mechanismofgenomicchange
Genomicvariation,geneticdiversity,acquirednewvirulent
determinates
Geneticdrift,spontaneousmutation
Geneticshift,

reassortment
recombination,
Defectiveinterferingvirus
majorchangeofvirusprotein
9

Fig.435 Antigenicshiftsininfluenzavirus. Onetheoryproposesthatantigenicshiftsoccurwhenahuman

influenzavirus(blue)
(
) andanavianinfluenzavirus(red)
( ) coinfect aspeciesthatispermissiveforboth.The8
p
p
ssRNA strandsarecoexpressedinthesameinfectedcell,resultinginmixingofthestrandssothatahybrid
viruscanbeproduced.Thehybridvirusindicatedherecontainsallthegeneticinformationoftheoriginal
virusthatinfectedhumans,butcontainsanewhemagglutinin (HA)containingstrandfromtheavianvirus.
Thi i
ThisvirusexpressesanewHAantigenandwillbelesssusceptibletoresidualimmunitythatnormally
HA ti
d ill b l
tibl t
id l i
it th t
ll
providespartialprotectionagainstyearlyinfluenzainfections.(FromMcCance KL:Pathophysiology:The
10
biologicbasisfordiseaseinadultsandchildren, ed 6,St.Louis,2010,Mosby.)

Viral diseases
Viraldiseases
Defensemechanism
Infection?Susceptibility?
p
y
Innateandadaptiveimmunesystem
BeneficialVs.harmful
Beneficial Vs harmful
i.e.,Tcellfunction,Interferon

11

Fig.436 PossiblerolesforTlymphocytesinimmunitytointracellularmicroorganisms.A, The

TlymphocyteactivatesintracellularkillingmechanismsbysecretionofcytokinessuchasIFN,
e.g.,inamacrophage.B, TheTlymphocytedirectlykillscellandparasite.C, TheTlymphocyte
destroysvitaltissueintheprocessofkillingtheparasite.D, BylysingcellstheTlymphocyte
allowsstilllivingparasitestodisseminate.E, Parasitesreleasedinthiswaymaybephagocytosed
byamoreeffectivehostcell.(FromGoeringR,Dockrell H,Roitt I,etal:Mimsmedical
12
microbiology, ed 4,St.Louis,2008,Mosby.)

Fig.437 Actionsofinterferon(IFN)inviralinfectionoftargetcells. (FromMcCance KL:

Pathophysiology:Thebiologicbasisfordiseaseinadultsandchildren, ed 6,St.Louis,2010,
Mosby.)
13

Viral diseases by body systems

Viraldiseasesbybodysystems
Mechanismsofinjuryindiseasescausedby
(
)
virus(Table44)
Celllysis
Cellproliferation
Cell proliferation
Inflammation
Neoplastictransformation
Celldysfunction
y

14

Rinderpest
p
(CattlePlaque,Morbillivirus,EnvelopedRNAVirus)

Similaritieswiththreeviraldiseasesinclinical
i il i i
ih h
i l di
i li i l
presentation,lesions,causativevirusand
mechanismsofinfectionandspread
Morbillivirus,local,regionalandsystemicinfection
andspreadandtheirtargetcells,canine
distemper
Bovineviraldiarrheamucosadisease,clinical
presentationandlesions
Parvoviruses,mechanismsusedtoinfectand
spreadbetweencells.
15

Rinderpest
p
(CattlePlaque,Morbillivirus,EnvelopedRNAVirus)

Mechanismsofinjury:dysfunctionanddeathofmucosalepithelialcells,dendriticcells,Mcells,
M
h i
fi j
d f ti
d d th f
l ith li l ll d d iti
ll M ll
lymphocytesandmacrophageinGI
Lesions:erosions,ulcerationsandhemorrhagesoftheoralcavityandsmallintestineoverPeyers patch.
Edemaandhemorrhageinthemesenterylymphnode.
Virusentry:
inhaled,depositedonandtrappedinthemucosa
Penetratemucuslayerandreachmucosalayer(mechanism?)
Infectionofsurfaceandregionallymphoidcells,macrophages,andlymphnodeviaLeukocyte
I f ti
f f
d
i
ll
h id ll
h
dl
h d i L k t
trafficking
SystemicinfectionthroughLeukocytetraffickingorbloodcirculation.
Enterocyteinfection:
GI?
Peyers patchthenadjacententerocytes
Polarizedpattern,restrictedtothebasolateral area,theareanearesttopeyers patchandM
cells
Mucosalulcerationandsheddingvirusinalimentarytract
Hasenvelopeandhemagglutinin/fusionsurfaceglycoproteins forattachmentandfusion,Vs.hostcell
membraneglycoproteinreceptorCD150(signalinglymphocyteactivationmolecule(SLAM)
SLAMhasbeendemonstratedonthemembraneoflymphocytes,monocytes,macrophages,
epithelialcellsofrespiratory,alimentaryandintegumentarysystems
16

Fig.438A Rinderpest.A, Oralmucosa,dentalpad.Notetheerosionsandulcers(arrows) adjacenttothe

dentalpadcausedbyRinderpest virus.B, Oralmucosa.Focalaggregatesofepithelialcellsinthemucosaare
swollen, necrotic, and some are detached (arrows). When abraded by ingesta orothertrauma,the
swollen,necrotic,andsomearedetached(arrows).Whenabradedbyingesta
or other trauma, the
mechanicalforceappliedtothelesioninA canseparatetheepitheliumoverlyingthelesionanditwillgrow
andleadtoulcersorabrasions,dependingondepthoftheepithelialloss.Notetheacuteinflammatory
responseinthelaminapropria.H&Estain.C, Ileum.ThemucosaoverlyingPeyers patchesisulceratedand
coveredwithfibrinmixedwithhemorrhage(arrows).Thislesionappearstoresultfromspreadofthevirus
d i h fib i
i d i hh
h
(
) Thi l i
l f
d f h i
fromunderlyinglymphocytesinPeyers patchestoepithelialcellsofthecrypts.D, Epithelialcellsofthe
cryptsarehyperplasticandformsyncytia(arrow).Inotherareas,cryptenterocytesandcellsintheadjacent
p p arenecrotic(arrowhead)
(
) andaccompaniedbyacuteinflammation.Thisprocessleadsto
p
y
p
laminapropria
ulcerationoftheintestinalmucosa.H&Estain.(A andC courtesyDr.C.Brown,CollegeofVeterinary
Medicine,TheUniversityofGeorgia.B andD courtesyDr.J.F.Zachary,CollegeofVeterinaryMedicine,
17
UniversityofIllinois.)

Fig.438B Rinderpest.A, Oralmucosa,dentalpad.Notetheerosionsandulcers(arrows) adjacenttothe

dentalpadcausedbyRinderpest virus.B, Oralmucosa.Focalaggregatesofepithelialcellsinthemucosaare
swollen,necrotic,andsomearedetached(arrows).Whenabradedbyingesta orothertrauma,the
mechanicalforceappliedtothelesioninA canseparatetheepitheliumoverlyingthelesionanditwillgrow
andleadtoulcersorabrasions,dependingondepthoftheepithelialloss.Notetheacuteinflammatory
responseinthelaminapropria.H&Estain.C, Ileum.ThemucosaoverlyingPeyers patchesisulceratedand
covered with fibrin mixed with hemorrhage (arrows) This lesion appears to result from spread of the virus
coveredwithfibrinmixedwithhemorrhage(arrows).Thislesionappearstoresultfromspreadofthevirus
fromunderlyinglymphocytesinPeyers patchestoepithelialcellsofthecrypts.D, Epithelialcellsofthe
cryptsarehyperplasticandformsyncytia(arrow).Inotherareas,cryptenterocytesandcellsintheadjacent
laminapropria arenecrotic(arrowhead) andaccompaniedbyacuteinflammation.Thisprocessleadsto
ulcerationoftheintestinalmucosa.H&Estain.(A andC courtesyDr.C.Brown,CollegeofVeterinary
Medicine,TheUniversityofGeorgia.B andD courtesyDr.J.F.Zachary,CollegeofVeterinaryMedicine,
18
UniversityofIllinois.)

Fig.438C Rinderpest.A, Oralmucosa,dentalpad.

Notetheerosionsandulcers(arrows) adjacentto
thedentalpadcausedbyRinderpest virus.B, Oral
mucosa Focal aggregates of epithelial cells in the
mucosa.Focalaggregatesofepithelialcellsinthe
mucosaareswollen,necrotic,andsomeare
detached(arrows).Whenabradedbyingesta or
othertrauma,themechanicalforceappliedtothe
lesioninA canseparatetheepitheliumoverlyingthe
lesionanditwillgrowandleadtoulcersorabrasions,
dependingondepthoftheepithelialloss.Notethe
acute inflammatory response in the lamina propria
acuteinflammatoryresponseinthelaminapropria.
H&Estain.C, Ileum.ThemucosaoverlyingPeyers
patchesisulceratedandcoveredwithfibrinmixed
withhemorrhage(arrows).Thislesionappearsto
resultfromspreadofthevirusfromunderlying
lymphocytesinPeyers patchestoepithelialcellsof
thecrypts.D, Epithelialcellsofthecryptsare
hyperplastic and form syncytia (arrow) In other
hyperplasticandformsyncytia(arrow).Inother
areas,cryptenterocytesandcellsintheadjacent
laminapropria arenecrotic(arrowhead) and
accompaniedbyacuteinflammation.Thisprocess
leadstoulcerationoftheintestinalmucosa.H&E
stain.(A andC courtesyDr.C.Brown,Collegeof
VeterinaryMedicine,TheUniversityofGeorgia.B
and D courtesyDr.J.F.Zachary,CollegeofVeterinary
andD
courtesy Dr J F Zachary College of Veterinary
Medicine,UniversityofIllinois.)
19

Fig.438D Rinderpest.A, Oralmucosa,dental

pad.Notetheerosionsandulcers(arrows)
adjacenttothedentalpadcausedbyRinderpest
virus.B,
i
B Oralmucosa.Focalaggregatesof
O l
F l
t
f
epithelialcellsinthemucosaareswollen,necrotic,
andsomearedetached(arrows).Whenabraded
byingesta
y g
orothertrauma,themechanicalforce
,
appliedtothelesioninA canseparatethe
epitheliumoverlyingthelesionanditwillgrow
andleadtoulcersorabrasions,dependingon
d th f th
depthoftheepithelialloss.Notetheacute
ith li l l
N t th
t
inflammatoryresponseinthelaminapropria.H&E
stain.C, Ileum.ThemucosaoverlyingPeyers
p
patchesisulceratedandcoveredwithfibrinmixed
withhemorrhage(arrows).Thislesionappearsto
resultfromspreadofthevirusfromunderlying
lymphocytesinPeyers patchestoepithelialcells
of the cr pts D Epithelialcellsofthecryptsare
ofthecrypts.D,
Epithelial cells of the cr pts are
hyperplasticandformsyncytia(arrow).Inother
areas,cryptenterocytesandcellsintheadjacent
laminapropria
p p arenecrotic(arrowhead)
(
) and
accompaniedbyacuteinflammation.Thisprocess
leadstoulcerationoftheintestinalmucosa.H&E
stain.(A andC courtesyDr.C.Brown,Collegeof
Veterinary Medicine The University of Georgia B
VeterinaryMedicine,TheUniversityofGeorgia.B
andD courtesyDr.J.F.Zachary,Collegeof
VeterinaryMedicine,UniversityofIllinois.) 20

ParvovirusEnteritis
(nonenvelopedDNAvirus)

C
Canineandfelineparvovirusenteritis
i
d f li
i
t iti
Mechanismofinjuryisdeathofcryptepithelial
cells and lymphocytes including in those in bone
cellsandlymphocytesincludinginthoseinbone
marrow.
Lesions:enterocytesnecrosisandvillousatrophy,
Lesions: enterocytes necrosis and villous atrophy
hemorrhage,acuteinflammationandfibrin
exudates
Infectionrequiredahostcellderivedduplex
transcriptiontemplate,onlyavailableincell
p
p
,
y
underSphaseofthecellcycle.
UnabletoturnonDNAsynthesisinhostcells,
21

ParvovirusEnteritis
(nonenvelopedDNAvirus)

Virusentry:
Vi
Inhaledoringested,depositedonmucosaortrappedinmucuslayer
Howthevirusreachtomucosalayer?
Spreading:leukocytetraffickingorcellfreevirusdisseminated
Experimentally,virusreachpeyers patchisearlierbeforeitreachcontiguouscrypt
enterocytes
Polarizedpatterninfection,restrictedtothebasolateral
P l i d tt
i f ti
t i t d t th b l t l area,theareanearesttopeyers
th
tt

patchandMcells
Cellreceptor,dog:capsidproteinbindtotransferrinreceptors;cat:neuraminiacidand
transferrin receptor
transferrinreceptor
Osmoticmalabsorptionandmaldigestiondiarrhea,enterocyteskilledandsloughedfrom
mucosaafterviralreplicationcompletion,
Lifespanofenterocyte48h
Life span of enterocyte 48h
Lostofsupplementofenterocytefromcryptepithelium
Lostofdigestivefunctionofenterocyte
Villousatrophy
Villous atrophy
Barrierlostandexposedlaminapropria
22
Fermentationofbacteriaandendotoxinperfusion,enterotoxic shockandDIC

Fig.7160A Parvovirusenteritis,smallintestine,dog.A, Segmentsofthesmall

intestinearediffuselyreddened(activehyperemiaofthemucosa),andtheserosal
surface is roughened, faintly granular, and petechiated. B, Themucosaofthesmall
surfaceisroughened,faintlygranular,andpetechiated.B,
The mucosa of the small
intestineisnecrotic.Notetheroughened,granular,focallypetechiated,andfocally
sloughingmucosa.(A courtesyCollegeofVeterinaryMedicine,UniversityofIllinois.B
courtesyDepartmentofVeterinaryBiosciences,CollegeofVeterinaryMedicine,The
Ohio State University and NoahssArkive,CollegeofVeterinaryMedicine,The
OhioStateUniversityandNoah
Arkive College of Veterinary Medicine The
UniversityofGeorgia.)
23

24

25

26

27

TransmissibleGastroenteritis
(EnvelopedRNAvirus)

Mechanismofinjuryisdysfunctionanddeathofepithelialcells(villus
h i
fi j
i d f
i
d d h f i h li l ll ( ill enterocytes)
)
coveringtipandsidesofintestinalvilli.
Lesions:congestionandthinningofsmallGIwall,shortening(atrophy)ofvilli.
Virusentry:
Ingestionandswallowing
Trappedinmucusofmucosalayer
Trapped in mucus of mucosa layer
ViralenvelopeSproteinfacilitatesitsentryintovillus enterocytes
Bindsialic acid(mucin likeglycoproteins)inthemucus
Bindaminopeptidase
d
d
N,expressedonapicalsurfaceofvillus
d
l f
f ll enterocytes
Cellkilledandsloughed,butcouldbereplaced
Amalabsorptionosmoticdiarrheaoccurred
Carbohydrateaccumulated,bacterialfermentation,denudedepitheliummaybe
susceptibletobacterialtoxinwhichaffectscardiovascularandhemodynamic
y
system
28

Fig.439A
Fig
439A Mechanismofviralinfectionsthat
Mechanism of viral infections that
targetvillusabsorptiveenterocytes.A,
Transmissiblegastroenteritisvirusand
rotavirus use similar mechanisms to infect
rotavirususesimilarmechanismstoinfect
villusenterocytesandcausedisease.B, Small
intestine,villusatrophy.Followingtheinitial
lossoftipenterocytes(arrows),
p
y (
), thevilli
contract,reducingthesurfaceareatobe
reepithelialized.Notethecryptepithelium
becomeshyperplasticwithnumerousmitoses
andthevilliarecoveredbyalessspecialized,
usuallylowcuboidalepithelium.Thevillus
laminapropriaisinfiltratedbyacute
inflammatorycells.H&Estain.(A fromGoering
R,Dockrell H,Roitt I,etal:Mimsmedical
microbiology, ed 4,St.Louis,2008,Mosby.B
courtesyDr.J.F.Zachary,CollegeofVeterinary
Medicine,UniversityofIllinois.)
29

Fig.439B Mechanismofviralinfectionsthattargetvillusabsorptiveenterocytes.A, Transmissible

gastroenteritisvirusandrotavirususesimilarmechanismstoinfectvillusenterocytesandcausedisease.B,
Smallintestine,villusatrophy.Followingtheinitiallossoftipenterocytes(arrows), thevillicontract,reducing
thesurfaceareatobereepithelialized.Notethecryptepitheliumbecomeshyperplasticwithnumerous
mitosesandthevilliarecoveredbyalessspecialized,usuallylowcuboidalepithelium.Thevilluslamina
propria is infiltrated by acute inflammatory cells H&E stain (A fromGoeringR,Dockrell
propriaisinfiltratedbyacuteinflammatorycells.H&Estain.(A
from Goering R Dockrell H,Roitt
H Roitt I,etal:
I et al:
Mimsmedicalmicrobiology, ed 4,St.Louis,2008,Mosby.B courtesyDr.J.F.Zachary,CollegeofVeterinary
Medicine,UniversityofIllinois.)
30

FootandMouthDisease
(Aphthovirus,nonenveloped RNAvirus)
M
Mechanismsofinjury:similartoswinevesiculardisease
h i
fi j
i il t
i
i l di
andvesicularexanthemaofpigs,celldysfunctionanddeath
leadingtointercellularedema(vesiculation),ruptureof
vesiclesandsubsequenterosionsandulcersonthemucosa
andskin.
Viralentry
Viral entry
Inhalationoringestion,establishedlocalinfection,then
regionallymphoidtissue,thensystemicspread
Systemicallytoinfect,replicateinandlysed epithelialcells
ofstratumspongiosum ofmucosaandskinresultingin
vesicles.
Capsidprotein,VP14asaligand;integrin (V1,V3,
andV6)expressedinthehostcellsareusedasreceptor.
31

FMD

FMD

FMD

Fig.440A
g
Footandmouthdisease.A,, Ox.Notetheulceronthemucosaoftheupperdental
pp
pad.Suchulcersbeginasfluidfilledvesiclesthatruptureusuallyfromthetraumaofmastication
orprehension.Vesiclesandulcersthatresultfromtheirrupturemayoccuronallmucosaeof
thebodyincludingthedentalpad,tongue,gingiva,coronarybands,andteatsasexamples.B,
Themucosahasalargefocusofapreviousvesicle,whichisnowpartiallyfilledwithedemafluid,
fibrin,cellulardebris,andacuteinflammatorycellsformingapustule.H&Estain.(A courtesyDr.
M.Adsit,CollegeofVeterinaryMedicine,TheUniversityofGeorgiaandNoahsArkive,College
ofVeterinaryMedicine,TheUniversityofGeorgia.B courtesyDr.C.Brown,CollegeofVeterinary
Medicine,TheUniversityofGeorgia.)
35

Fig.440B Footandmouthdisease.A, Ox.Notetheulceronthemucosaoftheupperdentalpad.Such

ulcersbeginasfluidfilledvesiclesthatruptureusuallyfromthetraumaofmasticationorprehension.
l
b i
fl id fill d
i l h
ll f
h
f
i i
h i
Vesiclesandulcersthatresultfromtheirrupturemayoccuronallmucosaeofthebodyincludingthedental
pad,tongue,gingiva,coronarybands,andteatsasexamples.B, Themucosahasalargefocusofaprevious
vesicle, which is now partially filled with edema fluid, fibrin, cellular debris, and acute inflammatory cells
vesicle,whichisnowpartiallyfilledwithedemafluid,fibrin,cellulardebris,andacuteinflammatorycells
formingapustule.H&Estain.(A courtesyDr.M.Adsit,CollegeofVeterinaryMedicine,TheUniversityof
GeorgiaandNoahsArkive,CollegeofVeterinaryMedicine,TheUniversityofGeorgia.B courtesyDr.C.
36
Brown,CollegeofVeterinaryMedicine,TheUniversityofGeorgia.)

InfectiousBovineRhinotracheitis
(bovineherpesvirus,alphaherpesvirus,envelopedDNAvirus)

M
Mechanismsofinjury,deathofciliated(mucociliary
h i
fi j
d th f ili t d (
ili
apparatus)andnonciliated epithelialcellsoftheoral,nasal,
pharyngeal,andrespiratorymucosa.
Lesions:hyperemia,hemorrhage,edema,andnecrosis
leadingtolargeareasofmucosalerosionsandulcersoften
covered with a fibrinous membrane
coveredwithafibrinousmembrane.
Virusentry:
inhaledandingested,trappedinthemucus
Ligandreceptor:
viralenvelopeglycoproteinB,C,Dareusedtoattachandentera
varietyofhosttargetcellsviaanarrayofglycoaminoglycan receptor
suchasherpesvirus
h h
i entrymediatorA,netin
di
i 1and2(herpesentry
d 2 (h
proteinCandB),and3osulfatedheparinsulfate,commonlyexpress
onthemucosaepitheliumandsensorynerveendings.

37

InfectiousBovineRhinotracheitis
(bovineherpesvirus,alphaherpesvirus,envelopedDNAvirus)

Virusentry:
Vi
t
Gainaccesstosensorynerveendingsinthe
respiratory mucosa trigeminal and olfactory nerve via
respiratorymucosa,trigeminalandolfactorynervevia
retrogradeaxonaltransportandtootherCNS
Nervecells:reservoir,noMHCIIandlowconcentrationof
MHCI l
MHCI,lesslikelybeingrecognizedbyimmunesurveillance
lik l b i
i db i
ill
Duringlatency,notantigen(viralprotein)aresynthesized

With
Withactivation,virusre
activation, virus reestablishes
establishesitsreplication
its replication
cycleandthroughaxonaltransportmechanismspread
backtothenerveendingofthemucosa,infect
adjacent epithelial cells and transmit the disease
adjacentepithelialcellsandtransmitthedisease.

38

InfectiousBovineRhinotracheitis
(bovineherpesvirus,alphaherpesvirus,envelopedDNAvirus)

Herpesproteins
H
t i
Disruptthesynthesisoftheinterferon
Blocktherecognitionofvirusinfectedcellsbycytotoxic
g
y y
T
lymphocytes
BlockthehomingofTlymphocytestoviralinfectedcells

Virus
ViruscouldInducehighlevelofapoptosisinThelpercells,
could Induce high level of apoptosis in T helper cells
thussuppressingtheadaptiveimmuneresponsetovirus.
Infectedcellsaremoresusceptibletobacterialinfection
likepasteurellosis andMannheimioisis
Immunesuppression
Functionalabortedmucocilliary
Functional aborted mucocilliary apparatusandsensorynerve
apparatus and sensory nerve
endings.

39

Fig.441 Mechanism
ofmucosalinfections
causedby
rhinotracheitis viruses.
viruses
Forsimplification,the
epitheliumis
representedasonecell
thick.(FromGoeringR,
Dockrell H,Roitt I,etal:
Mimsmedical
microbiology ed 4,St.
microbiology,
4 St
Louis,2008,Mosby.)
40

ClassicalSwineFever
(HogCholera,Pestivirus,envelopedRNAvirus)
M
Mechanismsofinjury,deathofendothelialcellsofmultiple
h i
fi j
d th f d th li l ll f
lti l
organsystemsandofhemopoietic cells.
Lesions:hemorrhageinmultipleorgans(kidneyandspleen),
g
p
g
(
y
p
),
necrosisinthepalatinetonsil.
Viralentry:
iingestionandlikelyinhalation,mechanicaltransfer(vehicleor
ti
d lik l i h l ti
h i lt
f ( hi l
instruments)
Infectandreplicateintonsilcrypt
Howtopenetratemucuslayer?
Erns andE2andotherenvelopglycoproteins areligand andbind
tocellsurfaceglycosaminoglycan
gy
gy
likeheparinsulfate
p
Leukocytetraffickingandcellfreeviremia,regionalreplication
andsystemicspreading
41

ClassicalSwineFever
(HogCholera,Pestivirus,envelopedRNAvirus)

EEndothelialinjury
d h li l i j
Infectedmacrophagesinteractwithcellsbyadheringtoandmigratingthrough
endothelium,likelybyactivatingtheleukocytesadhesioncascade
Directinjurytoinfectedendothelialcellscauseacuteinflammatoryresponse.
Direct injury to infected endothelial cells cause acute inflammatory response
Lesions:endothelialswelling,degeneration,andnecrosis,andacuteandchronic
inflammation.
Necrosisofvascularmyocytes,andthrombusformationleadingtoedemaand
Necrosis of vascular myocytes and thrombus formation leading to edema and
hemorrhageinmanytissuesandorgans,likeinkidney.
Hemopoietic cellinjury
Virusspreadbymacrophageorbyfreevirustolymphoidtissueandbonemarrow.
Virus spread by macrophage or by free virus to lymphoid tissue and bone marrow
Infectsandkillthesecells,
Severelyimpairedadaptiveimmuneresponse
Decreaseneutralizingantibodyproduction
Decrease neutralizing antibody production
Decreasenumberofphagocytes
Decreasedcellmediatedimmuneresponse
Infectedpigmaybemoresusceptibletootherinfectiousagents
Infected pig may be more susceptible to other infectious agents
42

Fig.442A Classicalswinefever(hogcholera). Lesionsin

classicalswinefeveraresimilartothoseobservedin
African swine fever, but usually less severe. See Fig. 443
Africanswinefever,butusuallylesssevere.SeeFig.4
43
forlesionsofAfricanswinefever.A, Thetonsil(ofthesoft
palate), atissueofchoiceforisolationandidentificationof
thevirus,containsfociofhemorrhageandnecrosis
(
(arrows),
) theresultofnecrosisofmucosalepithelialcellsin
h
l f
i f
l i h li l ll i
tonsillar cryptsandnecrosisoftheadjacentendothelial
cellsandlymphocytesinthelaminapropriafrominfection
with virus. B, Kidney.Thecorticalsurfacehasnumerous
withvirus.B,
Kidney. The cortical surface has numerous
randomlydistributedpetechia causedbyinjurytoand
subsequentnecrosisofendothelialcellsfollowingtheir
infectionwithclassicalswinefevervirus.C, Mesenteric
l
lymphnodes(arrows)
h d (
) areenlargedandcongesteddueto
l
d d
dd
vascularinjurycausedbyvirus,resultinginbloodinthe
subcapsular sinuses.D, Tonsillar cryptlymphoidnodules.
Notethefocalnecrosisoflymphocytes(rightlowerhalfof
y p y ( g
f f
image) inthenodulescausedbyinfectionwithvirus.H&E
stain.(A courtesyDr.R.Breeze,PlumIslandAnimalDisease
CenterandNoahsArkive,CollegeofVeterinaryMedicine,
Th U i
TheUniversityofGeorgia.B
it f G
i B courtesyDr.D.Gregg,Plum
t
D D G
Pl
IslandAnimalDiseaseCenterandNoahsArkive,Collegeof
VeterinaryMedicine,TheUniversityofGeorgia.C courtesy
Dr.M.D.McGavin,CollegeofVeterinaryMedicine,
,
g
y
,
UniversityofTennessee.D courtesyDr.J.F.Zachary,College
ofVeterinaryMedicine,UniversityofIllinois.)
43

Fig.442B
Fi
4 42B Classicalswinefever(hogcholera).
Cl i l i f
(h
h l ) Lesionsinclassicalswinefeveraresimilartothoseobserved
L i
i l i l i f
i il
h
b
d
inAfricanswinefever,butusuallylesssevere.SeeFig.443forlesionsofAfricanswinefever.A, Thetonsil(of
thesoftpalate), atissueofchoiceforisolationandidentificationofthevirus,containsfociofhemorrhage
andnecrosis(arrows),
and
necrosis (arrows), the
theresultofnecrosisofmucosalepithelialcellsintonsillar
result of necrosis of mucosal epithelial cells in tonsillar crypts
cryptsandnecrosisofthe
and necrosis of the
adjacentendothelialcellsandlymphocytesinthelaminapropriafrominfectionwithvirus.B, Kidney.The
corticalsurfacehasnumerousrandomlydistributedpetechia causedbyinjurytoandsubsequentnecrosisof
endothelialcellsfollowingtheirinfectionwithclassicalswinefevervirus.C, Mesentericlymphnodes(arrows)
areenlargedandcongestedduetovascularinjurycausedbyvirus,resultinginbloodinthesubcapsular
l
d d
t dd t
l i j
db i
lti i bl d i th
b
l
sinuses.D, Tonsillar cryptlymphoidnodules.Notethefocalnecrosisoflymphocytes(rightlowerhalfof
image) inthenodulescausedbyinfectionwithvirus.H&Estain.(A courtesyDr.R.Breeze,PlumIsland
,
g
y
,
y
g
AnimalDiseaseCenterandNoahsArkive,CollegeofVeterinaryMedicine,TheUniversityofGeorgia.B
courtesyDr.D.Gregg,PlumIslandAnimalDiseaseCenterandNoahsArkive,CollegeofVeterinaryMedicine,
TheUniversityofGeorgia.C courtesyDr.M.D.McGavin,CollegeofVeterinaryMedicine,Universityof
44
Tennessee.D courtesyDr.J.F.Zachary,CollegeofVeterinaryMedicine,UniversityofIllinois.)

Fig.442C
Fi
4 42C Classicalswinefever(hogcholera).
Cl i l i f
(h
h l ) Lesionsinclassicalswinefeveraresimilartothoseobserved
L i
i l i l i f
i il
h
b
d
inAfricanswinefever,butusuallylesssevere.SeeFig.443forlesionsofAfricanswinefever.A, Thetonsil(of
thesoftpalate), atissueofchoiceforisolationandidentificationofthevirus,containsfociofhemorrhage
andnecrosis(arrows),
and
necrosis (arrows), the
theresultofnecrosisofmucosalepithelialcellsintonsillar
result of necrosis of mucosal epithelial cells in tonsillar crypts
cryptsandnecrosisofthe
and necrosis of the
adjacentendothelialcellsandlymphocytesinthelaminapropriafrominfectionwithvirus.B, Kidney.The
corticalsurfacehasnumerousrandomlydistributedpetechia causedbyinjurytoandsubsequentnecrosisof
endothelialcellsfollowingtheirinfectionwithclassicalswinefevervirus.C, Mesentericlymphnodes(arrows)
areenlargedandcongestedduetovascularinjurycausedbyvirus,resultinginbloodinthesubcapsular
l
d d
t dd t
l i j
db i
lti i bl d i th
b
l
sinuses.D, Tonsillar cryptlymphoidnodules.Notethefocalnecrosisoflymphocytes(rightlowerhalfof
image) inthenodulescausedbyinfectionwithvirus.H&Estain.(A courtesyDr.R.Breeze,PlumIsland
,
g
y
,
y
g
AnimalDiseaseCenterandNoahsArkive,CollegeofVeterinaryMedicine,TheUniversityofGeorgia.B
courtesyDr.D.Gregg,PlumIslandAnimalDiseaseCenterandNoahsArkive,CollegeofVeterinaryMedicine,
TheUniversityofGeorgia.C courtesyDr.M.D.McGavin,CollegeofVeterinaryMedicine,Universityof
45
Tennessee.D courtesyDr.J.F.Zachary,CollegeofVeterinaryMedicine,UniversityofIllinois.)

Fig.442D
Fi
4 42D Classicalswinefever(hogcholera).
Cl i l i f
(h
h l ) Lesionsinclassicalswinefeveraresimilartothoseobserved
L i
i l i l i f
i il
h
b
d
inAfricanswinefever,butusuallylesssevere.SeeFig.443forlesionsofAfricanswinefever.A, Thetonsil(of
thesoftpalate), atissueofchoiceforisolationandidentificationofthevirus,containsfociofhemorrhage
andnecrosis(arrows),
and
necrosis (arrows), the
theresultofnecrosisofmucosalepithelialcellsintonsillar
result of necrosis of mucosal epithelial cells in tonsillar crypts
cryptsandnecrosisofthe
and necrosis of the
adjacentendothelialcellsandlymphocytesinthelaminapropriafrominfectionwithvirus.B, Kidney.The
corticalsurfacehasnumerousrandomlydistributedpetechia causedbyinjurytoandsubsequentnecrosisof
endothelialcellsfollowingtheirinfectionwithclassicalswinefevervirus.C, Mesentericlymphnodes(arrows)
areenlargedandcongestedduetovascularinjurycausedbyvirus,resultinginbloodinthesubcapsular
l
d d
t dd t
l i j
db i
lti i bl d i th
b
l
sinuses.D, Tonsillar cryptlymphoidnodules.Notethefocalnecrosisoflymphocytes(rightlowerhalfof
image) inthenodulescausedbyinfectionwithvirus.H&Estain.(A courtesyDr.R.Breeze,PlumIsland
,
g
y
,
y
g
AnimalDiseaseCenterandNoahsArkive,CollegeofVeterinaryMedicine,TheUniversityofGeorgia.B
courtesyDr.D.Gregg,PlumIslandAnimalDiseaseCenterandNoahsArkive,CollegeofVeterinaryMedicine,
TheUniversityofGeorgia.C courtesyDr.M.D.McGavin,CollegeofVeterinaryMedicine,Universityof
46
Tennessee.D courtesyDr.J.F.Zachary,CollegeofVeterinaryMedicine,UniversityofIllinois.)

AfricanSwineFever
(Asfivirus,envelopedDNAvirus)
Mechanismsofinjury
SimilartoCSFV
Butmoresevere
Virusentry
InadditiontotheentryroutesofCSFV,Africanswinefever
viruscangainaccesstothebloodvascularsystemand
direct infect macrophage through bites of ticks
directinfectmacrophagethroughbitesofticks
Hemopoietic cellinjury
Viralglycoproteinp12,p54,andp30aretheligands
Vi l l
t i 12 54 d 30
th li d forthe
f th
attachmentandenteringintotargetcells,receptorisnot
yet identified
yetidentified
DICleadingtocollapseofthecirculatorysystemandshock47
islikelythecauseofdeathintheinfectedpigs.

Fig.443A Africanswinefever. LesionsinAfricanswinefeveraresimilartothoseobservedinclassical

swinefever,butusuallymuchmoresevere.SeeFig.442forlesionsofclassicalswinefever.A, Epicardium
and pericardial cavity. The epicardium andsubjacentmyocardiumhavenumerousrandomlydistributed
andpericardialcavity.Theepicardium
and subjacent myocardium have numerous randomly distributed
ecchymoses causedbyinjurytoandsubsequentnecrosisofendothelialcellsfrominfectionwithAfrican
swinefevervirus.Notetheaccumulationofafibrinous effusioninthepericardialcavity.B, Splenomegaly,
bloodyspleen.Thespleeniscongestedwithbloodandfriableasaresultofvasculardamagecausedbythe
virus.Lymphnodes(notshownhere)arealsocongestedandedematous(seeclassicalswinefever).C,
i
L
h d (
h
h )
l
d d d
(
l i l i f
) C
Endothelialcellsandlymphoidcellsofwhitepulpofthespleenarenecrotic(e.g.,pyknosis,karyolysis).H&E
stain.D, Endothelialcellsliningsinusoidsoftheliverarenecrotic(e.g.,pyknosis,karyolysis).Alsonotethe
necrosis of some hepatocytes. H&E stain. (A courtesyDr.C.Brown,CollegeofVeterinaryMedicine,The
necrosisofsomehepatocytes.H&Estain.(A
courtesy Dr. C. Brown, College of Veterinary Medicine, The
UniversityofGeorgia.B courtesyDr.D.Gregg,PlumIslandAnimalDiseaseCenterandNoahsArkive,College
ofVeterinaryMedicine,TheUniversityofGeorgia.C andD CourtesyDr.J.F.Zachary,CollegeofVeterinary
48
Medicine,UniversityofIllinois.)

Fig.443B Africanswinefever. LesionsinAfrican

swinefeveraresimilartothoseobservedinclassical
swinefever,butusuallymuchmoresevere.SeeFig.
4 42 f l i
442forlesionsofclassicalswinefever.A,
f l i l i f
A
Epicardium andpericardialcavity.Theepicardium
andsubjacentmyocardiumhavenumerousrandomly
distributedecchymoses
y
causedbyinjurytoand
y j y
subsequentnecrosisofendothelialcellsfrom
infectionwithAfricanswinefevervirus.Notethe
accumulationofafibrinous effusioninthe
pericardialcavity.B,
i di l
it B Splenomegaly,bloodyspleen.
S l
l bl d
l
Thespleeniscongestedwithbloodandfriableasa
resultofvasculardamagecausedbythevirus.Lymph
nodes(notshownhere)arealsocongestedand
(
)
g
edematous(seeclassicalswinefever).C, Endothelial
cellsandlymphoidcellsofwhitepulpofthespleen
arenecrotic(e.g.,pyknosis,karyolysis).H&Estain.D,
E d th li l ll li i
Endothelialcellsliningsinusoidsoftheliverare
i
id f th li
necrotic(e.g.,pyknosis,karyolysis).Alsonotethe
necrosisofsomehepatocytes.H&Estain.(A courtesy
Dr.C.Brown,CollegeofVeterinaryMedicine,The
,
g
y
,
UniversityofGeorgia.B courtesyDr.D.Gregg,Plum
IslandAnimalDiseaseCenterandNoahsArkive,
CollegeofVeterinaryMedicine,TheUniversityof
G
Georgia.C
i C andD
d D CourtesyDr.J.F.Zachary,Collegeof
C t
D JF Z h
C ll
f
VeterinaryMedicine,UniversityofIllinois.)
49

Fig.443C Africanswinefever. LesionsinAfrican

swinefeveraresimilartothoseobservedinclassical
swinefever,butusuallymuchmoresevere.SeeFig.
4 42 for lesions of classical s ine fe er A
442forlesionsofclassicalswinefever.A,
Epicardium andpericardialcavity.Theepicardium
andsubjacentmyocardiumhavenumerousrandomly
distributedecchymoses
y
causedbyinjurytoand
y j y
subsequentnecrosisofendothelialcellsfrom
infectionwithAfricanswinefevervirus.Notethe
accumulationofafibrinous effusioninthe
pericardial cavity B Splenomegaly,bloodyspleen.
pericardialcavity.B,
Splenomegaly bloody spleen
Thespleeniscongestedwithbloodandfriableasa
resultofvasculardamagecausedbythevirus.Lymph
nodes(notshownhere)arealsocongestedand
edematous(seeclassicalswinefever).C, Endothelial
cellsandlymphoidcellsofwhitepulpofthespleen
arenecrotic(e.g.,pyknosis,karyolysis).H&Estain.D,
Endothelial cells lining sinusoids of the liver are
Endothelialcellsliningsinusoidsoftheliverare
necrotic(e.g.,pyknosis,karyolysis).Alsonotethe
necrosisofsomehepatocytes.H&Estain.(A courtesy
Dr.C.Brown,CollegeofVeterinaryMedicine,The
UniversityofGeorgia.B courtesyDr.D.Gregg,Plum
IslandAnimalDiseaseCenterandNoahsArkive,
CollegeofVeterinaryMedicine,TheUniversityof
Georgia C andD
Georgia.C
and D CourtesyDr.J.F.Zachary,Collegeof
Courtesy Dr J F Zachary College of
VeterinaryMedicine,UniversityofIllinois.)
50

Fig.443D Africanswinefever. LesionsinAfricanswine

feveraresimilartothoseobservedinclassicalswine
fever,butusuallymuchmoresevere.SeeFig.442for
lesionsofclassicalswinefever.A, Epicardium and
pericardialcavity.Theepicardium andsubjacent
myocardiumhavenumerousrandomlydistributed
ecchymoses causedbyinjurytoandsubsequentnecrosis
caused by injury to and subsequent necrosis
ofendothelialcellsfrominfectionwithAfricanswine
fevervirus.Notetheaccumulationofafibrinous effusion
inthepericardialcavity.B, Splenomegaly,bloodyspleen.
Thespleeniscongestedwithbloodandfriableasaresult
h
l
d
h bl d d f bl
l
ofvasculardamagecausedbythevirus.Lymphnodes
(notshownhere)arealsocongestedandedematous
(see classical swine fever). C, Endothelialcellsand
(seeclassicalswinefever).C,
Endothelial cells and
lymphoidcellsofwhitepulpofthespleenarenecrotic
(e.g.,pyknosis,karyolysis).H&Estain.D, Endothelialcells
liningsinusoidsoftheliverarenecrotic(e.g.,pyknosis,
k
karyolysis).Alsonotethenecrosisofsomehepatocytes.
l i ) Al
h
i f
h
H&Estain.(A courtesyDr.C.Brown,Collegeof
VeterinaryMedicine,TheUniversityofGeorgia.B
courtesy Dr. D. Gregg, Plum Island Animal Disease Center
courtesyDr.D.Gregg,PlumIslandAnimalDiseaseCenter
andNoahsArkive,CollegeofVeterinaryMedicine,The
UniversityofGeorgia.C andD CourtesyDr.J.F.Zachary,
CollegeofVeterinaryMedicine,UniversityofIllinois.)

51

AfricanHorseSickness
(Orbivirus,Nonenveloped RNAvirus)
IT
ITissimilartoBluetongueDisease.
i i il t Bl t
Di
Themechanismsofinjury,endothelialcellbarrier
dysfunction virusinduced
dysfunction,virus
induceddysfunctionanddeathof
dysfunction and death of
endothelialcells.
Characterizedvascularinjurycauselesionsinclude
j y
edema,activehyperemia,petechial andecchymotic
hemorrhageindifferentorgansandtissues,
hydrothorax hydroepicardiium ascites and
hydrothorax,hydroepicardiium,ascites
and
rhabdomyocytic necrosis.
Thevirusalsoinfectscellsofdendritic,lymphoidand
, y p
monocytemacrophagesystem.
Noncontagiousdiseaseofhorses,donkeys,andmules.
52

AfricanHorseSickness
(Orbivirus,Nonenveloped RNAvirus)

Virusentry
Vi
t
Throughbitewoundfrommidges,
thenintovessels
orcutaneous
or cutaneous connectivetissue,dendriticcellsormacrophagesmaycarrythevirustocirculationor
connective tissue, dendritic cells or macrophages may carry the virus to circulation or
regionalLN,thensystemicspread.
Viralcapsidproteins(VP2andVP5)areattachmentproteinsthatbindtoglycoaminocan onthecell
membraneoftargetcells.
E d th li l ll
Endothelialcellscanbeinfectedthroughinteractionofmacrophageswithactivationofleukocytic
b i f t d th
hi t
ti
f
h
ith ti ti
f l k ti
adhesioncascade.
Theviruscanbereplicatedintheendothelialcellsresultingdirectinjuryandinducingacute
inflammatoryresponse
Vascularlesionsareprobablylytic,andcharacterizedbyendothelialswelling,degenerationand
necrosis
Vasculitis canbeoccurredafterhemorrhageandedemaaffectthelung(andseveralorgans)and
g
vascularthrombosisleadingtotissueinfarction.
Necrosisofrhabdomyocyrtes intheheart
Releaseofendogenouscatecholamines
Microthrombosis ofmyocardialcapillarieslikelyresultinginmyocyte ischemia
NS3,aviralproteininsertedinthehostcellmembranemaybecytotoxic (viroporin thatalterhostcell
membranepermeability.
53

Fig.444A
Fi
4 44A Africanhorsesickness.A,
Af i
h
i k
A Pulmonaryedema.Theinterlobularseptaarewidelyseparatedand
P l
d
Th i
l b l
id l
d d
distendedwithedemafluid.Edemafluidisalsopresentinalveoliandalveolarsepta.Alsonotethesuffusive
hemorrhageofthevisceralpleura.Theselesionsarecausedbyinfectionofendothelialcellsofthecapillaries
of the interlobular and alveolar septa by African horse sickness virus resulting in endothelial cell barrier
oftheinterlobularandalveolarseptabyAfricanhorsesicknessvirusresultinginendothelialcellbarrier
malfunctionanddeathofendothelialcells.B, Colonicserosa,petechialandecchymotic hemorrhages.These
lesionsarealsocausedbyinfectionofanddamagetoendothelialcells.C, Lung,interlobularedema.The
interlobularseptumandalveolicontainedemafluid.Capillariesandvenules aresurroundedbybronchiole
associatedlymphoidtissue(BALT).H&Estain.D,
i t dl
h id ti
(BALT) H&E t i D HighermagnificationofC.
Hi h
ifi ti
f C Theendothelialcellsofvenules
Th
d th li l ll f
l
areswollen,havevacuolatedandreticulatedcytoplasm,andlargereactivenucleiconsistentwithresponses
toinjurycausedbyinfectionofthesecellsbyAfricanhorsesicknessvirus,butisnotpathognomonic.Note
y p
(
) ( courtesyDr.D.Gregg,PlumIslandAnimalDisease
y
gg,
thebronchioleassociatedlymphoidtissue(BALT).(A
CenterandNoahsArkive,CollegeofVeterinaryMedicine,TheUniversityofGeorgia.B courtesyDr.R.Breeze,
PlumIslandAnimalDiseaseCenterandNoahsArkive,CollegeofVeterinaryMedicine,TheUniversityof
54
Georgia.C andD courtesyDr.J.F.Zachary,CollegeofVeterinaryMedicine,UniversityofIllinois.)

Fig.444B
Fi
4 44B Africanhorsesickness.A,
Af i
h
i k
A Pulmonaryedema.Theinterlobularseptaarewidelyseparatedand
P l
d
Th i
l b l
id l
d d
distendedwithedemafluid.Edemafluidisalsopresentinalveoliandalveolarsepta.Alsonotethesuffusive
hemorrhageofthevisceralpleura.Theselesionsarecausedbyinfectionofendothelialcellsofthecapillaries
of the interlobular and alveolar septa by African horse sickness virus resulting in endothelial cell barrier
oftheinterlobularandalveolarseptabyAfricanhorsesicknessvirusresultinginendothelialcellbarrier
malfunctionanddeathofendothelialcells.B, Colonicserosa,petechialandecchymotic hemorrhages.These
lesionsarealsocausedbyinfectionofanddamagetoendothelialcells.C, Lung,interlobularedema.The
interlobularseptumandalveolicontainedemafluid.Capillariesandvenules aresurroundedbybronchiole
associatedlymphoidtissue(BALT).H&Estain.D,
i t dl
h id ti
(BALT) H&E t i D HighermagnificationofC.
Hi h
ifi ti
f C Theendothelialcellsofvenules
Th
d th li l ll f
l
areswollen,havevacuolatedandreticulatedcytoplasm,andlargereactivenucleiconsistentwithresponses
toinjurycausedbyinfectionofthesecellsbyAfricanhorsesicknessvirus,butisnotpathognomonic.Note
y p
(
) ( courtesyDr.D.Gregg,PlumIslandAnimalDisease
y
gg,
thebronchioleassociatedlymphoidtissue(BALT).(A
CenterandNoahsArkive,CollegeofVeterinaryMedicine,TheUniversityofGeorgia.B courtesyDr.R.Breeze,
PlumIslandAnimalDiseaseCenterandNoahsArkive,CollegeofVeterinaryMedicine,TheUniversityof
55
Georgia.C andD courtesyDr.J.F.Zachary,CollegeofVeterinaryMedicine,UniversityofIllinois.

Fig.444C
Fi
4 44C Africanhorsesickness.A,
Af i
h
i k
A Pulmonaryedema.Theinterlobularseptaarewidelyseparatedand
P l
d
Th i
l b l
id l
d d
distendedwithedemafluid.Edemafluidisalsopresentinalveoliandalveolarsepta.Alsonotethesuffusive
hemorrhageofthevisceralpleura.Theselesionsarecausedbyinfectionofendothelialcellsofthecapillaries
of the interlobular and alveolar septa by African horse sickness virus resulting in endothelial cell barrier
oftheinterlobularandalveolarseptabyAfricanhorsesicknessvirusresultinginendothelialcellbarrier
malfunctionanddeathofendothelialcells.B, Colonicserosa,petechialandecchymotic hemorrhages.These
lesionsarealsocausedbyinfectionofanddamagetoendothelialcells.C, Lung,interlobularedema.The
interlobularseptumandalveolicontainedemafluid.Capillariesandvenules aresurroundedbybronchiole
associatedlymphoidtissue(BALT).H&Estain.D,
i t dl
h id ti
(BALT) H&E t i D HighermagnificationofC.
Hi h
ifi ti
f C Theendothelialcellsofvenules
Th
d th li l ll f
l
areswollen,havevacuolatedandreticulatedcytoplasm,andlargereactivenucleiconsistentwithresponses
toinjurycausedbyinfectionofthesecellsbyAfricanhorsesicknessvirus,butisnotpathognomonic.Note
y p
(
) ( courtesyDr.D.Gregg,PlumIslandAnimalDisease
y
gg,
thebronchioleassociatedlymphoidtissue(BALT).(A
CenterandNoahsArkive,CollegeofVeterinaryMedicine,TheUniversityofGeorgia.B courtesyDr.R.Breeze,
PlumIslandAnimalDiseaseCenterandNoahsArkive,CollegeofVeterinaryMedicine,TheUniversityof
56
Georgia.C andD courtesyDr.J.F.Zachary,CollegeofVeterinaryMedicine,UniversityofIllinois.)

Fig.444D Africanhorsesickness.A, Pulmonaryedema.Theinterlobularseptaarewidelyseparatedand

distendedwithedemafluid.Edemafluidisalsopresentinalveoliandalveolarsepta.Alsonotethesuffusive
hemorrhageofthevisceralpleura.Theselesionsarecausedbyinfectionofendothelialcellsofthecapillaries
of the interlobular and alveolar septa by African horse sickness virus resulting in endothelial cell barrier
oftheinterlobularandalveolarseptabyAfricanhorsesicknessvirusresultinginendothelialcellbarrier
malfunctionanddeathofendothelialcells.B, Colonicserosa,petechialandecchymotic hemorrhages.These
lesionsarealsocausedbyinfectionofanddamagetoendothelialcells.C, Lung,interlobularedema.The
interlobularseptumandalveolicontainedemafluid.Capillariesandvenules aresurroundedbybronchiole
associatedlymphoidtissue(BALT).H&Estain.D,
i dl
h id i
(
) &
i
HighermagnificationofC.
i h
ifi i
f Theendothelialcellsofvenules
h
d h li l ll f
l
areswollen,havevacuolatedandreticulatedcytoplasm,andlargereactivenucleiconsistentwithresponses
toinjurycausedbyinfectionofthesecellsbyAfricanhorsesicknessvirus,butisnotpathognomonic.Note
the bronchioleassociated
thebronchiole
associatedlymphoidtissue(BALT).(A
lymphoid tissue (BALT). (A courtesyDr.D.Gregg,PlumIslandAnimalDisease
courtesy Dr. D. Gregg, Plum Island Animal Disease
CenterandNoahsArkive,CollegeofVeterinaryMedicine,TheUniversityofGeorgia.B courtesyDr.R.Breeze,
PlumIslandAnimalDiseaseCenterandNoahsArkive,CollegeofVeterinaryMedicine,TheUniversityof
57
Georgia.C andD courtesyDr.J.F.Zachary,CollegeofVeterinaryMedicine,UniversityofIllinois.)

EquinePolioencephalitisPolioencephalomyelitis
(Alphavirus,EnvelopedRNAvirus)

Themechanismsofinjury,disruptionanddeathofneuronintheCNS.
The
mechanisms of injury disruption and death of neuron in the CNS
Lesions:activehyperemia,vasculitis,hemorrhage,andyellowwhitegray
areaofnecrosisingraymatterofthenervoussystem,especiallyinspinal
cord.
cord
Agroupofthreedisease(arbovirus ),
Easternequineencephalomyelitis,
Westernequineencephalomyelitis,and
Western equine encephalomyelitis and
Venezuelanequineencephalomyelitis.
St.Louisencephalomyelitisisthehumancountedpartdisease.
Viralentry,mosquitoesbites
i l
i
bi
Freevirusandcellassociatedvirus(macrophageordendriticcell
engulfed),regionalandsystemicspread
Causenecrosisinthemyeloidcellsinbonemarrowandlymphocytes
C
i i h
l id ll i b
dl
h
inlymphnodesandspleen.
MechanismofCNSinjuryisundetermined
58

EquinePolioencephalitisPolioencephalomyelitis
(Alphavirus,EnvelopedRNAvirus)
Vi
Viralenvelopecontainstwomembraneanchored
l
l
t i t
b
h d
glycoprotein,E1andE2
AttachmentproteinE2
p
FusionproteinE1isusedtoentercellthroughendocytosis
Proinflammatorycytokine,suchasIFNrandanti
inflammatory cytokine such as IL 10 produced by infected
inflammatorycytokine,suchasIL10producedbyinfected
lymphocytes,makingitmoresusceptibletoinfection
Osteoblast providesviralreplicationinEasternequine
encephalomyelitis.
The
ThepathogenesisandmechanismofinjuryinWestNile
pathogenesis and mechanism of injury in West Nile
PolioencephalitisPolioencephalomyelitis (Flavirus,enveloped
virus)aresimilartopreviousone.
59

Fig.445 Mechanismof
arbovirus andWestNilevirus
infections. M/O, Macrophage;
NK, naturalkillercell.(From
GoeringR,Dockrell H,Roitt I,et
al:Mimsmedicalmicrobiology,
ed 4,St.Louis,2008,Mosby.)

60

Fig 1479A Neuronalnecrosisandvasculitis,easternequinepolioencephalomyelitis,brainstemand

Fig.1479A
Neuronal necrosis and vasculitis eastern equine polioencephalomyelitis brainstem and
spinalcord,horse.A, Brain,transversesectionatthelevelofthehippocampus,horse.Thegraymatter
ofthebrainstemhasdarkredtoblackdiscolorationasaresultofcongestionandhemorrhage.The
lesionistheresultofviralinfection,whichhasanaffinityforneurons;thisvirusalsocausesvascular
necrosisfollowedbythrombosis,butthisisnotcommon.B, Spinalcord,horse.Notetheredtobrown
di l ti
discolorationofthegraymatterinthedorsalandventralhorns(causedbycongestionandhemorrhage).
f th
tt i th d
l d
t lh
(
db
ti
dh
h )
Thelesionistheresultofviralinfectionthathasanaffinityforneurons;however,thisviruscanalso
causevascularnecrosisfollowedbythrombosis.(CourtesyCollegeofVeterinaryMedicine,Universityof
61
Florida;andNoahsArkive,CollegeofVeterinaryMedicine,TheUniversityofGeorgia.)

POX
((cowpox[Orthopoxvirus],sheeppox
[O th
i ] h
andgoatpox
d
t
[C i ]
[Capripox],
Swinepox[Suipox],EnvelopedDNAvirus)

Poxisusedasagroupofdisease.
i
d
f di
Themechanismsofinjury,dysfunctionanddeath
ofdendriticandepithelialcellsofskin,
Sheeppox
pp andgoatpox
g p aremorevirulentand
causesystemicdisease,whereascowpoxand
swinepoxdonotcausesystemicdisease.
Transmission:
animalanimal
animal animalcontactormechanicalorpenetrating
contact or mechanical or penetrating
bywoundorinsectbitesincowppox andswinepox.
Inhalationoringestioninsheeppox
g
andgoatpox
g
62

POX
((cowpox[Orthopoxvirus],sheeppox
[O th
i ] h
andgoatpox
d
t
[C i ]
[Capripox],
Swinepox[Suipox],EnvelopedDNAvirus)

Local,regional,andsystemicspreadingusingmonocyteandmacrophagesystemor
l
i
l d
i
di
i
d
h
cellfreevirusinsheepandgoatpox
Inskin,virusspreadsfrommigratingmacrophagesandlymphocytesandinfects
andreplicatesinendothelialcells,resultingtodirectinjuryandacute
inflammatoryresponse.
Endothelialinjuryaccompaniedbyvasculardilation,activehyperemiaandacute
inflammation==macules andpapules
Langerhans cellsareclosecontactwithendothelialcellsinMalpighian layer
(epidermal)oftheskin,
thevirusmaycomefromendothelialcellsortraffickingleukocytesandinfect
Langerhans cells,
thenspreadvirustocontiguousskinepithelialcellsofstratumbasale
then spread virus to contiguous skin epithelial cells of stratum basale and
and
spinosum.
Epidermalcellsdeath,formingvesiclewithedemaandcelldebris,
pustular stageoccursafterformingacuteinflammation,
stage occurs after forming acute inflammation
scarformationafterimmuneresponsewhichresolvetheviralinfection
63

POX
((cowpox[Orthopoxvirus],sheeppox
[O th
i ] h
andgoatpox
d
t
[C i ]
[Capripox],
Swinepox[Suipox],EnvelopedDNAvirus)

Pneumonia(systemicinfection),
lesionsarevariablesizedandrandomlydistributes
y
pocklesionsintheformoflargeirregularlyshaped
lobularareaofconsolidation.
hematogenous spreadvialeukocytestraffickingin
virusinfected
virus
infectedmacrophagestopulmonary
macrophages to pulmonary
endothelialcellsandthentobronchiolarand
alveolar epithelial cells
alveolarepithelialcells
causecelldeathandacuteinflammation
64

Fig.1731 Schematicdiagramofthedevelopmentofapoxviruslesionovertime.A, Ballooningdegeneration.B,

Reticular degeneration with cytoplasmic inclusion bodies of keratinocytes Both A andB
Reticulardegenerationwithcytoplasmicinclusionbodiesofkeratinocytes.BothA
and B aresubclinicalstages.C,
are subclinical stages C
Congestion,edema,margination,andmigrationofleukocytes(blackdots) formthemaculestage.D, Continued
epidermalreticulardegeneration,epidermalhyperplasia(acanthosis),dermaledema,andperivascularinflammation
formthepapulestage.E, Thevesiclestagedevelopsbycoalescingofareasofreticulardegeneration(disruptionof
swollenkeratinocytes).F, Inflammatorycellsmigratefromthedermalvesselsintothevesicleandaccumulateinthe
vesicletoformthepustulestage.G,
p
g
, Theepidermisbeginstoproliferateandbecomesmoreacanthotic,andtheold
p
g
p
,
pustuleismovedtowardtheepidermalsurface.H, Epidermalhyperplasiaprogresseswiththeformationofelongated
epidermaldermalinterdigitations,andtheoldpustulerupturestoformacrust.Largerpustulescanbeumbilicated,
involvethedermis,andresultinscarring.(RedrawnfromDr.AnnM.Hargis,DermatoDiagnostics;andDr.PamelaE.
65
Ginn,CollegeofVeterinaryMedicine,UniversityofFlorida.)

Fig.1742A Capripoxvirus,skin,lamb.A, Theclinicallesionsaremultifocalcoalescing

maculesandplaquesthatareindurated,hemorrhagic,andnecroticlikelyaresultof
l
l
h
h
h
lk l
l f
vasculitis.B, Notenecrosisofvesselwallwithfibrindeposition,redbloodcells,and
neutrophilsandlymphocytesintheborderingdermis(vasculitis)(arrow). H&Estain.
(A courtesyofForeignanimaldiseases, ed 7,2008,UnitedStatesAnimalHealth
Association.B courtesyDr.A.M.Hargis,DermatoDiagnostics.Photographedfrom
slidesprovidedbyDivisionofAnimalMedicine,AnimalTechnologyInstituteTaiwan.
66
FromAFIPWSCOctober8,2008,Conference5,CaseIII.)

Fig.1744A Swinepox,skin,piglet.A, Notethefour

umbilicated pustulesintheabdominalskin.B, Note
keratinocytes with ballooning degeneration and eosinophilic
keratinocyteswithballooningdegenerationandeosinophilic
cytoplasmicinclusionbodies(arrowheads). Ballooning
degenerationdevelopsbeforevesicleformation.H&Estain.(A
courtesyDr.M.D.McGavin,CollegeofVeterinaryMedicine,
U i
UniversityofTennessee.B
it f T
B courtesyDr.A.M.Hargis,
t
D AM H i
DermatoDiagnostics.Photographedfromslidesprovidedby
DepartmentofVeterinaryPathology,WesternCollegeof
y
,
y
VeterinaryMedicine,UniversityofSaskatchewan.FromAFIP
WSCJanuary21,1998,Conference15,CaseIV.)
67

Fig.446A Sheeppox andgoatpox.A, Skin,teats,inguinalarea.Macules,papules,vesicles,crusts(scabs),

andpapillomas (epidermalhyperplasia)arepresentontheskinoftheinguinalareaandteats.Additional
information about the development and progression of pox virusinduced lesions is schematically illustrated
informationaboutthedevelopmentandprogressionofpoxvirusinducedlesionsisschematicallyillustrated
inFig.1731andmacroscopicallyandmicroscopicallyinFigs.1742(sheeppox)and1744(swinepox).B,
Lung,poxlesions.Thesecircumferentiallyexpandingdarkredtoplumcoloredlesionsofvariedsizesare
areasofproliferatingbronchialandbronchiolarmucosalepithelialcells,necroticepithelialcells,celldebris,
andinflammationdemonstratedinC.C, Lung,bronchiole.Thereisproliferationofmucosalepithelialcellsof
thelungsconductivesystemthatareinfectedwithpoxvirus.Notethemononuclearinflammatorylikely
bronchioleassociatedlymphoidtissue(BALT)inadjacentsupportingstroma.Inset, HighermagnificationofC.
H&E stain (A courtesyDr.D.Gregg,PlumIslandAnimalDiseaseCenterandNoah
H&Estain.(A
courtesy Dr D Gregg Plum Island Animal Disease Center and NoahssArkive,Collegeof
Arkive College of
VeterinaryMedicine,TheUniversityofGeorgia.B courtesyDr.R.Breeze,PlumIslandAnimalDiseaseCenter
andNoahsArkive,CollegeofVeterinaryMedicine,TheUniversityofGeorgia.C courtesyDr.J.F.Zachary,
68
CollegeofVeterinaryMedicine,UniversityofIllinois.)

Fig.446B Sheeppox andgoatpox.A, Skin,teats,inguinalarea.Macules,papules,vesicles,crusts(scabs),

andpapillomas (epidermalhyperplasia)arepresentontheskinoftheinguinalareaandteats.Additional
information about the development and progression of pox virusinduced
informationaboutthedevelopmentandprogressionofpoxvirus
inducedlesionsisschematicallyillustrated
lesions is schematically illustrated
inFig.1731andmacroscopicallyandmicroscopicallyinFigs.1742(sheeppox)and1744(swinepox).B,
Lung,poxlesions.Thesecircumferentiallyexpandingdarkredtoplumcoloredlesionsofvariedsizesare
areasofproliferatingbronchialandbronchiolarmucosalepithelialcells,necroticepithelialcells,celldebris,
andinflammationdemonstratedinC.C,
d i fl
i d
d i C C Lung,bronchiole.Thereisproliferationofmucosalepithelialcellsof
L
b
hi l Th
i
lif
i
f
l i h li l ll f
thelungsconductivesystemthatareinfectedwithpoxvirus.Notethemononuclearinflammatorylikely
bronchioleassociatedlymphoidtissue(BALT)inadjacentsupportingstroma.Inset, HighermagnificationofC.
( courtesyDr.D.Gregg,PlumIslandAnimalDiseaseCenterandNoahsArkive,Collegeof
y
gg,
,
g
H&Estain.(A
VeterinaryMedicine,TheUniversityofGeorgia.B courtesyDr.R.Breeze,PlumIslandAnimalDiseaseCenter
andNoahsArkive,CollegeofVeterinaryMedicine,TheUniversityofGeorgia.C courtesyDr.J.F.Zachary,
69
CollegeofVeterinaryMedicine,UniversityofIllinois.)

Fig.446C Sheeppox andgoatpox.A, Skin,teats,inguinalarea.Macules,papules,vesicles,crusts(scabs),

andpapillomas (epidermalhyperplasia)arepresentontheskinoftheinguinalareaandteats.Additional
informationaboutthedevelopmentandprogressionofpoxvirusinducedlesionsisschematicallyillustrated
inFig.1731andmacroscopicallyandmicroscopicallyinFigs.1742(sheeppox)and1744(swinepox).B,
Lung,poxlesions.Thesecircumferentiallyexpandingdarkredtoplumcoloredlesionsofvariedsizesare
areasofproliferatingbronchialandbronchiolarmucosalepithelialcells,necroticepithelialcells,celldebris,
and inflammation demonstrated in C C Lung,bronchiole.Thereisproliferationofmucosalepithelialcellsof
andinflammationdemonstratedinC.C,
Lung bronchiole There is proliferation of mucosal epithelial cells of
thelungsconductivesystemthatareinfectedwithpoxvirus.Notethemononuclearinflammatorylikely
bronchioleassociatedlymphoidtissue(BALT)inadjacentsupportingstroma.Inset, HighermagnificationofC.
H&Estain.(A courtesyDr.D.Gregg,PlumIslandAnimalDiseaseCenterandNoahsArkive,Collegeof
VeterinaryMedicine,TheUniversityofGeorgia.B courtesyDr.R.Breeze,PlumIslandAnimalDiseaseCenter
andNoahsArkive,CollegeofVeterinaryMedicine,TheUniversityofGeorgia.C courtesyDr.J.F.Zachary,
70
CollegeofVeterinaryMedicine,UniversityofIllinois.)

POX
((cowpox[Orthopoxvirus],sheeppox
[O th
i ] h
andgoatpox
d
t
[C i ]
[Capripox],
Swinepox[Suipox],EnvelopedDNAvirus)

Reservoir
i
Wildrodents
Cats
Indirectmechanism,huntingrodentsandinfect
throughskin
Directmechanism,inhalationandsystemicspread
through monocytes and macrophages
throughmonocytesandmacrophages

Attachmentproteintoglycoaminoglycan
receptorproteinonthetarget(abundant
t
t i
th t
t( b d t
publishedpaper).
71

Cryptosporidiosis
yp p
(Cryptosporidia parvum)
Mechanismofinjuries:dysfunctionofmicrovillusofthebrush
border,cytolysisafterbeingreleasedfrominfectedcells,
degenerative effect of digestive enzyme in inflammation
degenerativeeffectofdigestiveenzymeininflammation.
Lesion:nolesionsgrossly;microscopically,necrosisof
epithelial cells atrophy of villi andmucosalinflammation.
epithelialcells,atrophyofvilli
and mucosal inflammation
Viralentry
Contactwithfecesofinfectedanimals
Contact with feces of infected animals
Ingestion,contaminatedwaterandfood
Ingestionintoalimentarytractthroughperistalticactivity
Ingestion into alimentary tract through peristaltic activity
Oocysts interactwithgastricacids,pancreaticenzyme,bile
salts and undergo a process called excystation
saltsandundergoaprocesscalledexcystation
72

Cryptosporidiosis
yp p
(Cryptosporidia parvum)

Oocysts==sporozoites infectedepithelialbrushborder(microvlli
f
d
h l lb hb d (
ll with
h
glycocalyx)coveringtipsandsidesofmicrovilli.
Sporozoites
p
bindingenterocytesthroughCSL,(cryptosporidia
g
y
g
, ( yp p
parvum
p
sporozoites ligand)likesporozoitespecificlectin adherencefactor,
GP9000,adheretobrushborderofmicrovilli
Sustaininthemicrovilluslayeranddonotenterwithcytoplasmbut
Sustain in the microvillus layer and do not enter with cytoplasm but
communicatewithfeedingorganells
Differentiateintotrophozoites==
asexualmultiplication=schizont
Sexualmultiplication==gamatozon,Micogamont ormacrogamont
microgamontsmicrogamates
i
i
enterintomacrogamonts.Fertilize
i
F ili
macrogamates insidemacrogamont,formationofoocysts,
reinfection
orpassthroughfeces
73

Cryptosporidiosis
yp p
(Cryptosporidia parvum)

Additionalcelldeath,villousatrophy,amplifyseverityoftheinjury
dd
l ll d h ll
h
lf
f h
Parasiteinvasion,multiplicationandextrusion
Celldysfunctionanddamagefromcytokinesandinflammatory
Cell dysfunction and damage from cytokines and inflammatory
moleculesfromTlymphocytesandmacrophagesmediated
inflammation.
Increaseintercellularpermeability,altersecretory
i
ll l
bili
l
f
function,impair
i
i
i
absorptionofvillousenterocytes
Diarrhea
Osmoticdiarrhea(malabsorption),dysfunctionofdigestiveenzyme
functioninbrushborder
Failuretodigestcarbohydrates,impairhydrolysis,bacterial
F il
di
b h d
i
i h d l i b
i l
fermentation,osmoticdiarrhea
Secretarydiarrhea,Increaseintercellularpermeabilityfrom
y
,
p
y
inflammation
Enterotoxin?

74

Cryptosporidiosis
yp p
(Cryptosporidia parvum)
Flattenedsquamous likecells
Functionimmature,nomicrovilli
Function immature, no microvilli
Stretchedoverthebasemembrane
Earlyinthereparativeprocess
Regenerativecellsmigratefromcrypts
Regenerative cells migrate from crypts

75

76

77

78

EMexaminationof
cryptosporidiosis

79

80

Fungal Disease (Mycoses)

FungalDisease(Mycoses)
Bothformsintheirlifecycle
B th f
i th i lif
l
Branchedfilamentous
Yeast

Superficialmycoses
Candidiasis
Aspergillosis
A
ill i

Systemicordeepmycoses

Histoplasmosis
Coccidioidomycosis
Blastomycosis
Angioinvasive fungi
f
Cryptococcosis

81

Fig.447 LifecycleofCoccidioides immitis andotherdimorphicfungi.

82

Candidiasis
(Candidaalbicans)

Themechanismsofinjury:disruptionanddeathofcellsinmucosacausedby
h
h i
fi j
di
i
d d h f ll i
db
inflammationandtheconcurrentproliferationandinvasionoffilamentous
pseudohyphae andhyphae.
Havetwoforms:
yeast(commensal)
filamentouspseudohyphae
p
yp
andhyphae
yp
(pathogenic)
(p
g
)
Lesions:acutepseudomembranous glossitis withextensivewhitetoyellow
pseudomembrane consistingofdesquamatedepithelialcells,fibrin,andfungal
hyphae
yp
overthedorsalsurfaceofthetongue.
g
Viralentry:ingestion
Yeastformascommensal
Ligands:componentofyeastincludesmannose,C3dreceptor,manoproteins.
Li d
t f
ti l d
C3d
t
t i
Mucosareceptors:fibrinogen,fibronectin,thrombin,collagen,laminin,and
vitronectinbindingprotein
Balancebetweencommensalismanddisease
83

Candidiasis
(Candidaalbicans)

Morphologic(phenotypic)switches:yeasttopathogenicfilamentous
h l
( h
)
h
h
fl
hyphae orpseudohyphae.
Induciblechromosomalrearrangementsinthegenomeofyeastin
g
g
y
responsetochangeinmucosalenvironment.Switchingisirreversible.
25oCVs.37oC
Mucosalinjury,breakdown
li j
b kd
Excessiveuseofbroadspectrumantibioticsandcorticosteroids,
hyperglycemia,
yp g y
,
tissuedamagesecondarytochemotherapyorradiation,or
immunosuppression
Sustainofinnateandadaptiveimmunity
S
i fi
d d i i
i
Pseudohyphae andhyphae ofthefilamentousphaseexpressnew
adhesionligands,secrethydrolyticaspartyl
g
,
y
y
p y p
proteinase thatinjurythe
j y
mucosaandinvadethemucosaandsubmucosa(newadhesionmolecules)
84
Groupsofvirulentdeterminatesinvolvedintheprocess.

Fig.729 Thrush,tongue,foal. Apseudomembrane of

hyphaeofcandidaispresentonthedorsalsurface.Ithasbeen
yp
p
scrapedofftherostralendofthetongue(top) toreveal
normalmucosabeneaththefungalmat.(CourtesyDr.H.
Gelberg, College of Veterinary Medicine, Oregon State
Gelberg,CollegeofVeterinaryMedicine,OregonState
University.)
85

Fig.728 Thrush(oralcandidiasis),tongue,foal.A, Hyphae

ofCandidaalbicans aregrowinginthesuperficialkeratinof
g
g
p
thetongue.H&Estain.B, SamespecimenasA. Gomoris
methenamine silverstain.(CourtesyDr.J.F.Zachary,Collegeof
Veterinary Medicine, University of Illinois.)
VeterinaryMedicine,UniversityofIllinois.)
86

Cryptococcosis
yp
(Cryptococcusneoformans)

Mechanismofinjury
h
f
Celldeathlikelycausedbyatrophysecondarytotissuedistortionandcompressionfrom
expandingcryptococcal cystsinbrainparenchyma.Thereislittleornoinflammationin
thi di
thisdisease.

Lifecycleofthedimorphicfungus
Mycelial (basidiospores)phaseoccursinextracellularenvironment(25oC)
Yeastphase,intracellularly withincellofmonocytemacrophagesystem(37oC)

Lesions:formationofexpansile cysticspacefilledwithagelatinousmatrix
(capsu e) t
(capsule)withinthebrainandspinalcordleadingtocompressionand
t e b a a d sp a co d ead g to co p ess o a d
distortionofthetissue.
Viralentry
IInhalation,filamentousoryeastform(1.83um)canreachtolowerrespiratorytractand
h l ti
fil
t
tf
(1 8 3
)
ht l
i t
t t d
alveoli.
Basidiospores depositonthemucosa,readilybephagocytosed andkilledbyneutrophils
and alveolar macrophages
andalveolarmacrophages.
87

Cryptococcosis
yp
(Cryptococcusneoformans)

Forsurvivall
Basidiospores quicklygerminateinmucosaorinphagosome toyeasts
Yeastderivedglycosylceramide synthase isessentialforsurvivalinmucosabutnotin
phagocytes(?)
Phospholipase.Injurealveolarmacrophage,hindertheproductionandfunctionof
surfatant,enhancingadhesiontopneumocyte andreducedbeingphagocytosed.
Ligandreceptorspecificshouldpresentbutmoleculesnotbeingidentified.
Li d
ifi h ld
b
l l
b i id ifi d
Polysaccharidecapsuleofyeastpresentantiphagocytic andimmunosuppressive
capability.
Thedegreeofencapsulationprovidetheresistancetobephagocytosed
Th d
f
l ti
id th
it
t b h
t d andkilled
d kill d

Negativechargesofcapsules

Inhibitphagocytosis andkilling
Causecomplementdepletion
Antibodyunresponsive
Dysregulationofcytokinesecretion
Inhibitrecognitionofyeastbychemotaxis ofleukocytesfromthebloodstream,results
inthelacingofinflammationincyst.

88

Cryptococcosis
yp
(Cryptococcusneoformans)

Afterphagocytosisandphagosomelysosomefusion
f
h
i
d h
l
f i
Yeastsynthesizesadditionalpolysaccharidecapsulewithinthephagolysosome
ofthemacrophage
Dilutelysosomehydrolase andothertoxiccontent
Physicalbarrier
Macrophagescanbegreatlyenlarged>30um(underlyingmechanismofgross
Macrophages can be greatly enlarged >30 um (underlying mechanism of gross
lesions)
Componentsofcapsulealsosuppresstheimmunesystem
Twopolysaccharides,glucuronoxylomannan
Two polysaccharides glucuronoxylomannan andgalactoxylomannan
and galactoxylomannan ,and
and
smallquanity ofmannoprotein.
Brainlesions
Directexpansionintomeninges andneuropile fromnasalroute
Leukocytetrafflicking
Endothelialinfectioninbrain
Releaseofdeathfungusfromdeadmacrophage
89
Deadmacrophageassociateimmunemediation

Cryptococcosis
yp
(Cryptococcusneoformans)
Melanin
Facilitatesyeastsurvival
Facilitates yeast survival
Antioxidantandeliminatesreactiveoxygen
species
i
Usedopamine,norepinephrine,
p
,
p p
,
epinephrineassubstrateformelanin
production

90

Fig.1449 Cryptococcosis,thalamus,cerebellum,andmesencephalon,transverse
sections cat Notethe
sections,cat.
Note the cavitational
cavitational lesionscausedbyCryptococcusneoformans
lesions caused by Cryptococcus neoformans
(arrows). Althoughthelesionslooklikecavities,theyarefilledwithorganisms,andthe
faintgrayappearanceiscausedbythemucinouscapsulesofnumerouscryptococci.
Cryptococcusneoformans usuallyinducesagranulomatousinflammationinmost
domestic animals but in some animals especially the cat inflammation is minimal or
domesticanimals,butinsomeanimals,especiallythecat,inflammationisminimalor
absent.(CourtesyDr.M.D.McGavin,CollegeofVeterinaryMedicine,Universityof
Tennessee.)
91

Fig.14
Fig.
1450A
50A Leptomeningeal cryptococcosis.A,
cryptococcosis. A, Thethickunstainedmucinouscapsule
The thick unstained mucinous capsule
surroundingtheorganismresultsintheformationofaclearspace(halo)inH&E
stainedsections(arrow). Thisfeatureisusefulinidentifyingtheorganismincytologic
preparationsandtissuesections.AlsoseeFig.1448,B.H&Estain.B, Themucinous
capsule surrounding the organism also stains with mucicarmine providing a simple
capsulesurroundingtheorganismalsostainswithmucicarmine,providingasimple
methodtoidentifytheorganism(arrow). Mayersmucicarmine stain.(CourtesyDr.J.F.
Zachary,CollegeofVeterinaryMedicine,UniversityofIllinois.)

92

PrionDiseases
(Transmissiblespongiformencephalopathies)
Th
Themechanismsofinjury:metabolicdysfunctionofneuronsand
h i
fi j
t b li d f ti
f
d
neuralcellscausedbytheconversionofnormalcellularprion
protein(Prpc)toanabnormalform(Prpsc)andtheaccumulationof
Prpsc inneuronsandneuralcells.
in neurons and neural cells
Lesions:brainatrophymayoccurinthechroniccasesgrossly.
Microscopically,vacuolation inneurons(spongiformchange),
neuronal loss gliosis and an absence of leukocytes inflammation
neuronalloss,gliosis,andanabsenceofleukocytesinflammation.
Disease:scrapie (sheep),BSE,chronicwastingdisease(CWD)in
deerandelk,transmissibleminkencephalopathy,felinespongiform
encephalopathy and ungulate spongiform encephalopathy
encephalopathy,andungulatespongiformencephalopathy.
Sourceandoriginofprion proteinisundetermined.
Transmission:
Ingestion
Offal(wasteorcarcassfrominfectedanimal

Inhalationordirectcontact
93

PrionDiseases
(Transmissiblespongiformencephalopathies)

Initialencounter:mucosaoforalpharynx,tonsil,payerpatch
Initial
encounter mucosa of oral pharynx tonsil payer patch
Prioncanattachtoapicalsurfaceofmucosalepithelialcells,Mcellsand
dendriticcells,intonsillar,alimentary,andrespiratorymucosa,
respectively.
respectively
Transcytosis,ordendriticcellmigration,(ormacrophagemigration)may
provideprion topasstheepithelialcellsorMcells,totheirbasolaterial
g
,
p g
surfaceandtogainaccesstoinfectBandTcells,macrophageand
dendriticcellsintheGALTorBALT
FolliculardendriticcellsandBcellsaretheprimarysiteofreplication,then
spreadsystemicthroughleukocytetrafficking
Prionareabletoinfectnerveendingofvagus nerve,sympathethic nerve
andsensorynerve;anduseretrogradeaxonaltransporttogainaccessto
CNSandspreadinnervoussystemviasynapticallylinkedneuron
I
Inmacrophageanddendriticcells,prion
h
dd d i i
ll
i arelocatedinmultivesicular
l
di
li i l
endosomes andmaybetransferredbetweencellsinexosomes.Itmaybe
thewayintheinternuronal spreadwithinthenervoussystem.
94

PrionDiseases
(Transmissiblespongiformencephalopathies)
Cellreceptororligand:undetermined
MostcellshavePrpc .Thehighestconcentrationarepresentin
th
thenervoussystem,especiallyinsynapticmembraneasa
t
i ll i
ti
b
neuronalmembraneglycoprotein.Prpc isalsoexpressedin
the cells of immune system
thecellsofimmunesystem.
FunctionofPrpc isunknownbutitsphysiologicfunctionmay
includeimmunoregulation,signaltransduction,copper
g
, g
, pp
binding,synaptictransmission,inductionofapoptosis,or
protectionagainstapoptosis.
Inneuron,Prpsc servesastranslationtemplatethatconverts
(conformationalchange)normalPrpc to Prpsc ,Prpsc a
misfolded
i f ld d aaggregatedbsheetrichisoform
t db h t i hi f
ofPrp
fP c
95

PrionDiseases
(Transmissiblespongiformencephalopathies)
ThisfoldingpatternmakesPrpsc resistanttotheactionof
proteaseandcauseittoaggregateandaccumulateasan
insouluble amyloid intheneuronintheformoflargeamyloid
in the neuron in the form of large amyloid
andfibrousplaque.
ItisnotknownthatPrp
It is not known that Prpsc causesneuronaldegeneration;
causes neuronal degeneration;
however,
reducedantioxidantprotection,
p
,
increasedoxidativestress,
lostnormalPrp
lost normal Prpc function,
function,
ortoxicitycausedbyPrpsc
all related to the amyloid plaquehavebeenproposed
allrelatedtotheamyloid
plaque have been proposed
96

97

98

Fig.448 Howprionsinjurecells. 1,
Normalcellsexpresscellularprion
protein(PrPc)atthecellmembraneas
linearproteins.2, Abnormalform
(PrPSc)existsasafreeglobular
glycoprotein,whichcaninteractwith
PrPc.3, PrPc isreleasedfromthecell
S .
Sc
membraneandisconvertedintoPrP
b
d
d
4, CellsproducemorePrPc andthe
cycleisrepeated.5, PrPSc
accumulatesasplaquesandis
l t
l
di
internalizedbycells.(FromGoeringR,
Dockrell H,Roitt I,etal:Mims
medical microbiology ed 4,St.Louis,
medicalmicrobiology,
4 St Louis
2008,Mosby.)
99

100

Fig.449 Pathogenesisoftransmissiblespongiformencephalopathies. PrionsappeartouseMcells

(alsomacrophages)toenterPeyers patchesandinfectdendriticcellsaswellasmacrophagesand
lymphocytes.Dendriticcells(andlikelymacrophages)thenspreadprionsthroughleukocytetraffickingin
lymphaticvesselstolocal,regional,andsystemiclymphoidnodules,lymphnodes,and/orspleenwhere
infectionissustainedandamplified,especiallyinfolliculardendriticcells(FDC)ofthespleenandB
lymphocytes Prions released from dendritic cells are able to enter nerve endings in lymphoid tissues
lymphocytes.Prionsreleasedfromdendriticcellsareabletoenternerveendingsinlymphoidtissues,
andbyretrogradeandanterogradenervetransporttheyspreadthroughouttheCNS.Ithasbeen
hypothesizedthatprionsmayalsospreadtotheCNShematogenously,buttheexistenceofthisrouteis
101
uncertain.

HistologicalfeaturesofTSE

kuru

Scrapie

vCJD
C

CJD

BSE
102

HistopathologyofBSE

103

Lightandelectronmicroscopic
g
p
findingsofBSEandCJD

104

 Pathogenesisstudy
CSFVviroporin,2012JV
p
,
InteractionofPCV2andPRRSV

105