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Award Title: BiologyBSc (Hons)
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Module Code & Title:HUMAN BIOCHEMISTRY AND PHYSIOLOGY: BIOL50435
AssignmentDescription:Disease State Report
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Leader: Dr. David Skinglsey
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Date: 23/01/2015
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3. Viral Haemorrhagic Fever.
An insight into the biochemical and physiological
dysfunctions which are commonly associated.

4. Viral Haemorrhagicfever(VHFs) isaname givenreferringtoa groupof illnessesthatare causedby
several familiesof viruses,thistermisusedtodescribe asevere multisystemsyndromeinwhich
manyorgans withinthe bodyare effected.There are four maintaxonomicfamilies of viruseswhich
may cause a viral haemorrhagicfever,these are representedinfigure1.
As youcan see,dependingonthe responsibleVirusthe severity,withregardstofatalityrate,varies
fromup to 90% to lowerthan1%. The reasonfor thisrequiresanunderstandingof the different
challengesthateachvirusintroducestothe humanbodyonce an infectionhasoccurred.Depending
on the causative virus,the symptomsandclinical features thatoccurwithinthe bodyvary.The
severityof the altercationstothe body’snormal biochemistryandphysiology generally correlatesto
the virus’sfatalityrate.Due tothe highfatalityrate Iwill focusonthe Ebola virus;the causative virus
of EbolaHaemorrhagicFever(EHF),andthe challengesthe humanbodyispresentedwithupon and
duringan infection.
It isnecessarytonote that there are 5 speciesof Ebolavirus;Zaire,Bundibugyo,Sudan,Restonand
Taï Forest.Dependingonthe speciesthe symptomsmayvary,soto avoidconfusionthisreportwill
concernthe general biochemical andphysiological dysfunctionsthatmayoccur.EHF maylast forup
to 21 days,afterthe 4-10 dayincubationperiod,amultitude of biochemical andphysiological
altercationscanoccur duringthistime period(see figure2),howeverdetrimental effectspost-
infectionhave been reportedbyFormenty(1999) tolast up to 3 months.
Virus Family;(ViruseswithinFamily) Fatality rate
Filoviridae;(Ebolaand Marburg
viruses)
Ebola:50% to 90%,
Marburg: 23% to 70%
Arenaviridae;(NewWorld
haemorrhagic feverand Lassa fever)
New worldhaemorrhagicfever:15% to 30%,
Lassa fever:>1%
Bunyaviridae;(Rift Valleyfever,
Crimean-Congofever)
RiftValleyfever:14% to 17%
Crimean-Congofever:10% to 40%
Flaviviridae;(yellowfever,Omsk
haemorrhagic fever,Kyasanur Forest
disease)
Yellow fever:>50%
Omskhaemorrhagicfever:0.5% to 3%
KyasanurForestdisease:3% to10%
General Clinical features associated with (EHF).
Clinical Features Laboratory findingsdue toEHF
 vomiting,headache,prostration, fatigue
(< 1 week)
 Chestpain, Diarrhoea, Acute onsetof
fever,cough, pharyngitis
 Maculopapar rash
 Haemorrhagic manifestation
 Pancreatitis,hepatitis,conjunctival
inflammation
 CNS dysfunction
 Shock with DIC and organ failure ( < 7
days after symptoms begin)
 Sequelae:oculardisease,hearingloss,
pericarditis,arthralgia
 Leukopenia
 Leukocytosis
 Thrombocytopenia
 Elevatedliverenzymes
 Elevatedamylase
 Lab featuresof DIC
FIGURE 1. Represents virusesresponsible for causing viralhaemorrhagicfever with corresponding fatality rate. (S.F. Dept Public
health,2008).
FIGURE 2. Table displaying the general Clinical featuresand Laboratory findingsassociatedwith an EBOV infection (S.F. DeptPublic
health,2008)

5. Accordingto Lee & Sapphire (2009), Symptomsof EHF generally begintooccur withina4-10 day
incubationperiod,howeverinfatal cases,deathcanoccur as earlyas 6-9 daysafter onsetasa result
of uncontrolledviral replicationandmultiple organfailure.Tounderstandhow some of the
symptomswithintable 2become apparentwithinthe humanbody,itisnecessarytounderstandthe
initial stagesof EHF.Many studieshave beenconductedtodetermine the initialtargetcell of the
Ebolavirus (EBOV),andaccordingto Ströheret al (2001) morphological studiesonpost-mortem
material suggeststhatthe primarytargetfor viral replicationare;dendriticcellsandmacrophages
viaCD4 and CD8 receptors.These cellsare thenthoughttocirculate viathe lymphaticsystemto
regional lymphnodeswhere viral replicationcancontinue,andthe targetcell-associatedvirionsare
able to spread.HoweverEBOV isable toeffectothercellsindirectly,the virusdoesthisbyusing
infectedcellsalmostlikeabiochemical weapon,tocause dysfunctiontocellswhichdon’tappearto
be adequate hosts.
Lymphocytesare notdirectlyinfected byEBOV however,
studiesindicate thatlymphocyte apoptosisisaprominent
feature of infection(Bradfute etal,2010). It istherefore
hypothesisedthatfactorssecreted orexpressedbytarget
cellsare responsiblefortriggeringthe cell deathwithin
lymphocytes.Evidencesupportingthishypothesiscanbe
derivedfromastudyconductedbyGeisbertetal (2003),
data obtainedfromthisstudysuggestthatdendriticcells
and macrophagesincrease the expressionof tumour
necrosisfactor-α (TNFα) (see figure 3),aswell as
apoptosis-inducingligandandFastranscriptduringanEHF
infection.Thisdataissupportedbyseveral otherreports
statingsimilarresults (Formentyetal,1999), and mayhelp
to explainwhyLeukopeniatypicallyoccursduringthe
earlystagesof EHF. Asa resultof this the innate immune
response maybecome dysfunctional, leavingthe hostwith
little time toadaptivelyrespondtothe infection. Although
damage focuseswithin the lymphaticsysteminitially,itisalsostatedby Geisbertel al (2003a) that
whenEBOV entersthe blood system,the virus exhibitstissuetropismforthe;liver,adrenal gland
and spleen.
The Liverappearsto be an importanttargetof EBOV,data obtainedbyGeisbertetal (2003) suggests
that Kupffercellsare anadequate hostcell thus;viral replicationcontinueswithinthe Liver.Initial
infectionof the liveroccurswithinthe earlystagesof the infectioncausingdamage directlyto
hepatocytesandothercellsfoundwithinthe liver. Reportshave shownthatenzymes; Aspartate
aminotransferase,andAlanine aminotransferaseare bothelevated(see figure 4).Thissupports that
the viruscausesdamage to livertissue eitherdirectlyviareplicationorasa resultof a biochemical
imbalance due tofactorsreleaseduponcell lysis.
As a resultof the damage it maybe difficultforthe livertocontinue itsfunctionbothbiochemically
and physiologically,the liverplaysvitalroleswithinawide range of systemswithinthe body,
therefore progressiveliverdysfunctioncanbe catastrophictothe body’snormal homeostatic
procedures(see figure5).
FIGURE 3. Displaysthe increase ofTumour NecrosisFactor
during an EHF in Cynomolgusmacaques, data obtained by
Geisbert etal, (2003a).

6. POSSIBLE BIOCHEMICAL DYSFUNCTION
ASSOCIATED WITH LIVER DAMAGE; WITH
RELEVANCE TO EHF.
EFFECTS ON BODY DUE TO DYSFUNCTION.
- Inadequate secretionof precursor
molecule angiotensinogen.
- As the precursorto hormone
Angiotensin,inadequate amountsof
angiotensinogenmayinhibitthe
vasoconstrictionprocessthus
preventingvasoconstriction;aprocess
crucial for raisingbloodpressure and
slowingdown haemorrhage/acute
bloodloss.Thismayplaya role inthe
amplificationof the haemorrhagic
feature associatedwiththisinfection.
- Inadequate secretion,viathe liver,of
glycoproteinhormone;
thrombopoietin.
- Responsible forstimulating
Megakaryocytopoiesis,aninadequate
amountof thrombopoietinmayleadto
a reducedplateletproductionthus
directlyeffectingthrombusformation;
causingthrombocytopeniaandmassive
altercationstothe clottingcascade.
- Inabilitytosecrete/synthesizesufficient
quantitiesof glycogen
- Insufficientquantitiesof Glycogenmay
cause the bodyto entera
hypoglycaemicstate.Thisdysfunction
wouldrenderthe liveruselessan
unresponsive withinthe feedback
systemsimplementedforbloodglucose
homeostasis.
- Disruptiontothe livernormal
metabolicpathways
- Inabilityforthe livertocarry outits
normal metabolicfunctionsismassively
detrimental tothe body,asa resultof
such dysfunctionsmanysystemswithin
the bodywouldbe effected.In
particularthe Central NervousSystem
wouldnotreceive sufficient nutrients
to supportfunctionthuscausingCNS
dysfunction.
FIGURE 4. Biochemical valuesduring EHF; noteelevated ASTandALT. ALT-Alanine aminotransferase, AST-Aspartate
aminotransferase in comparisonto referencestandard. Data obtained by Formentyet al,(1999)
FIGURE 5. Showsexamplesof biochemical dysfunctionsthat may be causedby liver damage;an organ thatis largely damaged
during EHF.

7. In relationtothe liver,ithasbeenreportedthatnumerousorgansare manifestedwithEBOV during
EHF, for example Geisbertetal (2003) constructeda graph,showninfigure 6, whichrepresentssuch
activity.
In relationtothe liver,the adrenal glandappearstobe directlyaffectedbyEHF,data obtainedby
Geisbertetal,(2003a) indicatesthaton day 4 of an infectionEBOV wasdetectedinadrenal cortical
cellswithinthe zonafasciculate andzonareticularis. EBOV wasalsodetectedwithinstromacellsin
the adrenal cortex and withinfibrocytesinthe adrenal capsule,thisthenfurtherdevelopedinto
multifocal congestionof the adrenal cortex andmultifocal degradationof the adrenal cortical cells
(Geisbertetal,2003a). It isknowthat the adrenal cortex playsanimportantrole withinthe renin-
angiotensin-aldosterone systemwhichregulatesbloodpressure,figure7representsthisfeedback
system.
FIGURE 6. Showsmean infectivity of6 Cynomolgusmacaques; note themulti-organ involvement. LN-LymphNode. (Geisbertet al,
2003a)
FIGURE 7. A)Shows negativefeedback system involving kidneys and adrenalglands implementedfor controlofBlood pressure
homeostasis and thecontrol ofbloodelectrolytelevels. B)Adrenalcortex biochemicalinvolvement inthesynthesis ofhormones
Aldosteroneand Corticosterone. Image fromRossier (2010).

8. Adrenocortical necrosis,asaresultof EHF, has beenreportedinhumansbyFormentyetal, (1999),
and innon-humanprimatesby Geisbertetal, (2003a),thus renderingthe organunresponsive within
the negative feedbacksystemrepresentedinfigure 7a.Asa result of such dysfunctionthe adrenal
glandis be unable tosynthesizesufficientaldosterone,this preventsthe kidneyfromregulatingNa+
and K+
and, as a resultof this,ultimatelychronicbloodvolume;andthusbloodpressure (Boothetal,
2002). It is reportedbyFeldman(2011) that impairedsecretionof aldosterone leadstohypotension
and Na+
losswithhypovolaemia,therefore impairmentof adrenocortical functioncouldhave an
importantrole inthe shockthat typicallyoccursinlaterstagesof EHF. There are manyother
dysfunctionsthatoccurwithinthe body,the coagulationcascade alsoseemstobe largelyeffected
duringEHF.
A prominentmanifestationof EHFis disseminatedintravascularcoagulation(DIC),thisisthe
formationof microthrombi via activationof the clottingcascade.These microthrombi mayrestrict
bloodsupplytherefore maybe acontributingfactorto the multiple organdysfunctioncharacteristic
of EHF. Infact pathological dataobtainedbyGando(1999) suggeststhatfibrindepositionisafactor
that contributestomultipleorganfailure.Howeverbefore acute DICcanbecome apparentthere
mustbe sufficientstimulustooverwhelmthe natural anticoagulationprocesses (Feldmann&
Geisbert,2011). Anticoagulationfactors whichare mainlysynthesizedprimarilywithinthe liver
Parenchymal cells,whichhave mostlikelyalreadybeendamaged atthispointdue to viral assault,
act to inhibitthe formationof microthrombi,howeverif the rate at whichthese factorsare
consumedexceedsrate of synthesis;levelsof
inhibitorswithinplasmawill decline (Feldmann&
Geisbert,2011). For example Geisbertetal
(2003a) reportedthatactivatedProteinC,an
importantsubstance whichpreventsthrombus
formation,concentrationdropssignificantly
duringEHF (see figure 8);thisgoesto show that
the virusis able toovercome the body’snatural
anticoagulationsystems.
DuringDIC, the extrinsiccoagulationpathway,
whichisTissue Factor (TF) dependent,isthe
dominantroute forthrombinproductionand
thusfibrindeposition(Geisbertetal,2003b). The
factor that inducesDICwithinEHFismost likelyan
increase of TF,the majorinitiatorof the
coagulopathywitnessedwithinEHF,howeverin
orderto explainhowthisoccurswe
needtobeginwiththe initial targetof
EBOV;monocytes/macrophages.Data
obtainedby Geisbertetal,(2003b)
suggeststhatthe expressionof TFwas
onlyobserved in
monocytes/macrophagesthatshow
evidence of EBOV replication,thus
suggestingthatexpressionof TFmay
be directlyincreasedbyEBOV infection
(Geisbertetal,2003b).
FIGURE 8. ShowsconcentrationsofProtein C during EHF,
note the concentrationonly returns to 60% when
compared to pre-infectionconcentration.Data obtained
by Geisbert et al, (2003b).
FIGURE 9. Representsthe increase ofTF during EHF. Indirectfluorescent
antibodyanalysis was performedfor TF from peripheral blood mononuclear
cells ofanEBOV-infected rhesus macaqueat day 2 (B) andatday5 (C)
(Geisbertetal, 2003b).

9. As youcan see infigure 9, the concentrationof TF withinthe bloodincreasesduringthe progression
of an infection,thisishypothesizedby Geisbertetal (2003b) to be an importantfactorinthe
diagnosisof DICwithinEHF.DIC resultsinwidespreadactivationof the clottingcascade andthusthe
formationof multiplefibrinthrombi withinsmall vesselsthroughoutthe body.
As a resultof this,bloodflowisrestrictedthroughoutthe bodyandorgansreceive inadequate blood
supply,thisthenleadstoand/orhemorrhagicshock,whichappearstobe a lot like septicshock,
multiple organfailureandfinallydeathof the host(Geisbertetal,2003a); all featureswhichare
reportedby S.F.DeptPublichealth(2008) infigure 2.
Aroundday4-5, afterincubation,of EHF it may become clearwhetherthe hostismore likelyto
survive the infection, productionof antibodies,orwhetherthe infectionwillbe fatal, progressionto
hypercytokinemia,referredtoasthe “cytokine storm”;possiblythe final eventof EHF. It is
necessarytonote that thismay notoccur inall casesand dysfunctionswhichprecede thisstage may
be a significantfactorinthe deathof the host.Like manyof the symptomsassociatedwithEbola,
theymostlyall originate fromdysfunctionscausedtothe primarytargetcells. AccordingtoPérezet
al (2014), macrophage cellsare mainlyresponsibleforthe increasedsecretionof anti andpro-
inflammatorycytokinesduringEHF,thisreportalsoindicatesthatEBOV glycoprotein(GP) are the
likelyroute usedforactivationof the cytokinecascade viamacrophages,thisisshowninfigure 10.
As youcan see,endothelialcellsappeartobe affecteddue tothe release of cytokineswhichare
activatedandsecreteddue toEBOV GP. It has beenreportedbyWahl-Jensenetal (2005) that EBOV
causesa deregulatedinflammatorycytokine response,whichisresponsible inthe decreased
endothelial cellbarrierfunctionassociatedwiththisinfection.
FIGURE 10; Role ofshed GP during EHF. It is reported further by Pérez et al (2014) that EBOV GP aresecretedfrom infected cells, as
well as replicated virions, theseGP then bind tofurther cells using TLR-4,wherethey then activate thecells ability tosecrete various
cytokines. Image fromPérez et al(2014).

10. In fact studieshave shedfurtherlightonthisarea, Geisbertetal (2003c) emphasizedthe
involvementof TumorNecrosisFactor-α (TNFα) withinthe lossof vascularintegrity.TNFα isnow
consideredtobe the majorcytokine responsiblefor increasedpermeabilityof vasculartissue,and
data acquiredby Geisbertetal (2003c) supportsthis. InrelationtothisEBOV GP is able toinfect
endothelial cellsdirectly,thisproducescytopathiceffectsanddirectdamage tothe cellsbarrier,via
viral replication.Thisaccompaniedbythe cytokine effectsonendothelial cells leadstothe lossof
vascularintegrity,andasa resultlarge quantitiesof small breaksoccurthroughoutthe circulatory
systemamplifying;andfurtherreducing
bloodpressure.Incontrastto this
pressures,due tofluidleakage,within
organ cavitiesmayincrease,causing
excessivestresstoorganswhich,atthis
stage,may alreadybe dysfunctional,
causingfurtherdamage andamplifying
physiological damage. Inadditionto
thisit hasbeenreportedby Geisbertet
al (2003c) that withinendothelialcells,
small molecularweightproteinAlbumin
showsa significantdecreaseinvalue
whenthe cell become infected (see
figure 11),causinga vastnet decrease of
Albuminthroughoutthe body.Since itis
knowthat thisproteinhasa major function
inthe control of colloidosmoticpressure,anexcessive reducedamountwouldreduceplasma
osmoticpressure,thisdysfunctioncouldthenresultinedema. Furtherswellingtothe bodycould
induce furtherCNSdysfunctionandpossiblyleadtopermanentphysiological dysfunctionof organs
such as the brain(Geisbertetal,2003c).
It isalso thoughtthatduringthe late stagesof EHF, Nitricoxide (NO) levels begintoelevate(see
figure 12), possiblyasa response tothe heavyvirusloador may resultfromcytokine-induced
overexpressionof inducibleNOsynthase inphagocyticcellsthroughoutthe body(Sanchezetal.
(2004). Anincrease of NOwithinthe bloodcancause some seriousphysiological dysfunctions, for
example Sanchezetal (2004) reportedthatfatal
cases,whichexhibithighNOconcentrations,are
associatedwithcardiacstressandheart failure.It
alsosuggestedthatelevatedNOmaycontribute
to the hypotensioncharacteristicof EHF,as well
as the possibilityof thisfactorformingtoxic
molecule whichmayfurtherstressthe host.
To summarize EHFis capable of causing a wide
range of biochemical dysfunctions toahost, which
resultsina wide range of physiological
dysfunctionswithinthe humanbody;andnon-
humanprimates(Geisbertetal,2003a). Examples
withinthisreportare accompaniedwithmanyother
dysfunctionsthatoccurduringEHF.
Figure 12; Shows acomparisonoffatal and non-
fatal NOlevels in peripheral blood ofEbola-S
virus-infected
Patients. (Sanchezet al, 2004)
Figure 11; Showstotal serum protein and albumin valuespost-
infection in Cynomolgus monkeys. Note the decreaseofprotein
Albumin. Data obtainedfrom Geisbert etal, (2003c).

11. The initial attackappearsto be on monocyteswithinthe immune system, the virusisable to
transcribe andsynthesize variousfactorsandproteinswhichallow ittorecruitfurthercellsforviral
replication.Inthisprocessbiochemical imbalancesare created,causingothercells,suchas
lymphocytes, tobecome effected. Transportation,viathe lymphaticsystem,tothe spleenisthe
likelyroute usedtoenterthe vascularsystem, where the virus isthenable toaffectorganssuchas
the adrenal glandand the liverwhere necrosisoccurscausinglarge amountsof
physiological/biochemical dysfunction(Feldmanetal,2011). Asa resultof thisfurtherorganssuch
as the kidneysmaybecome effectedindirectlybyevenfurtherbiochemicalimbalancesdue to
necrosiswithinotherorgans.Forexamplethe kidneysinabilitytoregulate K+
andNa+
due
insufficientAldosterone synthesiswithinthe zonaglomerulosaof the adrenal gland,subsequently
causinghypotensionNa+
loss. InfactGeisbertetal,(2003a) foundthat almostall organsare effected
eitherdirectlyorin-directly,thishighlightsthe level of dysfunction,bothphysiological and
biochemical,whichoccursduringEHF.DIC alsooccurs whichresults ininadequate bloodsuppliesto
mostorgans throughoutthe body,resultinginmultiple organfailure andeventuallydeath.With
little treatmentavailable,therapiesonlyappearto rehydrate patientsinahope that theirimmune
systemwill produce antibodies.
If the hostsurvivesduring the multiple organfailureassociatedwithEHFthenthe infectionmay
progression intoitspreliminaryphase,which presentsamassive cytopathicattackon numerouscells
throughoutthe body.Thisiscombinedwithabodywide activationof masscytokine secretion,
causingconsiderate fluidlossanduncontrollablebleeding;deathmostlikelyfollowsthisphase.
Althoughactivationof the cytokine cascade isanimmune responsewhichusuallyoccursduring an
infectioncausedbyanewor particularlyharmful pathogen;italsoinflictsalarge amountof damage
to the host. In the unlikelysituationthatthe hostsurvivesthensubsequent conditionssuchas
deafnessandhairlosshave beenreportedbyFormenty etal,(1999).
So to trulyconclude;it’snotthe virusthat killsthe host,it’sthe hostsownbiochemical functionsand
immune responseswhichare hijackedduringEHFthat are the mostlikelycause of death.

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