Immune effector modules: T cells activate discrete cell ...
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Immune effector modules: T cells activate discrete cell populations
Facultative and obligate intracellular organisms
Extracellular bacteria and fungi
Helminths and biting insects
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Viruses
Obligate intracellular organisms
Bypass barriers - insects vectors, animal bites, trauma, ulcerations
Exploit mucosal M cells
Co-evolution with receptors drives narrow host specificity
Viremia needed to seed organs required for transmission - kidneys (urine), skin, salivary glands (secretions), digestive tract (feces)
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Viruses
Flavors: ssRNA, dsRNA, DNA
Encoded within virally encoded capsid proteins
Enveloped or not
Classes: Lytic (cytopathic) (polio, flu) versus nonlytic (hepatitis B, LCMV)
Latency: special property of some lytic viruses
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Viral Life Cycle
1. Breach barriers
2. Disseminate via lymph nodes
3. Viremia to seed target organs
4. Shedding to new hosts
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Immune cells make good targets…
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Key players: interferons and its transcription factors
Type 1 interferons: Interferon-/Interferon- (14)
Type 2 interferon: Interferon-
Hybrid interferons: Interferon- (3) {IL-28A, IL-28B,
IL-29}
Auto-enforcing loop: IRF-3 > IFN > Stat1/2 + IRF-9 > IRF7 > IFN’s
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Amplification by Type 1 interferons
IRF-3
IRF-7
IFNAR
Stat 1,2,4
IRF-3IRF-7
IFN-
IFN-
IFN
IFN-
IFN
IFN-
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Amplification by Type 1 interferons
IRF-3
IRF-7
IFNAR
Stat 1,2,4
IRF-3IRF-7
RNAseL
Anti-Viral State
PKR
IFN
IFN-
IFN
IFNa
IFN
IFN-
IFN-
Human Stat1-deficiency: lethal viral infection
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IRF-3
PIRF-3
CBP/p300
NF-B
IRS-7
P
IRS-7
PKR OAS
ISG15ISG54IP-10
iNOS
IRF-E
GAS
PRD NF-B
PRD-LE
ISRE ISRE
Tyk2JAK1
Stat2Stat1
Stat1
Stat1
Stat 2
Stat1
IRF-9
P
P
P
P
Auto-amplification in the Type 1 interferon response
IRF-1
IFN-
IFN-
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TRIF(TICAM-1)/TRAM: Anti-viral TLR Adapters
MyD88 MyD88Mal/
TIRAPTRIF
MyD88
NF-B JNK NF-B JNK AP-1 IRF-3
Interferons, RANTESIL-1, TNF, IL-6, IL-8, antimicrobial peptides
TLR 1, 2, 4, 6 TLR 3, 7, 9 TLR 4TLR 5, 7, 9
TRAM
MyD88
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Defects in UNC-93B abolish TLR3, 7, -8, -9 signaling against viruses.
Abolishes cross-priming.
Human mutations in UNC-93B and dominant-negative TLR3 associated with HSV encephalitis.
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Cytosolic dsRNA detectors - RNA helicases
Cell 122:645-7, 2005
dsRNA (5’-triP-ssRNA for flu) binds cytosolic RIG-I and/or Mda5, exposes CARD domain, binds MAVS/Cardif/IPS-1, activates kinase complexes leading to phosphorylation of IRF-3/IRF-7 and IB. MAVS targeted by HCV.
Seth RB et al., Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-B and IRF3. Cell 122:669-82, 2005.Kawai T et al., IPS-1, an adaptor triggering RIG-1 and Mda5-mediated type 1 interferon induction. Nature Immunol 6:981-8, 2005.Meylan E et al., Cardif is an adaptor protein in the RIG-1 antiviral pathway and is targeted by hepatitis C virus. Nature 437:1167-72.
NOTE: Dispensable in plasmacytoid DCs
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Cytosolic RNA/DNA recognition pathways
DNA::DAI
(DNA-dependent activator of IFN-regulatory factors)
TBK1::IRF3
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IFN-
Induced Synthesis
2-5(A) Synthetase
ATP 2-5(A)
dsRNA
RNaseL RnaseL
(inactive) (active)
AUG AAAAA
mRNA Degraded mRNA
Inhibition of Protein Synthesis
PKR, phosphorylated
(active)
dsRNA-dependent protein kinase, PKR
(inactive)
dsRNA+ ATP
eIF2 , eIF2 Phosphorylated
ATP
eIF2-GDP, phosphorylated
eIF2-GTP, Phosphorylated
GEF
IFNAR
KO with increased viral susceptibility
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IFN activates anti-viral cellular miRNAs
Activation by IFN is time- and dose-dependent…
Expression of IFN-inducible miRNAs inhibits viral replication…
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Intriguing Cell Biology - Utilization of MVBs by Viruses
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Plasmacytoid DC (pre-DC2)
Produce early IFN/ after incubation of PBMC with virus (independent of RNA helicase
pathway)
Prevalence: 0.1-0.3% PBMC
Phenotype: CD4+, CD11c-, IL3R+, CD62L+
Biology: Migrate to HEV and protect transiting naïve
lymphocytes
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TLRs activate the virus recognition response early in pDCs
Plasmacytoid DC
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pDCs use components of autophagy pathway for TLR7 ssRNA detection
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Anti-viral Cytokines
Type 1 Interferons Anti-viral
NK cytotoxicity
T cell survival, DC maturation
IL-6 Systemic response
Cell recruitment
IL-12 Type 1 immunity
NK cell activation
IL-15 CTL and NK growth,
survival
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NK Cells and Anti-Viral Host Immunity
Mechanism
IFN-/ Cytotoxicity, Anti-viral
IL-12 Cytokines
(IFN-, TNF, LT, TRAIL, TWEAK)
Antibody ADCC
Evidence
NK-deficient human (severe 1o HSV, VZV, CMV infections)
Mouse MCMV - requires Ly49H
Duncan’s syndrome (X-linked lymphoproliferative disease)
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NK Cells Target Herpesviruses
Genetic Evidence
NK-deficient girl with severe primary herpesvirus infections
Murine klra8 (Ly-49H) deficiency
Unable to clear murine CMV
Human SAP (SLAM-assoc. prot.) deficiency
Loss of functional 2B4 (CD244) NK activating receptor with fatal EBV infections
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Direct recognition of murine CMV-encoded proteins by NK receptors
Suggests NK receptor diversity may be driven by herpesviruses…
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Direct recognition of murine CMV-encoded proteins by NK receptors
Are NK cells simply antiviral T cells?
NK cell
MCMV-infected cells
Ly49P
H-2Dk/MCMV
Desrosiers M-P et al. Nature Genetics 37:593-99.
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SAP
2B4 ?
Duncan’s Syndrome
EBV-infected cell
NK Cell
SAP
2B4 ?
EBV-infected cell
Early death due to primary progressive EBV infection. Mutation in SAP (SLAM-associated protein), an X-linked adapter protein, or rarely in XIAP
(inhibitor of apoptosis).
Mutant SAP transduces negative instead of positive signals from engaged 2B4 receptors.
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NK Cells Localize Anti-Viral Immunity
Liver
MCMV
IFN-
IFN-
MIP-1
Mig
CD4 CD4
CD4
NK NK
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Major Viral Effectors: CD8+ CTL
% IFN
( )
Time (Hrs)
0 5 10
Infectious Virions 3-10 Hrs.
cytolysis
cytolysis
Virus peptide Remove peptide Replace peptide
Dogma:
Non-cytopath. virus: CTL
Cytopath. Virus: Ab
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CD8 Response to LCMV
Clonal Apoptosis Memory Burst Size
Burst (IFN) (perforin, IL-15, antigen)
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All Tetramer-Positive CTL Have Effector Function
No Bystander
Peptide-specific Activation
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Antibodies: Prevent Re-infection
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LCMV
Can’t maintain CD8’s without CD4 Help
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Viruses attack common cellular defense pathways
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Viruses block activation
of cellular apoptosis
pathways
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CMV attacks MHC class I pathways at multiple levels
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Large DNA viruses
(herpesviruses, poxviruses)
encode additional proteins to
mitigate host defense and
sustain infectivity
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Induction of MIC-A at foci of CMV in infected lungs
MIC-A
CMV
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cytolyticresponse
8CD (-)
-A restricted
Target
+ -orMICA
T cell
C R
CMVpeptide
NKG2D enhances cytolytic activity after TCR engagement
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IFN-
IL-2 IL-4
cytokinesecretion
8CD (-)
-A restricted
Stim
+ -orMICA
T cell
CMVpeptide
TNF
Decreasing Peptide
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Joe Bob Briggs:
“…three dead bodies, two dead birds, multiple seagull divebomb attacks, playground crow attack, bird migration, bird flocking, exploding gas station, two car crashes, crow kung-fu, kamikaze seagull…”
4 Stars. A classic. Check it
out!
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Influenza - Obligate Virology
Orthomyxovirus Negative-sense ssRNA, eight-segmented genome
Types A (avian, humans, responsible for pandemics), B (avian, humans, seals), C (avian, pigs, humans rare)
10 proteins:
PB1(-F2), PB2, PA Heterotrimeric polymerase (?mitochondrial apoptosis)
HA Homotrimeric binding and fusion element
NA* Homotetrameric enzymatic release factor
NP Nucleoprotein (nucleocapsid packaging)
M1 Transport of viral RNPs
M2^ Homotetrameric cation channel pore
NS1 Binds RNA; interdicts host translational machinery and defense (PKR,
cytokines)
NS2 Nuclear export of viral RNPs
* Neuraminidase inhibitor target
^Amantadine target
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Relevant Life Cycle Issues
1. An intestinal infection of wild waterfowl.
2. Crosses to mammals through close contact.
3. Multiple ‘crosses’ enhance capacity to establish
mutants and reassortment variants
adapted to mammalian hosts.
4. HA species specificity: sialic acid -2,3 galactose linkage (avian intestine)
sialic acid -2,6 galactose linkage (human trachea)
both (pig trachea)
5. NA compatibility: human viruses gain -2,6 activity
stalk length (longer NA enhances activity in humans)
6. HA, NA Adaptations HA glycosylation; HA1/HA2 fusion domain (expanded basic amino acid repeat in highly pathogenic chicken H5/H7/H9 flu -HPAI- enhances spectrum of proteases that can activate HA fusion event; may explain pathogenicity of co-infection with bacteria)
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Mutation and reassortment drive influenza A epidemics and pandemics
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Live chickens and ducks in same cages
Asian Live-Animal Markets -
The Great Zoonotic Mixer
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Influenza Pandemics
Year Common Name Subtype OriginDeaths
1889 - H2N2 ?Europe 6 million
1898 - H3N2 ?Europe 0.5 million
1918 Spanish Flu H1N1* ?Eurasia 40 million
1957 Asian Flu H2N2* China 4 million
1968^ Hong Kong Flu H3N2* China 2 million
1977^ Russian Flu H1N1+ China/Russia ?* Contained elements from avian viruses
+ Laboratory-derived from frozen stock (persons pre-’50s immune)
^Antigenic variants continue to co-circulate
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Relevant Immunology
Innate immunity: type 1 IFNs, TNF-, Mx proteins
HA antibodies: Neutralize infectivity, protective
NA antibodies: Restrict viral spread
Cytotoxic CD8 T cells: M2, PB2, HA, NP specificity common M2 specificity almost universal
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CD8 TCR / chains
V17/V10.2
HLA-A2 (A*0201)
Influenza A Matrix Protein amino acids 58-66
Stewart-Jones et al. Nature Immunol 7:657, 2003
The Most Common Human TCR in the World
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Treanor, NEJM 350:218, 2004
HA1 A/Panama/2007/99 HA1 A/Fujian/411/2002
Antigenic Drift - 2003/04
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Influenza NS1 protein sequesters
viral ss RNA to block cellular anti-
viral defense
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Why do they die?…
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Verified H5N1 influenza through October 2006
Human deaths/cases = 152/256 (59%)
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HIV
Worldwide: 42 million infected
29 million dead
14,000 new infections/day
2/3 infected persons in Africa
U.S.: ~1 million infected including 400,000 dead
(appeared 1983)
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Worldwide Estimates of Numbers of HIV-Infected Persons
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HIV Origins - Primate Lentiviruses
SIVcpz - West equatorial Africa = M group
Cameroon = N group
Gabon = O group
HIV-2 = SIVsm (sooty mangabey)
Infection/Disease in areas of active bushmeat trade.
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HIV Origins
SIVcpz - Asymptomatic infection of chimpanzees (up to 1% in areas of west Central Africa)
HIV-1: M group consists of 11 clades
Last common ancestor entered human population around 1930 (+ 20 yrs)
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Prevalent HIV Clades
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HIV is a primate lentivirus
Lentiviruses can infect nondividing cells
Replication driven from long terminal repeats
Structural genes - gag, pol, env
Regulatory genes - tat, rev
Accessory genes - vif, vpr, vpu, nef
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HIV life-cycle
TRIM5
APOBEC
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HIV vif sequesters
APOBEC enzymes from
the budding virions
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HIV Pathogenesis
M
DC-SIGN
1. Entry at sites of M cells or trauma (STDs)
2. Transit to LN via C-type lectins* on dendritic cells
3. Peak CD4+ T cell infection days 4-7
4. Viremia peaks day 14
5. All lymphoid tissues infected by day 23
*DC-SIGN, MR, Langerin
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HIV infection occurs predominantly at mucosa
Dendritic cells mediate transit of virus to regional lymph nodes via CLRs
Massive loss of mucosa-associated lymphocytes of the small intestine precedes systemic CD4 T cell loss
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HIV Receptors
CD4
R5
X4
1o Infection: M-tropic, CCR5
Turnover 1010 virions/day
Progressive CD4 T cell destruction
CXCR4
T-tropic
Syncytium-forming
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Natural History of Untreated HIV Infection
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HIV Resistance
1. CCR532 - slow progression if infected
20% W. European Caucasians Heterozygous
1% Homozygous
2. HLA class I homozygosity - rapid progression
3. Rare HLA class I alleles - slow progression (suggests virus near mutational threshold)
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SIV DNA Vaccine (gag/env + IL-2)
Rhesus
Lethal SIV Challenge
Day 0 Day 14 Day 70
CTL V 0.2-0.4% 18-40%
C 0 1-4%
Neutralizing Ab V 0 Equivalent
C 0 Equivalent Depressed with CD4
Virus V 106-107 <103
C 107-108 105-106
Outcome V All alive with normal CD4s
C 50% die, all with loss of CD4s
140 days
Barouch et al., Science 290:486, 2000
Caveat: CTL escape mutants
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Why no HIV vaccine?
1. Escape variants/altered peptide ligands - virus operates near mutational threshold
2. Neutralizing antibodies low-affinity, arise late (conformationally hidden, glycan shielding, mutational escape, evolutionary escape from ‘natural antibodies’, polyclonal B cell activation may impede)
3. Loss of CD4 help required for CD8, antibody responses
4. Immune exhaustion with PD-1 expression on CD4 and CD8 anti-HIV T cells