Virus-cell and virus-host interaction (virology 7)

VirusVirusVirusVirusVirusVirusVirusVirus--------cell and viruscell and viruscell and viruscell and viruscell and viruscell and viruscell and viruscell and virus--------host cellhost cellhost cellhost cellhost cellhost cellhost cellhost cell
interactioninteractioninteractioninteractioninteractioninteractioninteractioninteraction
Basic Medical Microbiology
Year 2 Semester 1
Date: March 30, 2015
Time: 1200-1300
10/24/201710/24/2017 11
Dr.Dr. TarekTarek MahbubMahbub KhanKhan
MBBS, M.Phil (Virology)MBBS, M.Phil (Virology)
Copy right: Dr. Tarek MahbubCopy right: Dr. Tarek Mahbub
Khan/tarekviro@yahoo.comKhan/tarekviro@yahoo.com
Time: 1200-1300

Learning objectivesLearning objectives
At the end of the sessionAt the end of the session students will be ablestudents will be able
to:to:
Describe the effect of virus on host cellDescribe the effect of virus on host cell::
–– CPE, Inclusion body, malignant transformation,CPE, Inclusion body, malignant transformation,–– CPE, Inclusion body, malignant transformation,CPE, Inclusion body, malignant transformation,
types of viral infections, pathogenesis of viraltypes of viral infections, pathogenesis of viral
infectioninfection
Explain how host cell deals with virus toExplain how host cell deals with virus to
control infectioncontrol infection
–– Active and passive immune responseActive and passive immune response
10/24/201710/24/2017 22Copy right: Dr. Tarek MahbubCopy right: Dr. Tarek Mahbub

Effect of virus on host cellEffect of virus on host cell
Viral Infection
No
Morphological
or
Cytopathic effect
(CPE)
Malignant
Transformation
Death
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or
Functional
Change
(CPE) Transformation
Herpes viruses
Paramyxo-viruses
Hepatitis B virus
EBV

Out comes of viral infection on host cellOut comes of viral infection on host cell
Incomplete viral replication
Cells are non-permissive.
Infection by a defective virus
Cell death before replication
1
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Cells are permissive
Persistent infection
Altered cell surface antigenicity
2

Effect of viral infection on host cellEffect of viral infection on host cell
Persistent infection
Altered cell growth, metabolism
Tumor transformation
3
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Caused by cytocidal viruses
Cell function shut-off
Infection is lytic in nature
Protein synthesis is affected
followed by DNA damage
4

Cell tropismCell tropism
Organ and cell specificity of a particularOrgan and cell specificity of a particular
virus in producing infection is called cellvirus in producing infection is called cell
tropismtropism
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tropismtropism
Tropism determines pattern of systemicTropism determines pattern of systemic
illnessillness

Causes of cell tropismCauses of cell tropism
1.1. Receptor affinity for particular virusReceptor affinity for particular virus
2.2. Expression of some cellExpression of some cell--type specifictype specific
viral genesviral genes
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viral genesviral genes
3.3. Proteolytic cleavage of envelopeProteolytic cleavage of envelope
glycoproteinglycoprotein
Example:Example: Hepatitis B virus has a tropismHepatitis B virus has a tropism
for hepatocytesfor hepatocytes

Cytopathic effect (CPE) :Cytopathic effect (CPE) :
Cellular changes areCellular changes are--
a.a. Rounding of cellsRounding of cells
b.b. Degeneration of cellsDegeneration of cells
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b.b. Degeneration of cellsDegeneration of cells
c.c. Multinucleated giant cell formationMultinucleated giant cell formation
d.d. Inclusion body formationInclusion body formation
e.e. Viral antigen expressionViral antigen expression
((egeg.. HaemaglutininHaemaglutinin))

Round, degenerated cellsRound, degenerated cells

Multi-nucleated
giant cell

Inclusion bodyInclusion body
Inclusion bodies are virusInclusion bodies are virus--specific intracellularspecific intracellular
masses produce during replication of Virus andmasses produce during replication of Virus and
visible under light microscopevisible under light microscope
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Three types:Three types:
a.a. Intranuclear:Intranuclear: Herpes virusesHerpes viruses
b.b. Intacytoplasmic:Intacytoplasmic: Rabies virusRabies virus
c.c. Both nuclear and cytoplasmic:Both nuclear and cytoplasmic:
Measles virusMeasles virus Copy right: Dr. Tarek MahbubCopy right: Dr. Tarek Mahbub

Inclusion bodyInclusion body

Owl’s eye inclusion body (in CMV)Owl’s eye inclusion body (in CMV)

Laboratory importance of CPE:Laboratory importance of CPE:
a.a. Viral detection by observing theViral detection by observing the
CPE in cultureCPE in culture
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b.b. Viral quantification by plaque assayViral quantification by plaque assay

Plaque assayPlaque assay

Malignant change:Malignant change:
Characterized byCharacterized by--
a. Unopposed cell growtha. Unopposed cell growth
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a. Unopposed cell growtha. Unopposed cell growth
b. Prolonged survivalb. Prolonged survival
c. Rounded, piledc. Rounded, piled--up cellsup cells

Steps in viral pathogenesisSteps in viral pathogenesis
A.A. Entry and primary replicationEntry and primary replication
B.B. Viral spread and cell tropismViral spread and cell tropism
C.C. Cell injury and clinical illnessCell injury and clinical illness
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C.C. Cell injury and clinical illnessCell injury and clinical illness
D.D. Recovery from infectionRecovery from infection
E.E. Virus sheddingVirus shedding

Routes of infectionRoutes of infection
1.1. Respiratory tract:Respiratory tract: InhalationInhalation
2.2. Gastrointestinal tract:Gastrointestinal tract: IngestionIngestion
3.3. Skin:Skin: InoculationInoculation
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3.3. Skin:Skin: InoculationInoculation
4.4. Genital tract:Genital tract: Direct contactDirect contact
5.5. ParenteralParenteral:: InoculationInoculation
6.6. PerinatalPerinatal: Transplacental, at the time: Transplacental, at the time
of birth, breast feedingof birth, breast feeding

Important viruses with portal of entryImportant viruses with portal of entry
Respiratory tract:Respiratory tract: Influenza,Influenza, RSV,EPV,MeaslesRSV,EPV,Measles,,
MumpsMumps
Gastrointestinal tract:Gastrointestinal tract: HAV, Polio virusHAV, Polio virus
Skin:Skin: Rabies, Dengue virusRabies, Dengue virus
Genital tract:Genital tract: HBV, HIV, HSVHBV, HIV, HSV--22
Blood:Blood: HBV, HCV, HIV, CMVHBV, HCV, HIV, CMV
Transplacental:Transplacental: CMV, Rubella virusCMV, Rubella virus

Virus causingVirus causing perinatalperinatal transmissiontransmission
Transplacental:Transplacental: CMV, Rubella virusCMV, Rubella virus
At birth canal:At birth canal: HBV,HCV, HSVHBV,HCV, HSV--2 , HIV2 , HIVAt birth canal:At birth canal: HBV,HCV, HSVHBV,HCV, HSV--2 , HIV2 , HIV
Breast feeding:Breast feeding: CMV, HTLVCMV, HTLV

ZoonoticZoonotic viral infectionviral infection
Virus Reservoir Transmission Diseases
Rabies virus Skunks, Dogs
Raccoons, bats
Animal bite
aerosol
Rabies
Hanta virus Deer mice Aerosol Pneumonia
Yellow fever virus Monkeys Mosquito bite Yellow fever
Dengue virus Monkeys Mosquito bite Dengue
SARS corona virus Civet cat Aerosol SARS
Avian influenza virus Chicken, fowls Aerosol Infleunza

Viral spreadViral spread
Blood stream:Blood stream: Presence of viruses inPresence of viruses in
blood is called viremiablood is called viremia
Free in plasma:Free in plasma: EnterovirusesEnteroviruses
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Free in plasma:Free in plasma: EnterovirusesEnteroviruses
Associated with cells:Associated with cells: Measles virusMeasles virus
Neuronal spread:Neuronal spread: Rabies virusRabies virus
LymphaticsLymphatics

Schematic presentationSchematic presentation
of systemic viralof systemic viral
infectioninfection
(e.g., Polio virus)(e.g., Polio virus)

Pathogenesis and ImmunopathogenesisPathogenesis and Immunopathogenesis
Direct cytopathic effect:Direct cytopathic effect:
–– Stops synthesis of cellular macromoleculesStops synthesis of cellular macromolecules
–– Block protein synthesisBlock protein synthesis
–– Degeneration of cellular nucleic acidDegeneration of cellular nucleic acid–– Degeneration of cellular nucleic acidDegeneration of cellular nucleic acid
Indirect host immune attack:Indirect host immune attack:
–– Cytotoxic T cell mediated immune attack to virusCytotoxic T cell mediated immune attack to virus
infected cellinfected cell
–– VirusVirus--antibodyantibody--complement mediated cellcomplement mediated cell
damagedamage

Evasion of host defenseEvasion of host defense
VirokinesVirokines ( viral virulence factors):( viral virulence factors):
–– Virus encoded receptor proteins against IL2, TNFVirus encoded receptor proteins against IL2, TNF
–– Reduce expression of MHC I (e.g., HIV, CMV)Reduce expression of MHC I (e.g., HIV, CMV)
–– Inhibit complement (e.g., HSV)Inhibit complement (e.g., HSV)–– Inhibit complement (e.g., HSV)Inhibit complement (e.g., HSV)
–– Reduce the activity of interferon (HIV, EBV )Reduce the activity of interferon (HIV, EBV )
–– Interfere NK cell activity by formation ofInterfere NK cell activity by formation of nRNAnRNA
Antigenic diversityAntigenic diversity::
–– Bypass viral neutralization by antibodyBypass viral neutralization by antibody

Stages of a typical viral infectionStages of a typical viral infection
1.1. Incubation period:Incubation period: Patient is asymptomaticPatient is asymptomatic
2.2. Prodromal period:Prodromal period: Non specific symptomNon specific symptom
3.3. SpecificSpecific--illness period:illness period: Specific sign andSpecific sign and
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3.3. SpecificSpecific--illness period:illness period: Specific sign andSpecific sign and
symptomssymptoms
4.4. Recovery period:Recovery period: Illness wanes andIllness wanes and
regaining of good healthregaining of good health

Persistent viral infectionPersistent viral infection
Presence of either intact virus or a subPresence of either intact virus or a sub
viral component after clinical recovery ofviral component after clinical recovery of
diseasedisease
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diseasedisease
Types:Types:
1.1. Chronic carrierChronic carrier
2.2. Latent InfectionLatent Infection
3.3. Slow virus infectionSlow virus infection

Mechanism of viral persistenceMechanism of viral persistence
Integration ofIntegration of proviralproviral DNA to host cell DNADNA to host cell DNA
Immune tolerance: lack of neutralizingImmune tolerance: lack of neutralizing AbAb
Formation of viral antibody complexesFormation of viral antibody complexesFormation of viral antibody complexesFormation of viral antibody complexes
Located within immune shelter organsLocated within immune shelter organs
Rapid antigenic variationsRapid antigenic variations
Inter cellular spreading of virusInter cellular spreading of virus
Immunosuppression (e.g., AIDS)Immunosuppression (e.g., AIDS)

1.1. ChronicChronic--Carrier Infection:Carrier Infection:
Continuous viral detectionContinuous viral detection
low level virus productionlow level virus production
Mild or no clinical symptomsMild or no clinical symptoms
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Mild or no clinical symptomsMild or no clinical symptoms
Example:Example: Chronic hepatitis by hepatitis BChronic hepatitis by hepatitis B
virus or hepatitis C virus infectionvirus or hepatitis C virus infection

2.2. Latent infectionLatent infection
Virus persist in occult, cryptic formVirus persist in occult, cryptic form
Viral production stops for some periodViral production stops for some period
Viral reactivation and disease recurrenceViral reactivation and disease recurrence
Example:Example:
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Example:Example:
Herpes simplexHerpes simplex virusvirus Sensory ganglionSensory ganglion
(Latency)(Latency)
ReactivationReactivation (Blisters)(Blisters)

3. Slow virus infections3. Slow virus infections
Prolong periods after initial infectionProlong periods after initial infection
Normal viral growth cycleNormal viral growth cycle
Conventional virusesConventional virusesConventional virusesConventional viruses
–– SSPE: Following measles infectionSSPE: Following measles infection
–– PML: Caused by JC virus with lymphomaPML: Caused by JC virus with lymphoma
Unconventional virus like particlesUnconventional virus like particles
–– CreutzfeldtCreutzfeldt--Jacob disease byJacob disease by PrionPrion

Host immune response
Non Specific Specific
Cell mediated Antibody mediated
•PMN cells
•Macrophage
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•Macrophage
•NK cell
•Interferon
•Mucocilliary
clearance
Cytotoxic T-cell IgA, IgM, IgG
Neutralization
Opsonization
Complement activation
Cytolysis
•Perforins
•Granzymes

InterferonInterferon
Interferons are heterogeneous group ofInterferons are heterogeneous group of
glycoproteinglycoprotein
Types:Types:
AlphaAlpha--Interferon:Interferon: MonocyteMonocyte and Band B--lympocytelympocyte
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1.1. AlphaAlpha--Interferon:Interferon: MonocyteMonocyte and Band B--lympocytelympocyte
2.2. BetaBeta--Interferon:Interferon: Fibroblast and epithelialFibroblast and epithelial
cellscells
3.3. GamaGama--Interferon:Interferon: Activated TActivated T--LymphocyteLymphocyte

Induction of InterferonsInduction of Interferons
Alpha and beta interferons:Alpha and beta interferons:
–– Virus :Virus : dsRNAdsRNA during replicationduring replication
Gamma interferon:Gamma interferon:
–– Other antigens: Plant, bacterial endotoxin,Other antigens: Plant, bacterial endotoxin,
intracellular bacteria, protozoaintracellular bacteria, protozoa
Induction is not virus specific but host specificInduction is not virus specific but host specific
No direct effect on extracellular virusNo direct effect on extracellular virus

Mechanism of actionMechanism of action
Interferon acts by inducing the synthesis ofInterferon acts by inducing the synthesis of
three cell encoded proteins thatthree cell encoded proteins that inhibit theinhibit the
translation of viral mRNAtranslation of viral mRNA without affectingwithout affecting
the translation of cellular mRNAthe translation of cellular mRNA
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the translation of cellular mRNAthe translation of cellular mRNA
IFNIFN--αα and IFNand IFN--ββ produced within one hourproduced within one hour
of infectionof infection

How interferon acts?How interferon acts?

Uses of interferonUses of interferon
Use of interferonUse of interferon--alpha:alpha:
1.1. In chronic hepatitis B and C infectionIn chronic hepatitis B and C infection
2.2. Prophylactic or therapeutic use inProphylactic or therapeutic use in
Immunocompromised patient predisposingImmunocompromised patient predisposingImmunocompromised patient predisposingImmunocompromised patient predisposing
to VZ or HSVto VZ or HSV--1 and HSV1 and HSV--2 infection2 infection
3.3. Prophylactic use in CMV infected patientProphylactic use in CMV infected patient
who had undergone renal transplantationwho had undergone renal transplantation
4.4. In AIDSIn AIDS-- associated Kaposi's sarcoma andassociated Kaposi's sarcoma and
hairy cell leukemiahairy cell leukemia

Uses of interferonUses of interferon
Uses of interferonUses of interferon-- gamma:gamma:
1.1. As anAs an immunoimmuno--stimulant in cancer treatmentstimulant in cancer treatment1.1. As anAs an immunoimmuno--stimulant in cancer treatmentstimulant in cancer treatment
2.2. In some cases of immunodeficiencyIn some cases of immunodeficiency
3.3. In treating recurrent granulomatous infectionIn treating recurrent granulomatous infection

NK cell killing of virus infected cellNK cell killing of virus infected cell

Alpha defensinsAlpha defensins
A family of positively charged peptideA family of positively charged peptide
Block entry of HIV virus into cell:Block entry of HIV virus into cell:
–– Disrupt HIV cell membraneDisrupt HIV cell membrane
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–– Binds with CXCR4 coBinds with CXCR4 co--receptor prevent fusionreceptor prevent fusion
–– Bind with gp120 blocking receptor bindingBind with gp120 blocking receptor binding
Result in some HIV infected persons areResult in some HIV infected persons are
long time ‘nonprogressor ‘long time ‘nonprogressor ‘

Apolipoprotein B RNAApolipoprotein B RNA--Editing EnzymeEditing Enzyme
((APOBEC3GAPOBEC3G))
Innate host defense against retrovirusInnate host defense against retrovirus
Block infectivity of virus:Block infectivity of virus:Block infectivity of virus:Block infectivity of virus:
–– Deaminate cytosine in mRNA and retroviral DNADeaminate cytosine in mRNA and retroviral DNA
–– Cause hyper mutation of HIV genomeCause hyper mutation of HIV genome

FeverFever
Damage envelop virusDamage envelop virus
Inhibit replication of some virusInhibit replication of some virusInhibit replication of some virusInhibit replication of some virus

Mucociliary clearance
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Protects respiratory tract
Smoking predispose infection

Specific defenseSpecific defense
Active immunityActive immunity
–– Antibody mediatedAntibody mediated
Mucosal antibody:Mucosal antibody: IgAIgA (short protection)(short protection)
Serum antibody:Serum antibody: IgMIgM,, IgGIgG (long protection )(long protection )Serum antibody:Serum antibody: IgMIgM,, IgGIgG (long protection )(long protection )
–– Cell mediatedCell mediated
Passive immunityPassive immunity
–– Transplacental:Transplacental: IgGIgG
–– Colostrum:Colostrum: IgAIgA
–– Immunoglobulin against Rabies, HBV, VZVImmunoglobulin against Rabies, HBV, VZV

How antibodies control viral infectionHow antibodies control viral infection

Original antigenic sinOriginal antigenic sin

Original antigenic sin: A nonOriginal antigenic sin: A non--neutralizingneutralizing
antibody provides weak immunityantibody provides weak immunity

Cytotoxic T cell against virus infected cellCytotoxic T cell against virus infected cell

QUIZ (QUIZ (TRUETRUE//FALSEFALSE))
1.1. All viruses produce cytopathic effect.All viruses produce cytopathic effect.
2.2. ‘Owl’s eye’ negribodies are produce in Rabies virus‘Owl’s eye’ negribodies are produce in Rabies virus
infection.infection.
3.3. Multinucleated giant cells are produced by virusMultinucleated giant cells are produced by virus3.3. Multinucleated giant cells are produced by virusMultinucleated giant cells are produced by virus
have fusion proteins.have fusion proteins.
4.4. In abortive infection cells are permissive.In abortive infection cells are permissive.
5.5. Viral DNA integration to cell DNA is invariably aViral DNA integration to cell DNA is invariably a
common feature of persistent infection.common feature of persistent infection.
6.6. Plaque assay is to quantify virus.Plaque assay is to quantify virus.

7.7. Cytomegalovirus is an example of transplacentalCytomegalovirus is an example of transplacental
transmission.transmission.
8.8. Host immune response to viral infection is alwaysHost immune response to viral infection is always
protective.protective.
9.9. Viral opsonization can be done by nonViral opsonization can be done by non--neutralizingneutralizing
antibody.antibody.
10.10. An original antigenic sin can happen betweenAn original antigenic sin can happen between
structurallystructurally unsimilarunsimilar viral antigens.viral antigens.
11.11. CD4 T cells are prime cells to destroy virusCD4 T cells are prime cells to destroy virus
infected cell.infected cell.

12.12. Localized viral infection mostly generatesLocalized viral infection mostly generates IgMIgM
antibody.antibody.
13.13. IgAIgA provides long term immunity against viralprovides long term immunity against viral
14.14. Most commonly passed transplacentalMost commonly passed transplacental
immunoglobulin isimmunoglobulin is IgMIgM..
15.15. Live attenuated vaccines are good candidates forLive attenuated vaccines are good candidates for
production of ‘HERD’ immunity.production of ‘HERD’ immunity.

ReferenceReference
Review of Medical MicrobiologyReview of Medical Microbiology and Immunology.and Immunology.
Warren Levinson, 12Warren Levinson, 12thth May 2012. McMay 2012. Mc GrawGraw--HillHill (Lange)(Lange)
JawetzJawetz,, MelnickMelnick andand Adelberg’sAdelberg’s Medical MicrobiologyMedical Microbiology
George F. Brooks, Karen C. Carroll, Janet S.George F. Brooks, Karen C. Carroll, Janet S. ButelButel,,
10/24/201710/24/2017 5252
2525thth Mar 2010Mar 2010.. McMc GrawGraw--HillHill (Lange)(Lange)
Bailey and Scott’sBailey and Scott’s Diagnostic MicrobiologyDiagnostic Microbiology..BettyBetty
A.ForbesA.Forbes,,
Daniel F.Daniel F. SahmSahm, Alice S., Alice S. WeissfeldWeissfeld,,1212thth 2007.2007. MosbyMosby
ElsevierElsevier

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