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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

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

ZHOU JIE, Jane

August 19, 2014

introduction
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.

genome wide association study gwas in a pilot cohort
Genome-wide association study (GWAS)in a pilot cohort

Selected genetic association result for CD55 SNPs in GWAS.

linkage disequilibrium ld pattern of cd55 variants
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

allele specific effect of rs2564978 on cd55 expression in peripheral blood monocytes

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

expression quantitative trait loci eqtl
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

luciferase assay of cd55 promoter variants

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

complement dependent cytolysis cdc assays in respiratory epithelial cell lines

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

influenza infection enhances cd55 expression

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

summary
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

on going study

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

acknowledgement
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