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Immunology of Immunology of ChikungunyaChikungunya and and implications for disease implications for disease
interventionsinterventions
Lisa F.P. Ng, PhDLisa F.P. Ng, PhD
Principal Investigator, Singapore Immunology NetworkPrincipal Investigator, Singapore Immunology Network
Adjunct Assistant Professor, National University of SingaporeAdjunct Assistant Professor, National University of Singapore
Challenges and insights towards understandingChallenges and insights towards understandingthe reemergence of the reemergence of ChikungunyaChikungunya
20 Mar 2009, York Hotel, Singapore20 Mar 2009, York Hotel, Singapore
Expand and strengthen the immunology Expand and strengthen the immunology expertise in Singaporeexpertise in Singapore
www.sign.a-star.edu.sg
ChikungunyaChikungunya FeverFever-1st isolated in a 1953 outbreak in Tanzania- Mosquito-transmitted: Aedes- Re-emerged in 2005 in the Indian Ocean Islands and has since spread to SE Asia and other parts of the world
Arthralgia
- Acute infection lasts 1-10 days: sudden onset of high fever, rash, painful arthralgia > incapacitating joint disease
- Pathogen: CHIKV, an alphavirus of the Togaviridae family- Positive-strand RNA virus of 11.8 kb
CHIKV
What are the current needs?What are the current needs?
Build up a strong platform in CHIKV clinical immunology research for better translation into medical applications
How?How?
- Identification of targets, immune mechanisms, and correlates of protection
FieldField BenchBench BedBed
Global Research InitiativesGlobal Research Initiatives
To gather fundamental knowledge on the immune To gather fundamental knowledge on the immune responses mounted against CHIKV with a view to exploit responses mounted against CHIKV with a view to exploit this to develop new immunethis to develop new immune--based preventive and based preventive and treatment strategiestreatment strategies
1. Candidate biomarkers from CHIKV-infected patients?
2. Innate immune responses against CHIKV-infection?
3. B- and T-cell responses?
Important QuestionsImportant Questions
Identify BiomarkersIdentify Biomarkers
-- Diagnostics for improved detectionDiagnostics for improved detection
-- Pathology to devise appropriate treatmentsPathology to devise appropriate treatments
-- Identify novel targetsIdentify novel targets
-- Development of novel assays for drug screenDevelopment of novel assays for drug screen
11stst Singaporean Outbreak: Jan Singaporean Outbreak: Jan –– Mar 08Mar 08
Demographic and epidemiologic data on 10 patients with PCR-confirmed chikungunya infection.
Patient No. Age (years) Gender NationalityDuration of fever (days) Illness severitya Pre-morbid condition Clinical Outcomeb
1 45 M Bangladeshi 2 Not Severe None Persistent arthralgia2 32 M Bangladeshi 4 Not Severe None Complete recovery3 33 M Indian 5 Not Severe None Complete recovery4 45 M Indian 5 Not Severe None Complete recovery5 28 M Malaysian 3 Not Severe None Complete recovery
6 65 M Singapore resident 10 SevereLiver cirrhosis, hypertension, atrial fibrillation, anaemia Complete recovery
7 34 M Indian 4 Severe None Complete recovery8 39 M Indian 6 Severe None Persistent arthralgia9 37 M Indian 9 Severe None Complete recovery10 22 M Malaysian 4 Severe None Developed myalgiaa Severity was defined as having a temperature >38.5degC or pulse rate >100/min or platelet count <100x10^9/Lb Clinical outcome at 2 weeks post-illness onset
Clinical features
Sign/Symptom No. (%) of patientsFever 10 (100)Arthralgia 9 (90)Rash 5 (50)Conjunctivitis 4 (40)Gastrointestinal symptom+ 3 (30)
Headache 3 (30)Eye pain 2 (20)Back pain 2 (20)Mylagia 1 (10)Arthritis 1 (10)+ Nausea, vomiting, diarrhoea, or abdominal pain
Patients had fever, rash and arthralgia
None had neurologic involvement
CH
IKV Positives
Non-severe
Severe
Healthycontrols
Blood Mediators during Acute CHIKV InfectionBlood Mediators during Acute CHIKV Infection
IL-6
Controls CHIK +ve0
50
100
150p = 0.0007
pg /
ml
IL-8
Controls CHIK +ve0
200
400
600p = < 0.0001
pg /
ml
IL-10
Controls CHIK +ve0
20
40
60p = 0.0297
pg /
ml
IL-2R
Controls CHIK +ve0
500
1000
1500p = < 0.0001
pg /
ml
Differences in Cytokines LevelsDifferences in Cytokines Levels
IL-5
Controls CHIK +ve0
10
20
30
40
50p = 0.0159
pg /
ml
IFN-a
Controls CHIK +ve0
100
200
300p = 0.0010
pg /
ml
IL-7
Controls CHIK +ve0
100
200
300p = < 0.0001
pg /
ml
IL-15
Controls CHIK +ve0
100
200
300p = 0.0016
pg /
ml
Differences in Cytokines LevelsDifferences in Cytokines Levels
IP-10
Controls CHIK +ve0
2000
4000
6000p = < 0.0001
pg /
ml
MIG
Controls CHIK +ve0
200
400
600
800
1000p = 0.0006
pg /
ml
Eotaxin
Controls CHIK +ve0
50
100
150
200
250p = 0.0030
pg /
ml
Differences in Differences in ChemokinesChemokines LevelsLevels
EGF
Controls CHIK +ve0
100
200
300p = < 0.0001
pg /
ml
HGF
Controls CHIK +ve0
200
400
600
800
1000p = 0.0030
pg /
ml
FGF-b
Controls CHIK +ve0
50
100
150
200p = < 0.0001
pg /
ml
VEGF
Controls CHIK +ve0
100
200
300p = < 0.0001
Differences in Growth Factors LevelsDifferences in Growth Factors Levels
High levels of pro-inflammatory cytokines
How do they contribute to immuno-pathology?
IL-1B
Controls Non Severe Severe0
100
200
300
400p = 0.0026
pg /
ml
IL-6
Controls Non Severe Severe0
50
100
150p = 0.0009
pg /
ml
RANTES
Controls Non Severe Severe0
5000
10000
15000
20000 p = 0.01
pg /
ml
Disease Severity?Disease Severity?
Clinical definition of Severity: Fever > 38.5 C;Maximum pulse rate > 100 beats/min;Platelet count < 100 x 109/L
Uninfected ChikungunyaInfection
SevereChikungunya
IL-2RIL-5IL-6IL-7IL-10IL-15IFN-aIP-10MIGFGF-basicVEGF
IL-8EotaxinHGFEGF
IL-1bIL-6
RANTES
11stst Singapore CHIKF Outbreak ProfileSingapore CHIKF Outbreak Profile
PLoS ONE 4: issue 1, e4261, 21 Jan 2009
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