Understanding Microbial Persistence and Adaptation in the Environment
Microbial Immune Evasion and Persistence · 2016-10-02 · Microbial Immune Evasion and Persistence...
Transcript of Microbial Immune Evasion and Persistence · 2016-10-02 · Microbial Immune Evasion and Persistence...
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Microbial Immune Evasionand Persistence
Lecturer: William Halford
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OverviewOverview
1. Introduction to persistent infections1. Introduction to persistent infections
2. Strategies that promote microbial persistence2. Strategies that promote microbial persistence
3. 3. AlphaherpesvirusesAlphaherpesviruses: a case study in persistence: a case study in persistence
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OverviewOverview
1. Introduction to persistent infections1. Introduction to persistent infections microbial growth microbial growth in vivoin vivo
HSV+
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Microbial replication in the labMicrobial replication in the lab
Time (hours)
log phase bacterial growth
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Microbial growth Microbial growth in vivoin vivoIncubation
periodrate of microbe rate of immune
replication clearancerate of microbe rate of immune
replication clearance>>
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Microbial growth Microbial growth in vivoin vivoIncubation
periodplateau
rate of microbe rate of immunereplication clearance
rate of microbe rate of immunereplication clearance=
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Microbial growth Microbial growth in vivoin vivoIncubation
periodplateau convalescent
period
rate of microbe rate of immunereplication clearance
rate of microbe rate of immunereplication clearance<<
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Acute infectionAcute infectionIncubation
periodplateau convalescent
period
microbe burdenreduced to 0
microbe burdenreduced to 0
resolution
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Persistent infectionPersistent infectionIncubation
periodplateau convalescent
period
microbe burden reduced,but not cleared
microbe burden reduced,but not cleared
resolution
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OverviewOverview
1. Introduction to persistent infections1. Introduction to persistent infections microbial growth microbial growth in vivoin vivo Why do some infections persist?Why do some infections persist?
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microbe host response
Microbial infections exist inMicrobial infections exist inan equilibrium an equilibrium in vivoin vivo
replicationreplication
immune controlimmune control
Microbe production = rate of microbe replication – rate of microbe clearancein vivo (immune killing)
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microbe host response
uncontrolledproliferation;
disease or death
When equilibrium tips in favorWhen equilibrium tips in favorof microbeof microbe……....
……..acute infectionacute infection progresses.progresses.
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microbe host response
microbe cleared;patient fully
recovers
When equilibrium tips in favorWhen equilibrium tips in favorof host responseof host response……....
……..acute infectionacute infection resolves.resolves.
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microbe host response
When microbial replication andWhen microbial replication andhost response generate equal and host response generate equal and
opposing forcesopposing forces……..persistent infectionpersistent infection..
microbe persists whilehost response limits spread
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Equilibrium concept = key to Equilibrium concept = key to understanding persistent infectionsunderstanding persistent infections
microbe host response
replicationreplication
immune controlimmune control
acute phase
clinically “latent” phase
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Equilibrium concept = key to Equilibrium concept = key to understanding persistent infectionsunderstanding persistent infections
microbe host response
replicationreplication
immune controlimmune control
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OverviewOverview
1. Introduction to persistent infections1. Introduction to persistent infections microbial growth microbial growth in vivoin vivo why do some infections persist?why do some infections persist? chronic versus latent infectionschronic versus latent infections
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Chronic infectionChronic infection: high level of replication : high level of replication (high burden) during clinically (high burden) during clinically ““latentlatent”” phasephaseacute phase
clinically “latent” phasemicrobe host response
replicationreplication
immune controlimmune control
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Latent infectionLatent infection: replication not detectable : replication not detectable (low burden) during clinically (low burden) during clinically ““latentlatent”” phasephaseacute phase
clinically “latent” phase
microbe host response
replicationreplication
immune controlimmune control
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Recurrent infectionRecurrent infection: microbial replication : microbial replication resumes resumes new diseasenew disease
acute phase
“latent”microbe host response
replicationreplication
immune controlimmune control
recurrent disease
“latent”
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OverviewOverview
1. Introduction to persistent infections1. Introduction to persistent infections
2. Strategies that promote microbial persistence2. Strategies that promote microbial persistence
HSV+
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Microbes that persist evadeMicrobes that persist evadeimmune clearanceimmune clearance
Strategy 1. Hide major antigens to avoid RECOGNITIONStrategy 1. Hide major antigens to avoid RECOGNITION Intracellular invasionIntracellular invasion
PlasmodiumPlasmodiumfalciparumfalciparum
microbe host response
replicationreplication
immune controlimmune control
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Microbes that persist evadeMicrobes that persist evadeimmune clearanceimmune clearance
Strategy 1. Hide major antigens to avoid RECOGNITIONStrategy 1. Hide major antigens to avoid RECOGNITION Intracellular invasionIntracellular invasion
PlasmodiumPlasmodiumfalciparumfalciparum
MycobacteriumMycobacteriumtuberculosistuberculosis SalmonellaSalmonella
typhimuriumtyphimurium
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Microbes that persist evadeMicrobes that persist evadeimmune clearanceimmune clearance
Strategy 1. Hide major antigens to avoid RECOGNITIONStrategy 1. Hide major antigens to avoid RECOGNITION Intracellular invasionIntracellular invasion DownregulationDownregulation of antigen synthesis (latency)of antigen synthesis (latency)
HerpesvirusesHerpesviruses MycobacteriumMycobacteriumtuberculosistuberculosis
microbe host response
replicationreplication
immune controlimmune control
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Antigenic shutdown (latency)Antigenic shutdown (latency)
HerpesvirusesHerpesviruses
LatencyLatency:: an indefinite period of reduced, or no, protein synthesis an indefinite period of reduced, or no, protein synthesis that allows a microbe to become that allows a microbe to become antigenicallyantigenically ““invisible.invisible.””
No antigen No antigen →→ no detection by immune systemno detection by immune system
MycobacteriumMycobacteriumtuberculosistuberculosis
microbe host response
replicationreplication
immune controlimmune control
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Microbes that persist evadeMicrobes that persist evadeimmune clearanceimmune clearance
Strategy 1. Hide major antigens to avoid RECOGNITIONStrategy 1. Hide major antigens to avoid RECOGNITION Intracellular invasionIntracellular invasion DownregulationDownregulation of antigen synthesis (latency)of antigen synthesis (latency) Polysaccharide cloaking device (capsule)Polysaccharide cloaking device (capsule)
-- Deposition of C3b and antibody inefficientDeposition of C3b and antibody inefficient
KlebsiellaKlebsiellapneumoniaepneumoniae
microbe host response
replicationreplication
immune controlimmune control
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Microbes that persist evadeMicrobes that persist evadeimmune clearanceimmune clearance
Strategy 1. Hide major antigens to avoid RECOGNITIONStrategy 1. Hide major antigens to avoid RECOGNITION
Strategy 2. Use of DNA as genetic materialStrategy 2. Use of DNA as genetic material-- Chemically stable over time.Chemically stable over time.-- May persist in absence of active replication.May persist in absence of active replication.
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Viral persistence: DNA Viral persistence: DNA vsvs RNA virusesRNA viruses
DNA viruses that persist for more than 6 monthsDNA viruses that persist for more than 6 months::•• all all herpesvirusesherpesviruses (8 human viruses)•• all retrovirusesall retroviruses (proviral form)•• hepatitis B virushepatitis B virus•• adenovirusadenovirus•• papillomaviruspapillomavirus•• molluscummolluscum contagiosumcontagiosum virusvirus (poxvirus)
RNA viruses that persist:RNA viruses that persist:•• hepatitis C virushepatitis C virus (has to replicate to be maintained)
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11stst phase of Retrovirus life cycle phase of Retrovirus life cycle (hours)(hours)
virion RNA
provirus = DNA
provirus
RNADNA
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provirus
22ndnd phase of Retrovirus life cyclephase of Retrovirus life cycle (days (days -- years)years)
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Microbes that persist evadeMicrobes that persist evadeimmune clearanceimmune clearance
Strategy 1. Hide major antigens to avoid RECOGNITIONStrategy 1. Hide major antigens to avoid RECOGNITIONStrategy 2. Use of DNA as genetic materialStrategy 2. Use of DNA as genetic material
Strategy 3. Change major antigens to avoid RECOGNITIONStrategy 3. Change major antigens to avoid RECOGNITIONA. Antigenic drift of HIV (within carrier)A. Antigenic drift of HIV (within carrier)B. AntigenicB. Antigenic--phase variation (within carrier)phase variation (within carrier)
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Flagella are a major antigenFlagella are a major antigenin many bacteriain many bacteria
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SalmonellaSalmonella encode >1 flagella:encode >1 flagella:antigenic phase variation antigenic phase variation
hixL hixR
hixLhixR
X
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hixL hixR
hixLhixR
SalmonellaSalmonella encode >1 flagella:encode >1 flagella:antigenic phase variation antigenic phase variation
DNA inversion in0.01% of bacteria
X X
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Microbes that persist evadeMicrobes that persist evadeimmune clearanceimmune clearance
Strategy 1. Hide major antigens to avoid RECOGNITIONStrategy 1. Hide major antigens to avoid RECOGNITIONStrategy 2. Use of DNA as genetic materialStrategy 2. Use of DNA as genetic material
Strategy 3. Change major antigens to avoid RECOGNITIONStrategy 3. Change major antigens to avoid RECOGNITIONA. Antigenic drift of HIV (within carrier)A. Antigenic drift of HIV (within carrier)B. AntigenicB. Antigenic--phase variation (within carrier)phase variation (within carrier)
Salmonella speciesSalmonella species BorreliaBorrelia species species (e.g., Lyme disease)(e.g., Lyme disease)
TrypanosomesTrypanosomes (e.g., African sleeping sickness)(e.g., African sleeping sickness)
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Antigenic phase variationAntigenic phase variation
TrypanosomesTrypanosomes
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Antigenic phase variationAntigenic phase variation
TrypanosomesTrypanosomes
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Antigenic phase variationAntigenic phase variation
TrypanosomesTrypanosomes
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Antigenic phase variationAntigenic phase variation
TrypanosomesTrypanosomes
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Antigenic phase variationAntigenic phase variation
TrypanosomesTrypanosomes
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Antigenic phase variation:Antigenic phase variation:antigenic shift within a single hostantigenic shift within a single host
TrypanosomesTrypanosomes
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Microbes that persist evadeMicrobes that persist evadeimmune clearanceimmune clearance
Strategy 1. Hide major antigens to avoid RECOGNITIONStrategy 1. Hide major antigens to avoid RECOGNITIONStrategy 2. Use of DNA as genetic materialStrategy 2. Use of DNA as genetic materialStrategy 3. Change major antigens to avoid RECOGNITIONStrategy 3. Change major antigens to avoid RECOGNITION
Strategy 4. Colonize sites difficult to ATTACKStrategy 4. Colonize sites difficult to ATTACK
MycobacteriumMycobacteriumtuberculosistuberculosis
EchinococcusEchinococcus tapewormtapeworm
granulomagranulomahydatidhydatid cystscysts
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Microbes that persist evadeMicrobes that persist evadeimmune clearanceimmune clearance
Strategy 1. Hide major antigens to avoid RECOGNITIONStrategy 1. Hide major antigens to avoid RECOGNITIONStrategy 2. Use of DNA as genetic materialStrategy 2. Use of DNA as genetic materialStrategy 3. Change major antigens to avoid RECOGNITIONStrategy 3. Change major antigens to avoid RECOGNITIONStrategy 4. Colonize sites difficult to ATTACKStrategy 4. Colonize sites difficult to ATTACK
Strategy 5. Active obstruction of immune Strategy 5. Active obstruction of immune effectoreffector mechanismsmechanisms Staph Staph aureusaureus protein A protein A binds binds IgGIgG’’ss FcFc regionregion renders bacteria renders bacteria opsonizationopsonization--resistantresistant Staph aureus
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OverviewOverview1. Introduction to persistent infections1. Introduction to persistent infections
2. Strategies that promote microbial persistence2. Strategies that promote microbial persistence
3. 3. AlphaherpesvirusesAlphaherpesviruses: a case study in persistence: a case study in persistenceA. AlphaA. Alpha--herpesvirusesherpesvirusesB. Immunity to virusesB. Immunity to virusesC. HSVC. HSV--encoded countermeasures encoded countermeasures D. The D. The ““paradoxparadox”” of recurrent herpesof recurrent herpes
HSV+
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OverviewOverview1. Introduction to persistent infections1. Introduction to persistent infections
2. Strategies that promote microbial persistence2. Strategies that promote microbial persistence
3. 3. AlphaherpesvirusesAlphaherpesviruses: a case study in persistence: a case study in persistenceA. AlphaA. Alpha--herpesvirusesherpesviruses
The playersThe players
HSV+
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HerpesvirusesHerpesvirusesMarek'sMarek's Disease VirusDisease VirusPseudorabiesvirusPseudorabiesvirusmacropodidmacropodid herpesvirusherpesvirus 11crocodylidcrocodylid herpesvirusherpesvirus 11ostreidostreid herpesvirusherpesvirus 11
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All All herpesvirusesherpesviruses..........
encode conserved set of 42 genes thatencode conserved set of 42 genes thatsynthesize and package viral synthesize and package viral dsDNAdsDNA into virionsinto virions
Establish lifeEstablish life--long infections in hostlong infections in host
Remain latent for long periodsRemain latent for long periods
Reactivate episodically, make new virions Reactivate episodically, make new virions transmissiontransmission
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Tropism.Tropism.• Broadly, the herpesviruses can be divided based on their use of
neurons or leukocytes as their permanent homes.
In humansIn humans…………• Neurotropic (-herpesviruses)
- Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2)- Varicella-Zoster Virus (VZV)
• Blood-borne (- and -herpesviruses)- Cytomegalovirus, HHV-6, HHV-7 >> monocytes (-herpesviruses)- Epstein-Barr Virus, HHV-8 >> lymphocytes (- herpesviruses)
Human Human herpesvirusesherpesviruses::Neurons or leukocytes?Neurons or leukocytes?
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Herpes simplex virus type 1Herpes simplex virus type 1Primary infection
virus spreads to trigeminalganglion neurons
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Herpes simplex virus type 1Herpes simplex virus type 1Recurrent infection
months to years later,virus reactivates
and spreads back to lip
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Human Human --herpesvirusesherpesviruses
Herpes simplex virus 1 (HSVHerpes simplex virus 1 (HSV--1)1)
Herpes simplex virus 2 (HSVHerpes simplex virus 2 (HSV--2)2)
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Herpes simplex virus type 2Herpes simplex virus type 2
Primary infectionvirus spreads to sacral
ganglia neurons
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Herpes simplex virus type 2Herpes simplex virus type 2Recurrent infection
months to years later,virus reactivates
and returns to genitalia
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Human Human --herpesvirusesherpesviruses
Herpes simplex virus 1 (HSVHerpes simplex virus 1 (HSV--1)1)
Herpes simplex virus 2 (HSVHerpes simplex virus 2 (HSV--2)2)
VaricellaVaricella--zoster virus (VZV)zoster virus (VZV)
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VaricellaVaricella--zoster viruszoster virusPrimary infection: varicellavirus spreads by viremia and nerves to trigeminal ganglia and all spinal ganglia
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VaricellaVaricella--zoster viruszoster virus
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VaricellaVaricella--zoster viruszoster virusRecurrent infection: zostervirus reactivates in 1 ganglion and
disease limited to 1 dermatome
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VaricellaVaricella--zoster viruszoster virusRecurrent infection: zostervirus reactivates in 1 ganglion and
disease limited to 1 dermatome
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VaricellaVaricella--zoster viruszoster virusRecurrent infection: zostervirus reactivates in 1 ganglion and
disease limited to 1 dermatome
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AlphaherpesvirusAlphaherpesvirus latency: an equilibriumlatency: an equilibrium
HSV-1 HSV-1latency replication
viral activators
host immunity
CD8+ T cells
IFN-
ICP34.5ICP0
viral genome
HSV+
neuron
CD3+
T cells
virus host response
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OverviewOverview1. Introduction to persistent infections1. Introduction to persistent infections
2. Strategies that promote microbial persistence2. Strategies that promote microbial persistence
3. 3. AlphaherpesvirusesAlphaherpesviruses: a case study in persistence: a case study in persistenceA. AlphaA. Alpha--herpesvirusesherpesviruses
The playersThe players Basic biology of HSVBasic biology of HSV
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
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Large DNA virus that is:• 152,000 bp.• contains ~75 genes.• too large to meaningfully discuss gene by gene……..
Herpes simplex virus 1Herpes simplex virus 1
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HSV gene functions.HSV gene functions.
5 IE proteins:5 IE proteins:modify the cell’s transcriptional machinery and thuscreate environment that allows E gene expression
25 E proteins:25 E proteins:• 5 nucleotide synthesis enzymes ( thymidine kinase )• 7 DNA replication proteins ( HSV DNA polymerase )
45 L proteins:45 L proteins:• 5 capsid proteins ( VP5 )• 15 tegument proteins ( VP16 )• 11 glycoproteins ( gD )• 6 involved in nucleocapsid assembly (protease, endonuclease )
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Steps in HSV replication Steps in HSV replication 1. Adsorption and Entry (1. Adsorption and Entry (gBgB and and gDgD))
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Steps in HSV replicationSteps in HSV replication2. Transport to nucleus2. Transport to nucleus
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Steps in HSV replication Steps in HSV replication 3. Viral IE and E gene expression3. Viral IE and E gene expression
VP16 IE mRNAs IE proteins (5)
E mRNAs E proteins (25)
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Steps in HSV replication Steps in HSV replication 4. Viral DNA synthesis4. Viral DNA synthesis
VP16 IE mRNAs IE proteins
E mRNAs E proteins
DNA replication
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Steps in HSV replication Steps in HSV replication 5. virion synthesis / egress5. virion synthesis / egress
DNA replication
L mRNAs L proteins (45)
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A bit more to scaleA bit more to scale…………
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HSVHSV--2 spread over2 spread over4 cycles of replication4 cycles of replication
Green HSV-2(8 h after infection)
movie
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HSVHSV--2 spread over2 spread over4 cycles of replication4 cycles of replication
Green HSV-2(8 h after infection)
Green HSV-2(56 h after infection)
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OverviewOverview1. Introduction to persistent infections1. Introduction to persistent infections
2. Strategies that promote microbial persistence2. Strategies that promote microbial persistence
3. 3. AlphaherpesvirusesAlphaherpesviruses: a case study in persistence: a case study in persistenceA. AlphaA. Alpha--herpesvirusesherpesviruses
The playersThe players Basic biology of HSVBasic biology of HSV HSV spread HSV spread in vivoin vivo
-- animal modelsanimal models
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
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(HSV-GFP)
Balb/c mice + no treatment
Balb/c mice + -irradiation
(HSV-GFP)
Balb/c mice + cyclophosphamide
Green HSV in mice Green HSV in mice ±± immune systemimmune system
(HSV-GFP)
1. Inoculate mice with green HSV virus in eyes2. photograph mouse eyes & faces over time
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GFPGFP++ herpes simplex virusherpes simplex virusin a mouse eyein a mouse eye
Day 1
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Day 3
normal -irradiated cyclophosphamide
GFPGFP++ herpes simplex virus in miceherpes simplex virus in mice
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normal -irradiated cyclophosphamide
Day 4
GFPGFP++ herpes simplex virus in miceherpes simplex virus in mice
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normal -irradiated cyclophosphamide
Day 5
GFPGFP++ herpes simplex virus in miceherpes simplex virus in mice
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normal -irradiated cyclophosphamide
Day 6
GFPGFP++ herpes simplex virus in miceherpes simplex virus in mice
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normal -irradiated cyclophosphamide
Day 7
GFPGFP++ herpes simplex virus in miceherpes simplex virus in mice
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normal -irradiated cyclophosphamide
Day 9
GFPGFP++ herpes simplex virus in miceherpes simplex virus in mice
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nerve fibers = primary conduit of viral spread
normal -irradiated cyclophosphamide
Why this pattern of HSV spread in animals?Why this pattern of HSV spread in animals?
virus host immune response
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OverviewOverview1. Introduction to persistent infections1. Introduction to persistent infections
2. Strategies that promote microbial persistence2. Strategies that promote microbial persistence
3. 3. AlphaherpesvirusesAlphaherpesviruses: a case study in persistence: a case study in persistenceA. AlphaA. Alpha--herpesvirusesherpesviruses
The playersThe players Basic biology of HSVBasic biology of HSV HSV spread HSV spread in vivoin vivo
-- animal modelsanimal models-- in humansin humans
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
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1. PrimaryInfection
Spread of HSVSpread of HSV--1 infection1 infectionDay 1Day 1
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Spread of HSVSpread of HSV--1 infection1 infectionDay 2Day 2
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Spread of HSVSpread of HSV--1 infection 1 infection Day 3Day 3
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Spread of HSVSpread of HSV--1 infection 1 infection Day 5Day 5
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Slowing of HSVSlowing of HSV--1 spread 1 spread Day 7Day 7
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HSVHSV--1 infection is latent1 infection is latent(Day 14 (Day 14 -- decades later)decades later)
2. Latent infection.
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3. Reactivation oflatent HSV genome.
Common triggers:- sunburn- fever- “exam stress”
HSV life cycle:HSV life cycle:3. Reactivation.3. Reactivation.
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4. Cold sores. Virus spread to new host.
HSV life cycle:HSV life cycle:4. Viral shedding & disease.4. Viral shedding & disease.
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Other presentations of recurrent herpes.Other presentations of recurrent herpes.
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Clinical presentations of recurrent herpes.Clinical presentations of recurrent herpes.
herpesgladitorium
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OverviewOverview1. Introduction to persistent infections1. Introduction to persistent infections
2. Strategies that promote microbial persistence2. Strategies that promote microbial persistence
3. 3. AlphaherpesvirusesAlphaherpesviruses: a case study in persistence: a case study in persistenceA. AlphaA. Alpha--herpesvirusesherpesvirusesB. Immunity to virusesB. Immunity to viruses
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
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Host immunity:Host immunity:hurdles to viral diseasehurdles to viral disease
CD8+ T cells
B cells / antibody
interferon / innate immunity
epithelium / innate barriers
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IFN-
Hurdle 1: The Interferon SystemHurdle 1: The Interferon System
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Resistant to viral infection
IFN-
Upregulation of:
- MHC class I- PKR IFN-
receptor
Host Interferon ResponseHost Interferon Response
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Effect of interferon on viral replication?Effect of interferon on viral replication?
cells + interferon-cells + no interferon
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Effect of interferon on viral replicationEffect of interferon on viral replication
cells + no interferon
Each red dot= 1 viral plaque
cells + interferon-
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InterferonsInterferons: an innate defense against: an innate defense againstviral spreadviral spread
InterferonInterferon: a virus: a virus--induced warning system that renders cells induced warning system that renders cells adjacent to a site of virus replication resistant (nonadjacent to a site of virus replication resistant (non--permissive) permissive) before infectious virions reach these cells.before infectious virions reach these cells.
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OverviewOverview1. Introduction to persistent infections1. Introduction to persistent infections
2. Strategies that promote microbial persistence2. Strategies that promote microbial persistence
3. 3. AlphaherpesvirusesAlphaherpesviruses: a case study in persistence: a case study in persistenceA. AlphaA. Alpha--herpesvirusesherpesvirusesB. Immunity to virusesB. Immunity to viruses
interferoninterferon--induced antiviral stateinduced antiviral state antibodies to virusesantibodies to viruses
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
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Antibody factories
Next hurdle: neutralizing,Next hurdle: neutralizing,virusvirus--specific antibodiesspecific antibodies
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Neutralizing antibodiesNeutralizing antibodies(competitive antagonists that bind to virion receptors)(competitive antagonists that bind to virion receptors)
Viruses: mechanism of action.Step 1 Step 2 Step 3
Neutralizing antibodiesblock Step 1.
Virion bindscell
Virion enterscell
Virus released;infection starts
Antibody blocksvirion receptors
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VirusVirus--specific antibodiesspecific antibodies::prevent prevent viremiaviremia, serve a pro, serve a pro--inflammatory roleinflammatory role
in virusin virus--infected tissues (recruit infected tissues (recruit WBCsWBCs))
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OverviewOverview1. Introduction to persistent infections1. Introduction to persistent infections
2. Strategies that promote microbial persistence2. Strategies that promote microbial persistence
3. 3. AlphaherpesvirusesAlphaherpesviruses: a case study in persistence: a case study in persistenceA. AlphaA. Alpha--herpesvirusesherpesvirusesB. Immunity to virusesB. Immunity to viruses
interferoninterferon--induced antiviral stateinduced antiviral state antibodies to virusesantibodies to viruses CD8CD8++ TT--cellscells
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
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CD8CD8++ T cells RECOGNIZET cells RECOGNIZEviral peptides + MHC Iviral peptides + MHC I
•• MHC class I is essential for CD8MHC class I is essential for CD8++ T cells T cells to to RECOGNIZERECOGNIZE virusvirus--infected cells.infected cells.
viral peptideviral peptide
+IFN-
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http://www.blink.biz/immunoanimations/index1.html
VirusVirus--specific CD8specific CD8++ T cellsT cellskill viruskill virus--infected cellsinfected cells
+IFN-
+IFN-
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OverviewOverview1. Introduction to persistent infections1. Introduction to persistent infections
2. Strategies that promote microbial persistence2. Strategies that promote microbial persistence
3. 3. AlphaherpesvirusesAlphaherpesviruses: a case study in persistence: a case study in persistenceA. AlphaA. Alpha--herpesvirusesherpesvirusesB. Immunity to virusesB. Immunity to virusesC. HSVC. HSV--encoded countermeasuresencoded countermeasures
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
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Host defense against viruses:Host defense against viruses:interferonsinterferons and T cellsand T cells
IFN-
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Effect of interferon on viral replicationEffect of interferon on viral replication
cells + interferoncells + no interferon
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inhibitors of PKRinhibitors of PKR• EBER (EBV)• K3L (vaccinia)• VAI (adenovirus)• TAR and tat (HIV)• US11 (HSV)
Viruses encode countermeasures toViruses encode countermeasures tohost interferonshost interferons
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inhibitors of PKRinhibitors of PKR
soluble IFNsoluble IFN-- receptorreceptor• B18R (vaccinia)
Viral countermeasures toViral countermeasures tohost interferonshost interferons
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inhibitors of PKRinhibitors of PKR
soluble IFNsoluble IFN-- receptorreceptor
reverses effects of reverses effects of IFNsIFNs• ICP0, ICP34.5 (HSV)• vIRF K9 (HHV-8)• E1a (adenovirus)
Viral countermeasures toViral countermeasures tohost interferonshost interferons
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Poxviruses take this conceptPoxviruses take this conceptone step further....one step further....
Molluscum contagiosum smallpox
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DECOY RECEPTORS VIRAL CYTOKINES• v TNF receptor• v IL-1 receptor• v IFN- receptor• v IFN-/ receptor
CYTOKINE BINDING PROTEINS• vIL-2 binding protein• vIL-18 binding protein• vIFN- binding protein
• v IL-8• v IL-10• v IL-17• v IL-6
Poxviruses hijack thePoxviruses hijack theentire host cytokine responseentire host cytokine response
Molluscum contagiosum smallpox
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Host defense against viruses:Host defense against viruses:interferons and interferons and T cellsT cells
IFN-
Ag presentation and CTLAg presentation and CTL @@ http://http://www.hhmi.org/biointeractive/disease/animations.html#ecoliwww.hhmi.org/biointeractive/disease/animations.html#ecoli
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CD8CD8++ T cells RECOGNIZET cells RECOGNIZEviral peptides within MHC class Iviral peptides within MHC class I
•• MHC class I is essential for CD8MHC class I is essential for CD8++ T cells T cells to to RECOGNIZERECOGNIZE virusvirus--infected cells.infected cells.
viral peptideviral peptide
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•• Some viruses prevent MHC class I from Some viruses prevent MHC class I from reaching cell surface.reaching cell surface.(block (block RECOGNITIONRECOGNITION).).
Evasion of CD8Evasion of CD8++ T cellsT cells((no MHC class I no MHC class I →→ no RECOGNITION)no RECOGNITION)
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MHC class I immuneMHC class I immuneevasion slidesevasion slides
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Block TAP (antigen loading)Block TAP (antigen loading)• ICP47 (HSV)• US6 (CMV)
Retain MHC I in ERRetain MHC I in ER• E3 (adenovirus)• US3 (CMV)
Target MHC I for degradationTarget MHC I for degradation• US2 and US11 (CMV)• Vpu (HIV)
Viral countermeasures toViral countermeasures toMHC class I pathwayMHC class I pathway
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OverviewOverview1. Introduction to persistent infections1. Introduction to persistent infections
2. Strategies that promote microbial persistence2. Strategies that promote microbial persistence
3. 3. AlphaherpesvirusesAlphaherpesviruses: a case study in persistence: a case study in persistenceA. AlphaA. Alpha--herpesvirusesherpesvirusesB. Immunity to virusesB. Immunity to virusesC. HSVC. HSV--encoded countermeasures encoded countermeasures D. The D. The ““paradoxparadox”” of recurrent herpesof recurrent herpes
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
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Paradox: people who experience recurrent herpes oftenParadox: people who experience recurrent herpes oftenhave the highest level of have the highest level of ““immunityimmunity”” to HSV.to HSV.
• e.g., highest levels of HSV-specific IgG antibody
Host Host ““immunityimmunity”” and recurrentand recurrentviral diseaseviral disease
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Paradox: people with recurrent herpes have Paradox: people with recurrent herpes have ““immunityimmunity”” to HSV.to HSV.• e.g. high levels of HSV-specific IgG antibody
Consider the mechanisms that confer antiviral immunity.Consider the mechanisms that confer antiviral immunity.• interferon-induced antiviral state
Host Host ““immunityimmunity”” and recurrentand recurrentviral diseaseviral disease
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HSV IE genesHSV IE genes
E genesE genes
L genesL genes
1.1. InterferonInterferon--induced blockinduced block
PKRPKRactivatedactivated
ObservationObservation
PP --eIFeIF--22
PKR activityshuts off viralprotein synthesis
no new virions =no viral spread
HSV infection activates cellular PKR
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no new virions =no viral spread
HSV IE genesHSV IE genes
E genesE genes
L genesL genes
HSV ICP34.5 = interferon antagonistHSV ICP34.5 = interferon antagonist
PKRPKR
ObservationObservation
ICP34.5
ProteinPhosphatase
1
PP --eIFeIF--22
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HSV IE genesHSV IE genes
E genesE genes
L genesL genes
HSV ICP34.5 removes blockHSV ICP34.5 removes block
PKR PKR
ObservationObservation
ICP34.5Protein
Phosphatase1
eIFeIF--22
PP ICP34.5 restoresviral proteinsynthesis
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Paradox: people with recurrent herpes have Paradox: people with recurrent herpes have ““immunityimmunity”” to HSV.to HSV.• e.g. high levels of HSV-specific IgG antibody
Consider the mechanisms that confer antiviral immunity.Consider the mechanisms that confer antiviral immunity.• ICP34.5 → interferon-induced antiviral state
Host Host ““immunityimmunity”” and recurrentand recurrentviral diseaseviral disease
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Paradox: people with recurrent herpes have Paradox: people with recurrent herpes have ““immunityimmunity”” to HSV.to HSV.• e.g. high levels of HSV-specific IgG antibody
Consider the mechanisms that confer antiviral immunity.Consider the mechanisms that confer antiviral immunity.• ICP34.5 → interferon-induced antiviral state• Antibodies
Host Host ““immunityimmunity”” and recurrentand recurrentviral diseaseviral disease
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AntibodiesAntibodies
Soluble mediators of RECOGNITION that tag proteins or cells Soluble mediators of RECOGNITION that tag proteins or cells expressing foreign proteins for destruction / clearance.expressing foreign proteins for destruction / clearance.
HSV-1 productivelyinfected cellnormal cell
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HSVHSV--1 glycoprotein E1 glycoprotein E--glycoprotein I:glycoprotein I:prevent immune system from prevent immune system from RECOGNIZING antibody tags bound to RECOGNIZING antibody tags bound to HSVHSV--1 infected cells.1 infected cells.
HSV-1 productivelyinfected cellnormal cell
gE-gI gE-gI gE-gI gE-gIgE-gI
AntibodiesAntibodies
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Paradox: people with recurrent herpes have Paradox: people with recurrent herpes have ““immunityimmunity”” to HSV.to HSV.• e.g. high levels of HSV-specific IgG antibody
Consider the mechanisms that confer antiviral immunity.Consider the mechanisms that confer antiviral immunity.• ICP34.5 → IFN--induced antiviral state• glycoprotein E-I dimer → IgG antibody
Host Host ““immunityimmunity”” and recurrentand recurrentviral diseaseviral disease
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Paradox: people with recurrent herpes have Paradox: people with recurrent herpes have ““immunityimmunity”” to HSV.to HSV.• e.g. high levels of HSV-specific IgG antibody
Consider the mechanisms that confer antiviral immunity.Consider the mechanisms that confer antiviral immunity.• ICP0 → IFN--induced antiviral state• glycoprotein E-I dimer → IgG antibody• complement cascade
Host Host ““immunityimmunity”” and recurrentand recurrentviral diseaseviral disease
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Paradox: people with recurrent herpes have Paradox: people with recurrent herpes have ““immunityimmunity”” to HSV.to HSV.• e.g. high levels of HSV-specific IgG antibody
Consider the mechanisms that confer antiviral immunity.Consider the mechanisms that confer antiviral immunity.• ICP34.5 → IFN--induced antiviral state• glycoprotein E-I dimer → IgG antibody• glycoprotein C → binds C3b split product
Host Host ““immunityimmunity”” and recurrentand recurrentviral diseaseviral disease
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Paradox: people with recurrent herpes have Paradox: people with recurrent herpes have ““immunityimmunity”” to HSV.to HSV.• e.g. high levels of HSV-specific IgG antibody
Consider the mechanisms that confer antiviral immunity.Consider the mechanisms that confer antiviral immunity.• ICP0 and ICP34.5 → IFN--induced antiviral state• glycoprotein E-I dimer → binds IgG antibody• glycoprotein C → binds C3b split product• CD8+ T cells
Host Host ““immunityimmunity”” and recurrentand recurrentviral diseaseviral disease
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CD8CD8++ T cellsT cells
ICP47bindsTAP
noMHCclass I
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Paradox: people with recurrent herpes have Paradox: people with recurrent herpes have ““immunityimmunity”” to HSV.to HSV.• e.g. high levels of HSV-specific IgG antibody
Recurrent herpes is not a paradox, when you consider that HSV Recurrent herpes is not a paradox, when you consider that HSV actively obstructs all three arms of antiviral immunity.actively obstructs all three arms of antiviral immunity.
ICP34.5 innate immunity
gC + gE-gI humoral immunity
ICP47 cell-mediated immunity
Host Host ““immunityimmunity”” and recurrentand recurrentviral diseaseviral disease
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3. Reactivationof latent virus
4. Disease. Spread of virus to new host.
HSV comes outHSV comes out……..over and over again.over and over again.
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Seroprevalence in United StatesSeroprevalence in United States• herpes simplex virus 1 (HSV-1) : ~200 million (66%)• herpes simplex virus 2 (HSV-2): ~ 50 million (16%)
Severity of diseaseSeverity of disease HSVHSV--11† HSVHSV--22†
80% 80%1% 2% (~3 million in U.S.)
Epidemiology:Epidemiology:seroprevalenceseroprevalence versus versus viral diseaseviral disease
unaware of infection:recurrent herpes infections ( >4/ yr):
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HerpesvirusHerpesvirus persistence: key featurespersistence: key features
1. Latent state = stable reservoir of virus1. Latent state = stable reservoir of virus--infected cells.infected cells.• ability to go into hiding explains success of human herpesviruses
– most of us are infected with 4 of the 8; HSV-1, VZV, CMV, and EBV
2. Immune evasion = promotes transmission after reactivation.2. Immune evasion = promotes transmission after reactivation.• reactivation = low-level / single cell herpesviral replication events• immune evasion proteins delay immune RECOGNITION long enough
that virions may be shed and transmitted to next person
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TakeTake--home messagehome message
Microbes that persist in humans typically employ one or more Microbes that persist in humans typically employ one or more strategies to do so:strategies to do so: intracellular invasion intracellular invasion immuneimmune--evasion strategiesevasion strategies antigenic driftantigenic drift antigenic phase variationantigenic phase variation latency, and/orlatency, and/or colonize sites difficult to ATTACKcolonize sites difficult to ATTACK
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
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TakeTake--home messagehome message
Microbes that persist in humans typically employ one or more Microbes that persist in humans typically employ one or more strategies to do so:strategies to do so:
Those microbes that persist establish infections that are:Those microbes that persist establish infections that are: chronicchronic episodicepisodic latent with infrequent recurrenceslatent with infrequent recurrences
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
HSV+
neuron
CD3+
T cells
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What is the difference betweenWhat is the difference betweentrue love and herpes?true love and herpes?
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Herpes is foreverHerpes is forever(because it evades the immune system)(because it evades the immune system)