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Genetic Variations of CD55 and Pathogenesis of Pandemic A(H1N1)2009 Influenza

Genetic Variations of CD55 and Pathogenesis of Pandemic A(H1N1)2009 Influenza. ZHOU JIE, Jane August 19, 2014. Introduction. Pandemic A(H1N1)2009 influenza First report on spring 2009 by US CDC. WHO signaled the 1 st influence pandemic in this centaury.

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Genetic Variations of CD55 and Pathogenesis of Pandemic A(H1N1)2009 Influenza

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  1. Genetic Variations of CD55 and Pathogenesis of Pandemic A(H1N1)2009 Influenza ZHOU JIE, Jane August 19, 2014

  2. Introduction Pandemic A(H1N1)2009 influenza • First report on spring 2009 by US CDC. WHO signaled the 1st influence pandemic in this centaury. • A(H1N1)pdm09 virus derived from a reassortment of avian H1N1, classical swine H1N1 and human seasonal H3N2 viruses. • people under 65 years of age infected preferentially. • high rate of severe infection in younger patients. As of Oct 2010, at least 299 severe infection and 83 death in HK. • 1/3 of the severe cases don’t have predisposing comorbidities, including chronic heart or pulmonary diseases and metabolic disorders. • WHO identified the studies of role of genetic factors on susceptibility to severe influenza as a priority. Aim: Host genetic variation may affect the disease severity of A(H1N1)pdm09 infection.

  3. Genome-wide association study (GWAS)in a pilot cohort Selected genetic association result for CD55 SNPs in GWAS.

  4. CD55 CD55, a complement regulatory protein.

  5. Linkage disequilibrium (LD) pattern of CD55 variants rs2564978 rs4844592 rs6691942 rs6700168 rs10864231 Rs1507758 Exon 1 2 3 4 5 6 78 9 10 11 12 13 14

  6. Genotypic distribution and logistic regression analysis of rs2564978 in study participants.

  7. 0.4 0.3 0.2 0.1 0 Allele-specific effect of rs2564978 on CD55 expression in peripheral blood monocytes P=0.0003 5 4 3 p=0.003 p=0.038 Log10 (MEFL) Relative CD55 mRNA levels T/T C/T C/C Genotype CC CT TT Genotype

  8. expression Quantitative Trait Loci (eQTL) • eQTL, expression-related variations, mapped by paralleled genome-wide analysis of gene expression and genetic variations in LCLs and various human tissues, populations and in response to different stimuli. • Interpret association signal, prioritize causal gene(s), provide immediate insight about disease pathogenesis… http://eqtl.uchicago.edu/Home.html

  9. Luc CI -C---Ins--- p=0.0006 TD -T---Del--- p=0.0002 TI -T---Ins--- CD -C---Del--- 0 10 20 30 40 Relative Luc Activity Luciferase assay of CD55 promoter variants rs3841376 indel rs2564978 C>T

  10. PBS iso-ctrl α-CD55 Treatment Complement dependent cytolysis (CDC) assays in respiratory epithelial cell lines BEAS-2B A549 p=0.0001 p<0.00001 p=0.0004 p=0.0008 Cell lysis (%) Cell lysis (%) PBS iso-ctrl α-CD55 Treatment

  11. B mock H1N1pdm mock H1N1pdm 50 40 30 CD55 levels (pg/ml) 20 10 0 12hpi 24hpi 32hpi p=0.0193 NS 0.06 0.05 0.04 0.03 0.02 0.01 0.00 Influenza infection enhances CD55 expression A Normalized CD55 mRNA levels 7hpi 24hpi

  12. Summary • Genetic association study: rs2564978 T/T genotype associated with H1N1pdm severe infection. • CD55 expression assay: rs2564978 T/T genotype carriers showing the lower expression in human peripheral blood monocytes. • Luciferase assay: T/T genotype and rs3841376 del displaying lower transcriptional activity. The indel dictating CD55 transcriptional regulation. • CD55 protecting A549 and BEAS-2B cells from complement attack. • Upon flu infection, CD55 (membrane and soluble form) was up-regulated. Journal of infectious Diseases. ZHOU. J 2012

  13. 120 100 80 CD55KO 60 Balb/c 40 20 0 On-going Study To define the role of CD55 in influenza virus-infected CD55-KO mice. Survival Rate (%) 0 6 7 8 9 10 11 12 13 14 15 16 17 Day(s) post inoculation

  14. Acknowledgement • Professor Kwok-Yung Yuen 袁国勇教授 • My team: CHU Hin 朱轩 CHENG Zhongshan (Sam) 程中山 LI Cun 李存 WONG Ho Yin (Bosco) • Health and Medical Research Fund (HMRF), HKSAR & Providence Foundation Limited in memory of the late Dr Lui Hac Minh

  15. jiezhou@hku.hk

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