Supplementary information The Serum Profile of Hypercytokinemia Factors Identified in H7N9-Infected Patients can Predict Fatal Outcomes Jing Guo 1,2 *

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1 Supplementary information The Serum Profile of Hypercytokinemia Factors Identified in H7N9-Infected Patients can Predict Fatal Outcomes Jing Guo, *, Fengming Huang *, Jun Liu,5 *,Yu Chen, *, Wei Wang *, Bin Cao 6 *, Zhen Zou, Song Liu, Jingcao Pan 7, Changjun Bao 8, Mei Zeng 9, Haixia Xiao, Hainv Gao,, Shigui Yang,, Yan Zhao, Qiang Liu, Huandi Zhou, Jingdong Zhu, Xiaoli Liu,, Weifeng Liang,, Yida Yang,, Shufa Zheng,, Jiezuan Yang,, Hongyan Diao,, Kunkai Su,, Li Shao,, Hongcui Cao,, Ying Wu 5, Min Zhao 5, Shuguang Tan 5, Hui Li 6, Xiaoqing Xu, Chunmei Wang, Jianmin Zhang, Li Wang, Jianwei Wang, Jun Xu, Dangsheng Li, Nanshan Zhong, Xuetao Cao, George F Gao,,5,, Lanjuan Li,, Chengyu Jiang State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou,China. State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 5, China. National Institute for Viral Disease and Prevention, Chinese Center for Disease and Prevention, Beijing 6, China 5 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China 6 Department of Infectious Diseases and Clinical Microbiology, Beijing Chao-Yang Hospital, Beijing Institute of Respiratory Medicine, Capital Medical University,, Beijing, China. 7 Hangzhou Center for Disease and Prevention, Hangzhou, China. 8 Jiangsu Provincial Center for Disease and Prevention, Nanjing 9, China. 9 Children's Hospital, Fudan University, Shanghai, China. Laboratory of Protein Engineering and Vaccine, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 8, China. MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 7, China. Guangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Diseases, First Affiliated Hospital, Guangzhou Medical University, Guangzhou 5, China. Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. Chinese Center for Disease and Prevention (China CDC), Beijing 6, China. * These authors contributed equally to this work. Correspondence should be addressed to C.Y.J (jiang@pumc.edu.cn), L.J.L (ljli@zju.edu.cn) or G.F.G (gaofu@chinacdc.cn).

2 Supplementary Figure GM-CSF IL- VEGF IL-5 IL-7A * 8 HN(D-7) H7N9(D-7) * HN(D-7) H7N9(D-7) * 5 5 HN(D-7) H7N9(D-7) * HN(D-7) H7N9(D-7) * 9 * HN(D-7) H7N9(D-7) IL-8 * HN(D-7) H7N9(D-7) 5 5 IL-β MIP-α CTACK SDF-α * * 5 * * HN(D-7) H7N9(D-7) 5 5 HN(D-7) H7N9(D-7) * HN(D-7) H7N9(D-7) * HN(D-7) H7N9(D-7) * 9 HN(D-7) H7N9(D-7) IL- 5 * 5 5 HN(D-7) H7N9(D-7) IL- * HN(D-7) H7N9(D-7) 5 * HN(D-7) Basic FGF H7N9(D-7) * TNF- α IFN- γ HN(D-7) H7N9(D-7) * 8 G-CSF HN(D-7) H7N9(D-7) * 8 6 IL- HN(D-7) H7N9(D-7) * 5 5 IL-7 HN(D-7) H7N9(D-7) IL-9 * HN(D-7) H7N9(D-7) MIP-β * 8 HN(D-7) H7N9(D-7) 5 * 5 5 IL-ra HN(D-7) H7N9(D-7) 5 5 PDGB-bb HN(D-7) H7N9(D-7) IL-p7 HN(D-7) H7N9(D-7) RANTES * HN(D-7) H7N9(D-7)

3 Supplementary Table. Cytokine/chemokine Comparison Among 6 healthy controls, HN-infected patients and 6 H7N9-infected patients. HN(n=) H7N9(n=6) (n=6) Day-7 (n=) Day8- (n=7) Day5- (n=) Day-7 (n=) Day8- (n=) Day5- (n=) P m P n P o P d P e P f P j P k P l Mean SD Mean SD P a Mean SD P b Mean SD P c Mean SD P g Mean SD P h Mean SD P i GM-CSF < < < IP < < <.. <...79 IL < < <... VEGF < < IL < < <. <..5 IL < < <. <..67 IL-7A < < <. <..598 MIG < < IL < < <. <..96 HGF < < MCP < < < IL-beta < < <. <.. MIP-alpha <..6. < <. <..87 CTACK < < <.. <. <.. SDF-alpha < < <. <.. TNF-alpha < < <. <..598 IL < < <. <..79 IL < beta-ngf < < <.. <. <..695 basic-fgf < < <. <..896 IFN-gamma < < <. <..695 G-CSF < < <. <..5 IL < < <. <..99 IL <.. 9. < <. <..598 MIF < < < IL < < MIP- beta < < < SCF < <..9 IL-ra < < <..7 < IL < PDGF-bb <..5 IL-p RANTES < < < SCGF-beta a: Compare between and HN Day-7 groups b: Compare between and HN Day8- groups c: Compare between and HN Day5- groups d: Compare between HN Day-7 and HN Day8- groups e: Compare between HN Day-7 and HN Day5- groups f: Compare between HN Day8- and HN Day5- groups g: Compare between and H7N9 Day-7 groups h: Compare between and H7N9 Day8- groups i: Compare between and H7N9 Day5- groups j: Compare between H7N9 Day-7 and H7N9 Day8- groups k: Compare between H7N9 Day-7 and H7N9 Day5- groups l: Compare between H7N9 Day8- and H7N9 Day5- groups m: Compare between HN Day-7 and H7N9 Day-7 groups n: Compare between HN Day8- and H7N9 Day8- groups : Compare between HN Day5- and H7N9 Day5- groups

4 Supplementary Figure 5 HGF Week ρ :.77 P <. P*<. IL-8 Week ρ :.7 P <. P*=. SCF Week ρ :.656 P =. P*= MIG Week ρ :.6 P =. P*= IP- Week ρ :. P =. P*= beta-ngf Week ρ :.99 P =. P*= MIF Week ρ :.6 P =. P*=.7.5 Eotaxin Week ρ :. P =. P*=.7.5 MCP- Week ρ :.9 P =.6 P*=

5 Supplementary Figure SCF Week ρ :.8 P <. P*<. 5 HGF Week ρ :.796 P <. P*< SCGF-beta Week ρ :.7 P <. P*< MIF Week ρ :.68 P <. P*<. IL-8 Week ρ :.67 P <. P*< IP- Week ρ :.575 P =. P*= MIG Week ρ :.557 P =. P*=. 8 6 IL-6 Week ρ :.8 P =.5 P*=.9 5 MCP- Week ρ :.6 P =.8 P*= beta-ngf Week ρ :. P =. P*=

6 Supplementary Table. Outcomes in H7N9-infected Patients Cyto/Chemokines Hospitalized<8 days(n=) Week Death(n=5) P Value Hospitalized<8 days(n=6) Week Death(n=8) P Value Mean SD Mean SD Mean SD Mean SD MIF > <. MCP > SCF > HGF > SCGF-beta > IP > IL >

7 Supplementary Table. ROC Curve of Cytokine/Chemokines in The Second Week H7N9- infected Illness Onset Cyto/Chemokines Area under the ROC curve P value Std. Errora 95% Confidence Interval Lower Bound Upper Bound MIF.95 < SCF MCP HGF SCGF-beta IL IP IFN-gamma beta-ngf.79 > IL-6.79 > MIG.66 > IL-8.67 > MIP-beta.65 > SDF-alpha.586 > CTACK.57 > MIP-alpha.55 > IL-ra.55 > IL-9.5 > IL-.5 > G-CSF.5 > IL-7.77 > IL-5.5 > GM-CSF. > IL-beta. > IL-. > VEGF.6 > TNF-alpha. > IL-.9 > IL-.9 > basic-fgf. > IL-p7. > PDGF-bb.6 > IL-7A.58 > RANTES.88 >

8 Supplementary Figure IFN-gamma. MCP-. IL-8. IP HGF MIF SCF SCGF-beta IFN-gamma MCP- IL-8 IP- HGF MIF SCF SCGF-beta

9 Supplementary Table. Comparison Among H7N9, 9 S-OIV, URTI, H5N and SARS Induced Plasma Chemokine and Cytokine Levels. H7N9 (n=) P HN (n=) P URTI(n=5) [Ref8,7] H5N(n=6) [Ref] MCP-.(.8-.) <..5 (-.7-.9) <..6 (und-.). (.5.) IP- 5.(.8-5.) <..7 (.-.6) <..5 (.-.) 5. (.5 6.) IFN-γ.(.6-.) <.. (.-.) <.. (und-.). (und..) IL-6.(.7-.6) <..5 (.6-.9) <.. (und-.6). (und..7) MIG.7(.6-.8). (. 5.) IL-8.(.-.8) <.. (.-.) <..7 (und-.5). (.7.) IL-.(.-.5) <.. (.-.) <. und (und-.).5 (und..8) Levels are given as median log pg/ml (range). URTI., upper respiratory tract infection. und., undetectable. Comparison between H7N9 (-7 d of illness onset) and 9 swine flu (-8 d of illness onset) patients. Comparison between H7N9 (-7 d of illness) and 9 URTI patients. The blood specimens of patients infected with H5N were obtained -8 d of illness onset. H7N9 SARS [Ref8] -7 d of illness onset (n=) 8- d of illness onset -7 d of illness onset 8- d of illness onset (n=) (n=6) (n=9) MCP- 85.(8.) 85.(8.) 8.8 (6. 9.).6 (.9 68.) IP- 996.(8859.) 996.(886.) (5 665) 695 (95 76) RANTES 6.8(88.8) 6.8(88.8) 9 8 (8 9 7) 5 (6 6 ) MIG 58.(87.9) 58.(87.) 5 (75 98) 6 (6 ) IL-8 65.(6.) 65.(6.).7 (6.6.7) 8.9 (5..8) Levels are given as median pg/ml (IQR). H7N9(- d of illness onset, n=5) MCP- 9.±89. IP- 85.±667. IFN-γ 977.±5. IL-6 5.±76.9 IL-8 7.±. MIP-α 5.±.8 Levels are given as means pg/ml ± SD. SARS(progressive stage, n=) [Ref7] 75± 8± 85±5 ±6 75± 79±88

10 Figure Legend Supplementary Figure.Hypercytokinemia in Avian Influenza A (H7N9) Virus-Infected Patients A total of 6 patients infected with the avian influenza A (H7N9) virus, patients infected with the swine-origin influenza A (HN) virusand 6 healthy controls were recruited for this study. Their plasma levels of chemokines and cytokines at -7 days (n=), 8- days (n=) and 5 days (n=) after the onset of the disease were measured. Detailed information is shown in supplementary table. *P<.5,P<., *P<.. Supplementary Figure.The APACHE II Score was Correlated with the Plasma Levels of Chemokines and Cytokines and with Clinical Characteristics in The First Week of Disease Onset in Avian Influenza A (H7N9) Virus-Infected Patients. Correlations between the APACHE II score and the plasma chemokine and cytokine (HGF, IL-8, SCF, MIG, IP-, IL-6, MIF, Eotaxin, MCP-) levels in the first week of influenza H7N9 infection for patients.spearman's rank correlation analysis (ρ), P value and the Benjamini& Hochberg multiple testing correction (P*) to control for the false discovery rate (FDR) areshown in each graph. Supplementary Figure.The APACHE II Score was Correlated with the Plasma Levels of Chemokines and Cytokines and with Clinical Characteristics in the Second Week of Disease Onset in Avian Influenza A (H7N9) Virus-Infected Patients. Correlations between the APACHE II score and the plasma chemokine and cytokine levels (SCF, HGF, SCGF-β, MIF, IL-8, IP-, MIG, IL-6, MCP-, β-ngf) in the second week of influenza H7N9 infection in patients.spearman's rank correlation analysis (ρ), P value and the Benjamini& Hochberg multiple testing correction (P*) to control for the false discovery rate (FDR) areshown in each graph. Supplementary Figure.Correlation Heatmap of Plasma Cytokine/Chemokines Levels in the Second Week of H7N9-infected Illness Onsets. Spearman's rank correlation analysis between the plasma chemokine and cytokine levels (SCF, HGF, SCGF-β, MIF, IL-8, IP-, IFN-γ, MCP-) in the second week of influenza H7N9 infection. The blank represents the Spearman's rank correlation analysis P value >.5. Supplementary Table.Cytokine/chemokine Comparison Among 6 Healthy s, HN-infected Patients and 6 H7N9-infected Patients. Supplementary Table.Outcomes in H7N9-infected Patients Supplementary Table. ROC Curve of Cytokine/Chemokinesduringthe Second Week H7N9 Infection Supplementary Table.Comparison among H7N9, 9 S-OIV, URTI, H5N and SARS Induced Plasma Chemokine and Cytokine Levels

Supporting_Information_revise

Supporting_Information_revise Supporting Information The Synthesis and Bioactivity Investigation of the Individual Components of Cyclic Lipopeptide Antibiotics A-Long Cui, Xin-Xin Hu, Yan Gao, Jie Jin, Hong Yi, Xiu-Kun Wang, Tong-Ying