antibodies determine severity in dengue infection halstead.pdf · antibodies determine virulence in...
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ANTIBODIES DETERMINE VIRULENCE IN DENGUE
Scott B HALSTEAD, M.D.DIRECTOR, ResearchPediatric Dengue Vaccine InitiativeIVI, Seoul, Korea
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Global Spread of Dengue
Countries with active dengue + Aedes aegypti50-100 million infections/year
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Pathogenicity vsVirulence
Virulence, a quantitative term:Severe disease/total infections
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Dengue hemorrhagic fever/dengue shock
syndrome has occurred in some (but not all) dengue
epidemics since the 1950s.
WHY?
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Intuitive answer –
Differences in virus virulence
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IN 1950s HAMMON DISCOVERED NEW, “VIRULENT” DENGUE
VIRUSES THOUGHT TO BE HF-ASSOCIATED
PHILIPPINES DENV 3, 4: Hammon WMcD et al Science 131:1102-3,
1960THAILAND DENV 5, 6:
Hammon WMcD et al AJTMH 13:629-41, 1964
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Virulence hypothesis is very much alive
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WHAT FACTORS CONTROL
SEVERITY OF DENGUE?
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INTRINSIC HOST FACTORS(innate immunity)
• Humans: susceptibility resistance.– Race1: Caucasian/Asian African– HLA2: HLA-A*0207 HLA-A*0203
HLA-B*52 HLA-B*51– Age3: Children Adults– Nutrition4: Well nourished Malnourished
1. Guzman MG et al. AJTMH 442:179-184, 1990.2. Stephens HA et al. Tissue Antigens 60:309-318, 2002.3. Guzman MF et al. Int J Infect Dis 6:118-124, 2002.4. Thisyakorn U et al. CID 16:295-297, 1993
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EXTRINSIC FACTORSVIRUS
“VIRULENT” “NON-VIRULENT”
DEN 1, 3, 4 DEN 2 (American)1
DEN 2 (Asian)
1. Kochel T et al. The Lancet 360:1474-1479, 2002.
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CRITICAL ROLE OF ANTIBODIES
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DHF BANGKOK CHILDRENS HOSPITAL
0
100
200
300
400
500
600
700
<1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16AGE (YEARS)
1973-791980-891990-99
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DSS in a 6 month-old infant with primary dengue infection. Vietnam
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Infant DHF/DSS - 5% of all casesCHILDREN'S HOSPITAL, BANGKOK, THAILAND
0
5
10
15
20
25
30
35
40
0-2 2-4 4-6 6-8 8-10 10-12AGE (months)
1987
1990
1997
1998
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Antibody mediatedinfection of macrophages (ADE)
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In vitroIn vitro ADE modelADE model
% Infection without serum
Peak enhancement titer = titer at maximal% infection for the serum tested
Ratio of % infection at PENT/ ControlPowerPower
ControlControl
PENTPENT
Modified from Kliks et al, Am. J.Trop. Med Hyg 1989
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WHAT ABOUT VIRAL VIRULENCE?
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NON-VIRULENT DENGUE VIRUS: IQUITOS OUTBREAK
• School children cohorts followed from 1990 until now.
• DEN 1 transmitted in 1990 - 1994.• DEN 2 transmitted from 1995.• Prevalence of neutralizing antibodies
measured in 1993, 1994 and 1995 cohorts.
• In 1995, secondary DEN 2 infection rate estimated at 60.5%
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NO DHF with secondary DEN 2 (American genotype) infections
• Total population, 5 - 14 yrs-old = 81,479.• Total 2ndary DEN 2 infections = 49,266.• Expected hospitalized DHF = 887-
10247.• Expected deaths = 18 - 204.• DHF cases observed = 0
Watts DM et al Lancet 354:1431-4, 1999
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BUT, DENV 2 INFECTIONS ARE MODULATED BY DENV 1ANTIBODIES
34 DEN 1- IMMUNE HUMAN SERA NEUTRALIZE AMERICAN GENOTYPE DEN 2 VIRUSES
DEN-2 genotypes Virus DEN-1 AMER SE
ASIASE
ASIAStrain Venez
9842 IQT 2124
Venez 8041
Thai 16681
GMT 875 262 32 29 Kochel T, et al Lancet 360:310, 2002
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ONE-WAY CROSS:
17 DENGUE 2-IMMUNE SERA DO NOT NEUTRALIZE DENGUE-1 VIRUSES
DEN 1 viruses DEN 2 viruses
Geno- type
SE Asia Venez SE Asia Peru
Strain 16007 OBS 9842
16681 IQT 2913
GMT 20 27 635 417
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PLAUSIBLE HYPOTHESIS:
HETEROTYPIC DENGUE ANTIBODIES EITHER PREVENT OR
ENHANCE SECOND DENGUE INFECTIONS
“NON-VIRULENT” “VIRULENT”
Neutralizing Non-Neutralizing
ACTIVELY ACQUIRED (TWO INFECTIONS)or PASSIVELY TRANSFERRED IN UTERO1
1. Kliks S et al. AJTMH 40:444-451, 1989.
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Another example of viral “virulence”
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CUBAN DHF, 1997accelerated “virulence”
MAY JUNE JULY DHF/DSS 37 132 29 DEATHS 1 6 5 CONF DF 705 1785 244 DHF/DF 5.2 7.4 11.9 P<0.01 DEAD/T 0.14 0.33 2.04 P<0.01 CFR 2.7 4.5 17.2 P<0.05
Guzman MG et al, Lancet 355: 1902-3, 2000
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SHIFT FROM THREONINE TO SERINE AT NS1 aa 186
• All patients had secondary dengue infections.
• Based on 5 complete and 19 partial genome sequences.
• Reference strain: DENV 2 Jam 1407/83
Rodriguez-Roche R et al J Gen Virol (in press)
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- Increased severity only occurs during secondary dengue infections.
- That is, severity is antibody-dependent
- Perhaps, due to increased “fitness” for viral replication?
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INTRINSIC ADE
• Infectious immune complexes (IgG + virus) directly regulate viral infections in macrophages.
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Th1/Th2 responses in macrophages
• Ag presentation to M Φ ► IL-12 causes T cells to produce IFN γ (Th1 response)
• Ag + Ab presentation to M Φ ► IL-10 causes T cells to produce IL- 4 (Th2 response).
Anderson et al J Immunol 168:3957, 2002
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Suppression of antiviral transcription factors (STAT-1 and NF-KB complexes) by ADE
infection of macrophages by Ross River virus.Mahalingham S & Lidbury BA. PNAS 2002 99: 1392
• Polyclonal mouse anti-RRV used at 10-3• ADE infectivity of mouse macrophage cell line
increased 25-fold by 12 hours.• Nearly 50% of cells infected by viral RNA.• RRV plus simultaneous addition of irrelevant immune
complex did not increase infectivity. • Ablated or suppressed: NO production, IFN-1, IP-10 +
three IFN factors. IL-10 production increased.• Transcription factors shut down in bystander cells.• IL-10 thought to mediate this latter effect.
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Dengue virus ADE upregulates the production of anti-inflammatory cytokines but suppresses anti-dengue free radical and pro-inflammatory
cytokine production in THP-1 cells.Charoensrisuthigul S et al J Gen Virol 2007 88:265
• Human polyclonal antibodies from 2ndary DENV 3 DHF case incubated at 1:100,000 with 16681.
• DENV 2 infection of individual THP-1 cells increased by 10-fold at 24 hours.
• Suppression of STAT-1 phosphorylation and IRF-1 gene expression may be mechanism by which ADE infection down-regulates innate immunity.
• ADE facilitated production of IL-10 and decreased NO production.
• Transient suppression of TNF α.
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Increased number of cells and intrinsic viral Increased number of cells and intrinsic viral production with ADE in Mature DCproduction with ADE in Mature DC
Serum dilution factor
% D
V in fec ted ce lls
2.5x
>2-log
Marovich, M. personal communication
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IL-10 suppresses secondary cytokine responses via SOCS-3 activity
Ubol S et al. JID 2008
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Suppression of IFN synthesis in DENV-ADE infected THP-1
Ubol S et al. JID 2008
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Global PBMC gene expressionsecondary DF vs secondary DHF
1.DHF (enhanced infection) has stronger influence onthe gene expression profile than DF (partiallyprotected secondary infection).
2. 17 genes in immune response category are more strongly upregulated in DF PBMCsthan in DHF PBMCs. 40% of them are genes of the interferon system.
Ubol S et al. JID 2008
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Conclusion1. Dengue enhancing antibodies not only
facilitate entry into target cells but also modify post-entry events.
2. An outcome is the suppression of innate and adaptive intracellular anti-viral mechanisms.
3. These are mediated through IL-10 activity and via the mechanism upstream of MDA-5 and RIG-I activation.
4. Immune complexes directly regulate dengue virus infection productivity.
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DEN 3VIREMIA
●--● DSS▲- ▲DHF□--□ DF
LIBRATY DH et al JID 185:1213, 2002
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Sequential and cumulative viral distribution in tissuesduring dengue infection in 31 rhesus monkeys.
PEAK CELLULARINFECTION OCCURS AT OR AFTER DEFERVESCENCE
Marchette et alJID 1973 128:23
Halstead SBIn Schlesinger WTogavirusesAcademic Press1980: 107-173
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T4 EC
plasmaleakage
activ
atio
n lysis
lysisT8
T4
Mo
MoT8
IFNγIL-2TNFαTNFβ
TNFα
TNFα
complement
C3aC5a
+
+
lysis
EC
MoEC
Ab
DV
MHC I
MHC II
DV peptides
DV receptor
FcγR
monocyte
endothelial cell
T cell receptor
After Rothman, 2001
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TAKE HOME MESSAGE
• Intrinsic factors place many humans at reduced risk to severe dengue disease.
• In at risk humans antibodies (passive or actively acquired) regulate the severity (virulence) of dengue infections:– Homologous antibodies provide complete
protection.– Heterotypic neutralizing antibodies down-regulate
severe disease, usually with inapparent outcome.– Enhancing antibodies suppress innate antiviral
defenses leasing to increased infected cell mass and increased disease severity.
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VIRULENCE = ANTIBODIES
THE GREATER THE NUMBER OF DENGUE-INFECTED CELLS,
THE GREATER THE T- CELL RESPONSE, THE GREATER THE CYTOKINE
STORM, THE MORE SEVERE THE DISEASE
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FOR THE LEISHMANIACS
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Virulence = visceral leishmaniasis
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Leishmania-macrophage interactions….
L. amazonensis amastigotes have host IgG on their surface
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LOG FLOURESCENCE
Cou
nt
Control2oAb
1oAb+2oAb
Lesion-derived amastigotesare coated with host Ig
Axenic Lesion-derived
Mosser, D personal communication
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IgG Reconstitution of JH Mice and the Effect of α-IL10R
Days post-infection0 5 10 15 20 25 30
Lesi
on s
ize
(mm
)
0
1
2
3
4
5
Para
site
Bur
dens
107
108
109
1010
JH JH + IgG JH + IgG + α-IL-10R
JH IgG
IgG + α-IL-10R
JH
JH + IgG
JH + IgG + α-IL10R
Mosser , D. pers comm., Miles SA et al JEM 201:747-54, 2005
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0 10 20 30 40 50 60
0
2
4
6
foot
pad
swel
ling
(mm
)
Days post-infection
BALB/cIL-10 -/-(BALB/c)C57BL/6
IL-10-/- (BALB/c) mice controllesion development during L. major infection
*
* euthanized
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IL-1
0 (p
g/m
l)
0
500
1000
1500
2000
2500
3000LPS
LPS + E-IgG
LPS (ng/ml)
0 0.25 0.5 1 2 5 10 100 1000 0 0.25 0.5 1 2 5 10 100 1000
IL-10 induction following FcγR Ligation