Influenza Viruses: from Epidemiology to Host Jump

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1 Influenza Viruses: from Epidemiology to Host Jump George F Gao( 高福 )DPhil China CDC Institute of Microbiology, Chinese Academy of Sciences gaof@im.ac.cn

2 Influenza Viruses: Emerging and Re-emerging Re-emerging: Seasonal flu every year Emerging: Avian flu and Pandemics

3 News in the Media

4 News in the Media

5 Always Keep An Eye On 1. Epidemiology and Surveillance 2. Host Jump Interspecies Transmission

6 Pandemics and epidemics of influenza viruses H7N Nature Volume: 480,Pages:S2-S3 Date published:(08 December 2011)

7 Natural Cycle of the Influenza viruses

9 Ecology of Ebola: Bat>mammals>human Natural Hosts/Reservoir Hosts Intermediate Hosts Human Infections Human-tohuman transmission

10 MERS-CoV life cycle to infect humans Bat Humans

11 Henipahvirus Horse Bat Human

12 Why do we have so many emerging viruses? --SARS--Bird flu MERS Ebola Zika--.

13 Climate and ecological changes But the polar bear or penguin might not be the only threatened species How it threatens your health

14 Human behavior changes Green house gases [CO 2 ] have increased significantly Note: what is the impact of the global change to our health?

15 2013 全球航线

16 Host Adaptation Virus Stability Host Adaption: to increase the substitution rate for adaptation Virus Stability: to keep the substitution rate steady within hosts

17 May Sep-Nov Nature, 2015

18 Why is/are the next? Ross River virus? Chikungunya virus? Completely new name?

19 Enveloped Vs Non-enveloped viruses 囊膜病毒流感病毒非囊膜病毒腺病毒相关病毒 (AAV)

20 Looking for a receptor on the host cell surface to get into the cell Host cell cleavage of the precursor envelope protein

21 Proteolytic processing of viral envelope proteins

22 Classical virus fusion trigger modes Flu Dengue H+ HIV Type I:Single receptor-ligand interaction mediated fusion Herpesvirus H+ Type II:Multiple receptor-ligand interactions mediated fusion Type IV:No known receptor entry and low ph-induced fusion Type III:Single receptor-ligand interaction mediated entry and virusencoded protein mediated low phinduced fusion

23 Orthomyxoviridae 7 genera Influenza A Influenza B Influenza C Influenza D Thogotovirus Isavirus Quaranjavirus

24 Influenza virus Influenza A virus Influenza B virus Influenza C virus Family: Orthomyxoviridae HEF Enveloped, segmented, singlestranded, negative-sense RNA virus Influenza D virus Diameter: 80~120nM

25 1. Binding to receptor Sialic acid 3. ph-dependent fusion and uncoating 2. Internalisation into endosome 4. import cytoplasm Secretory pathway NA HA M2 NS1 Incoming vrnps 5. Replication 12. Budding M1 7. Protein synthesis pols NP 11. Assembly of progeny viruses 6. Export Viral mrna(+) 8. import M1 NS2 crna(+) nucleus vrna(-) 10. Formation of progeny vrnps 9. Assembly

26 HA: hemagglutinin, (H17, H18) Molecular basis Of Host Jump

27 How the virus adapt to different hosts at the molecular level Mutations of NT/AA

28 HA: 血凝素, (H17/18) NA: 神经氨酸酶, (N10/11)

29 Host jump Avian-like receptor Human-like receptor

30 The hemagglutinin and host receptors α-2,3 receptor 190-helix glycan Sialic acid 220-loop Cleavage site 130-loop α-2,6 receptor glycan Sialic acid

Green, reaction with Sambucus nigra lectin, indicating the presence of sialic acid linked to galactose by an 2,6-linkage (SA 2,6Gal).

31 Distribution of a-2,3 and a-2,6 receptors in human airway a, Nasal mucosa; b, paranasal sinuses; c, bronchus; d, bronchiole; e, alveolus. Res, respiratory bronchiole (adjacent to alveoli); Ter, terminal bronchiole (distal to alveoli); Alv, alveolus. Green, reaction with Sambucus nigra lectin, indicating the presence of sialic acid linked to galactose by an 2,6-linkage (SA 2,6Gal). Red, reaction with Maackia amurensis lectin, indicating the presence of SA 2,3Gal. Cells were counterstained with DAPI (4,6-diamidino-2-phenylindole). Adapted from Nature 440, ,2006

32 Different types of influenza virus replicate in different regions of human airway α2,3 α2,3 α2,3 α2,6 α2,6 α2,6 H1N1 H7N9 H5N1 α2,6 α2,3 α2,3 & α2,6

33 2009 ph1n1 Binding to human and avian receptors

34 Similar binding specificity shift due to D225G substitution in 1918 and 2009 pandemic viruses Zhang et al., 2013, Journal of Virology

35 Loss of salt bridge resulting in dual binding specificity Zhang et al., 2013, Journal of Virology

36 两种 H7N9 病毒 : A/Anhui/1/2013, Anhui1 (prevalent) A/Shanghai/1/2013, Shanghai1 (nonprevalent) 基因调频?

37 病毒的受体结合 Blue: α-2,3 glycans Red: α-2,6 glycans Shi et al., 2013, Science

38 蛋白水平的受体结合 Shi et al., 2013, Science

39 上海 1 和安徽 1 病毒血凝素在氨基酸水平上的差异受体结合位点只有 4 个氨基酸的不同 Shi et al., 2013, Science

40 HA-L226Q mutant of Anhui1 can still bind to a-2,6 SA receptor 与 H5N1 的突变不同 Shi et al., 2013, Science

41 安徽 1 的受体结合槽要比上海 1 的结合槽大而宽 Green: Anhui-H7N9 HA Light blue: Shanghai-H7N9 HA Yellow: 1957 pandemic H2N2 HA Shi et al., 2013, Science

42 Mammalian cell-expressed H16 protein exhibits similar resistance to trypsin digestion

43 HA0 structure of H16 subtype has an α-helix structure in the cleavage site

44 The H17 Protein does not Bind to Canonical Sialic Acid Receptor

45 Biochemical and Biophysical Characterization of the Soluble H17 protein

46 Low thermostability of H17 compared with other common HAs

47 Exposed fusion peptide in H17 structure

48 Closed cavity may result in exposed fusion peptide

49 H7N9: 4 years path From low pathogenic to highly pathogenic AIV Hemagglutinin 4 AA insertion for efficient cleavage: R(G)KRT(I) PKRKRTARGL PKGKRIARGL PKGKRTARGL

50 Shi et al. Nature Reviews Microbiology, 2014 For seasonal flu: H1, H2, H3; Read this paper

51 What s the next? HxNy?

52 2013 年 6 月 : 台湾发生 H6N1 感染人事件

53 Receptor binding properties of three representatives from early, late and recent stages at protein level Early stage Late stage Recent stage Avian receptor binding Dual receptor binding Human receptor preference

54 The key residues responsible for the receptor binding properties of H6 protein V190E + S228G P186L Late stage Mimic early stage Avian receptor binding: P186-E190-G228 Dual receptor binding: P186-V190-S228 Human receptor preference: L186-V190-S228 Mimic recent stage

55 Receptor binding properties of three representatives from early, late and recent stages at virus level Early stage (A/duck/Taiwan/0526/72) Late stage (A/chicken/Taiwan/A2837/2013) Recent stage (A/Taiwan/2/2013) Avian receptor binding Dual receptor binding Human receptor preference

56 H10N8? An immune compromised patient

57 Direct comparison of receptor binding of H10N8 and two H7N9 isolates at virus level

58 Direct comparison of receptor binding of H10N8 and two H7N9 isolates at protein level

59 Direct comparison of receptor binding of H10N8 and two H7N9 isolates at tissue staining level

60 Structural basis for preferential avian receptor binding by H10N8 The residue R137 forms a hydrogen bond with the 220- loop, stabilizing the conformation of 220-loop and providing a hydrophilic environment, which are favorable for the avian receptor binding but unfavorable for the

61 H5N6, May 2014 Guangdong,Yunnan, 2015?

62 Ecosystem model for the production and cross-species transmission of novel reassortant AIV in China.

63 Poultry carrying H9N2 avian influenza virus: Incubators for novel human-infecting AIV Liu et al., 2014, The Lancet

64 What we have seen are only the piece above the sea... 16H X 9N 144 H7N3 H5N1 H7N2 H7N7 H9N2 H7N9 H10N8 H6N 1 H5N5 H12N3 H6N8 H4N1 H11N2 H5N7H13N6 H14N5 H15N4 H16N3 H8N6... HxNy

66 内吞体中埃博拉病毒表面 GP 蛋白的激活过程 Carbohydrate chain NPC1 GP1 130 kda GP1 GP1 Cathepsin L 20 kda Cathepsin B 19 kda H+ GP2 Fusion loop Additional Factors (NPC1) Viral membrane Priming Triggering

67 激活态 GP 蛋白结合 NPC1 分子的腔内结构域 C (NPC1-C) Domain A Domain C Domain I

68 Wang, et at., Nature, 2015

70 The 5 th fusion triggering mode 流感病毒登革病毒 H+ H+ Type III: 结合细胞膜表面受体后, 内吞到内体中, 低 ph 值环境里, 单个蛋白介导膜融合埃博拉病毒艾滋病毒 Type I: 结合受体或辅助受体, 单个蛋白介导膜融合疱疹病毒 Type II: 结合受体, 多个蛋白介导膜融合 Type IV: 内吞到内体里, 低 ph 值环境里, 不结合受体, 单个蛋白介导膜融合 Type V: 结合内体受体后, 低 ph 值环境里, 单个蛋白介导膜融合 H+

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宫颈上皮内瘤变 ; IgG1 IgG2 亚类 ; 酶联免疫吸附试验 R A (2009)

宫颈上皮内瘤变 ; IgG1 IgG2 亚类 ; 酶联免疫吸附试验 R A (2009) 2009 年第 19 卷第 11 期 CHINA ONCOLOGY 2009 Vol.19 No.11 831 免疫球蛋白 G(immunoglobulin G,IgG) 是血清和细胞外液中含量最高的免疫球蛋白, 其某个亚类的升高, 可能与宫颈上皮内瘤变 (cervical intraepithelial neoplasia, CIN) 的发生发展及转归有密切相关然而对于 CIN 患者血清人乳头瘤病毒样颗粒