Identification of hub genes and key pathways in the early therapy of septic shock based on bioinformatics analysis_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

KANG Jinhua ^1,2 , NING Yile ¹ , LONG Wenjie ¹ , LIU Qingqing ¹ , WANG Linjun ^1,2 , XIAN Shaoxiang ^1,2 ,  YANG Zhongqi ^1,2

1. The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P. R. China;
2. Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P. R. China;

Corresponding author：

YANG Zhongqi, Email: yzq_xuexi@163.com

Keywords：

Septic shock; early supportive hemodynamic therapy; bioinformatics; hub differential genes

DOI：

10.7507/1671-6205.202101027

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Objective To identify potential hub genes and key pathways in the early period of septic shock via bioinformatics analysis. Methods The gene expression profile GSE110487 dataset was downloaded from the Gene Expression Omnibus database. Differentially expressed genes were identified by using DESeq2 package of R project. Then Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were constructed to investigated pathways and biological processes using clusterProfiler package. Subsequently, protein-protein interaction (PPI) network was mapped using ggnetwork package and the molecular complex detection (MCODE) analysis was implemented to further investigate the interactions of differentially expressed genes using Cytoscape software. Results A total of 468 differentially expressed genes were identified in septic shock patients with different responses who accepted early supportive hemodynamic therapy, including 255 upregulated genes and 213 downregulated genes. The results of GO and the KEGG pathway enrichment analysis indicated that these up-regulated genes were highly associated with the immune-related biological processes, and the down-regulated genes are involved in biological processes related to organonitrogen compound, multicellular organismal process, ion transport. Finally, a total of 23 hub genes were identified based on PPI and the subcluster analysis through MCODE software plugin in Cytoscape, which included 19 upregulated hub genes, such as CD28, CD3D, CD8B, CD8A, CD160, CXCR6, CCR3, CCR8, CCR9, TLR3, EOMES, GZMB, PTGDR2, CXCL8, GZMA, FASLG, GPR18, PRF1, IDO1, and additional 4 downregulated hub genes, such as CNR1, GPER1, TMIGD3, GRM2. KEGG pathway enrichment analysis and GO functional annotation showed that differentially expressed genes were primarily associated with the items related to cytokine-cytokine receptor interaction, natural killer cell mediated cytotoxicity, hematopoietic cell lineage, T cell receptor signaling pathway, phospholipase D signaling pathway, cell adhesion molecules, viral protein interaction with cytokine and cytokine receptor, primary immunodeficiency, graft-versus-host disease, type 1 diabetes mellitus. Conclusions Some lymphocytes such as T cells and natural killer cells, cytokines and chemokines participate in the immune process, which plays an important role in the early treatment of septic shock, and CD160, CNR1, GPER1, and GRM2 may be considered as new biomarkers.

Citation： KANG Jinhua, NING Yile, LONG Wenjie, LIU Qingqing, WANG Linjun, XIAN Shaoxiang, YANG Zhongqi. Identification of hub genes and key pathways in the early therapy of septic shock based on bioinformatics analysis. Chinese Journal of Respiratory and Critical Care Medicine, 2022, 21(2): 102-111. doi: 10.7507/1671-6205.202101027 Copy

1.	Shankar-Hari M, Phillips GS, Levy ML, et al. Developing a new definition and assessing new clinical criteria for septic shock: for the third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA, 2016, 315(8): 775-787.
2.	Seymour CW, Liu VX, Iwashyna TJ, et al. Assessment of clinical criteria for sepsis: for the third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA, 2016, 315(8): 762-774.
3.	Vincent J L, Jones G, David S, et al. Frequency and mortality of septic shock in Europe and North America: a systematic review and meta-analysis. Critical Care, 2019, 23(1): 1-11.
4.	Barcella M, Pinto BB, Braga D, et al. Identification of a transcriptome profile associated with improvement of organ function in septic shock patients after early supportive therapy. Critical Care, 2018, 22(1): 1-13.
5.	Dessimoz C, Škunca N. The gene ontology handbook. Methods in molecular biology. New York: Humana Press, 2017: 1446.
6.	Yu G, Wang LG, Han Y, et al. ClusterProfiler: an R package for comparing biological themes among gene clusters. OMICS, 2012, 16(5): 284-287.
7.	Franceschini A, Szklarczyk D, Frankild S, et al. STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res, 2013, 41(Database issue): D808-D815.
8.	Tyner S, Briatte F, Hofmann H. Network visualization with ggplot2. R Journal, 2017, 9(1): 27-59.
9.	Bandettini WP, Kellman P, Mancini C, et al. MultiContrast Delayed Enhancement (MCODE) improves detection of subendocardial myocardial infarction by late gadolinium enhancement cardiovascular magnetic resonance: a clinical validation study. J Cardiovasc Magn Reson, 2012, 14(1): 83.
10.	Walter W, Sánchez-Cabo F, Ricote M. GOplot: an R package for visually combining expression data with functional analysis. Bioinformatics, 2015, 31(17): 2912-2914.
11.	Patil NK, Guo Y, Luan L, et al. Targeting immune cell checkpoints during sepsis. Int J Mol Sci, 2017, 18(11): 2413.
12.	林颖韬, 陈伶莉, 胡雪峰. 免疫细胞的种类、功能及相关疾病概述. 生物学教学, 2020, 45(4): 77-80.
13.	Feuerecker M, Sudhoff L, Crucian B, et al. Early immune anergy towards recall antigens and mitogens in patients at onset of septic shock. Scientific reports, 2018, 8(1): 1754.
14.	de Pablo R, Monserrat J, Prieto A, et al. Role of circulating lymphocytes in patients with sepsis. Biomed Res Int, 2014, 2014: 671087.
15.	Piotrowska M, Spodzieja M, Kuncewicz K, et al. CD160 protein as a new therapeutic target in a battle against autoimmune, infectious and lifestyle diseases. Analysis of the structure, interactions and functions. Eur J Med Chem, 2021, 224: 113694.
16.	Tu TC, Brown NK, Kim TJ, et al. CD160 is essential for NK-mediated IFN-γ production. J Exp Med, 2015, 212(3): 415-429.
17.	Thomas AK, Maus MV, Shalaby WS, et al. A cell-based artificial antigen-presenting cell coated with anti-CD3 and CD28 antibodies enables rapid expansion and long-term growth of CD4 T lymphocytes. Clin Immunol, 2002, 105(3): 259-272.
18.	张安莉, 仇超, 徐建青. 淋巴细胞膜分子CD160结构与功能的研究进展. 中华微生物学和免疫学杂志, 2011, 31(4): 380-384.
19.	Miller MC, Mayo KH. Chemokines from a structural perspective. Int J Mol Sci, 2017, 18(10): 2088.
20.	Murdoch C, Finn A. The role of chemokines in sepsis and septic shock. Contrib Microbiol, 2003, 10: 38-57.
21.	冀林华, 任汉云. 趋化因子及其受体与免疫细胞关系研究进展. 陕西医学杂志, 2008, 37(12): 1678-1680.
22.	Venet F, Lepape A, Debard AL, et al. The Th2 response as monitored by CRTH2 or CCR3 expression is severely decreased during septic shock. Clin Immunol, 2004, 113(3): 278-284.
23.	Mizukami T, Kanai T, Mikami Y, et al. CCR9⁺ macrophages are required for eradication of peritoneal bacterial infections and prevention of polymicrobial sepsis. Immunol Lett, 2012, 147(1-2): 75-79.
24.	Benvenga MJ, Chaney SF, Baez M, et al. Metabotropic glutamate2 receptors play a key role in modulating head twitches induced by a serotonergic hallucinogen in mice. Front Pharmacol, 2018, 9: 208.
25.	Taylor DL, Jones F, Kubota ESFCS, et al. Stimulation of microglial metabotropic glutamate receptor mGlu2 triggers tumor necrosis factor α-induced neurotoxicity in concert with microglial-derived Fas ligand. J Neurosci, 2005, 25(11): 2952-2964.
26.	Gohar EY. G protein-coupled estrogen receptor 1 as a novel regulator of blood pressure. Am J Physiol Renal Physiol, 2020, 319(4): F612-F617.
27.	Waghulde H, Cheng X, Galla S, et al. Attenuation of microbiotal dysbiosis and hypertension in a CRISPR/Cas9 gene ablation rat model of GPER1. Hypertension, 2018, 72(5): 1125-1132.
28.	Pei SJ, Zhu HY, Guo JH, et al. Knockout of CNR1 prevents metabolic stress-induced cardiac injury through improving insulin resistance (IR) injury and endoplasmic reticulum (ER) stress by promoting AMPK-alpha activation. Biochem Biophys Res Commun, 2018, 503(2): 744-751.
29.	Van Wyngene L, Vandewalle J, Libert C. Reprogramming of basic metabolic pathways in microbial sepsis: therapeutic targets at last?. EMBO Mol Med, 2018, 10(8): e8712.
30.	Dejean AS, Joulia E, Walzer T. The role of Eomes in human CD4 T cell differentiation: a question of context. Eur J Immunol, 2019, 49(1): 38-41.
31.	Kong DH, Kim YK, Kim MR, et al. Emerging roles of vascular cell adhesion molecule-1 (VCAM-1) in immunological disorders and cancer. Int J Mol Sci. 2018, 19(4): 1057.
32.	Urbahn MA, Kaup SC, Reusswig F, et al. Phospholipase D1 regulation of TNF-alpha protects against responses to LPS. Sci Rep, 2018, 8(1): 10006.
33.	Lee SK, Kim SD, Kook M, et al. Phospholipase D2 drives mortality in sepsis by inhibiting neutrophil extracellular trap formation and down-regulating CXCR2. J Exp Med, 2015, 212(9): 1381-1390.

1. Shankar-Hari M, Phillips GS, Levy ML, et al. Developing a new definition and assessing new clinical criteria for septic shock: for the third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA, 2016, 315(8): 775-787.
2. Seymour CW, Liu VX, Iwashyna TJ, et al. Assessment of clinical criteria for sepsis: for the third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA, 2016, 315(8): 762-774.
3. Vincent J L, Jones G, David S, et al. Frequency and mortality of septic shock in Europe and North America: a systematic review and meta-analysis. Critical Care, 2019, 23(1): 1-11.
4. Barcella M, Pinto BB, Braga D, et al. Identification of a transcriptome profile associated with improvement of organ function in septic shock patients after early supportive therapy. Critical Care, 2018, 22(1): 1-13.
5. Dessimoz C, Škunca N. The gene ontology handbook. Methods in molecular biology. New York: Humana Press, 2017: 1446.
6. Yu G, Wang LG, Han Y, et al. ClusterProfiler: an R package for comparing biological themes among gene clusters. OMICS, 2012, 16(5): 284-287.
7. Franceschini A, Szklarczyk D, Frankild S, et al. STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res, 2013, 41(Database issue): D808-D815.
8. Tyner S, Briatte F, Hofmann H. Network visualization with ggplot2. R Journal, 2017, 9(1): 27-59.
9. Bandettini WP, Kellman P, Mancini C, et al. MultiContrast Delayed Enhancement (MCODE) improves detection of subendocardial myocardial infarction by late gadolinium enhancement cardiovascular magnetic resonance: a clinical validation study. J Cardiovasc Magn Reson, 2012, 14(1): 83.
10. Walter W, Sánchez-Cabo F, Ricote M. GOplot: an R package for visually combining expression data with functional analysis. Bioinformatics, 2015, 31(17): 2912-2914.
11. Patil NK, Guo Y, Luan L, et al. Targeting immune cell checkpoints during sepsis. Int J Mol Sci, 2017, 18(11): 2413.
12. 林颖韬, 陈伶莉, 胡雪峰. 免疫细胞的种类、功能及相关疾病概述. 生物学教学, 2020, 45(4): 77-80.
13. Feuerecker M, Sudhoff L, Crucian B, et al. Early immune anergy towards recall antigens and mitogens in patients at onset of septic shock. Scientific reports, 2018, 8(1): 1754.
14. de Pablo R, Monserrat J, Prieto A, et al. Role of circulating lymphocytes in patients with sepsis. Biomed Res Int, 2014, 2014: 671087.
15. Piotrowska M, Spodzieja M, Kuncewicz K, et al. CD160 protein as a new therapeutic target in a battle against autoimmune, infectious and lifestyle diseases. Analysis of the structure, interactions and functions. Eur J Med Chem, 2021, 224: 113694.
16. Tu TC, Brown NK, Kim TJ, et al. CD160 is essential for NK-mediated IFN-γ production. J Exp Med, 2015, 212(3): 415-429.
17. Thomas AK, Maus MV, Shalaby WS, et al. A cell-based artificial antigen-presenting cell coated with anti-CD3 and CD28 antibodies enables rapid expansion and long-term growth of CD4 T lymphocytes. Clin Immunol, 2002, 105(3): 259-272.
18. 张安莉, 仇超, 徐建青. 淋巴细胞膜分子CD160结构与功能的研究进展. 中华微生物学和免疫学杂志, 2011, 31(4): 380-384.
19. Miller MC, Mayo KH. Chemokines from a structural perspective. Int J Mol Sci, 2017, 18(10): 2088.
20. Murdoch C, Finn A. The role of chemokines in sepsis and septic shock. Contrib Microbiol, 2003, 10: 38-57.
21. 冀林华, 任汉云. 趋化因子及其受体与免疫细胞关系研究进展. 陕西医学杂志, 2008, 37(12): 1678-1680.
22. Venet F, Lepape A, Debard AL, et al. The Th2 response as monitored by CRTH2 or CCR3 expression is severely decreased during septic shock. Clin Immunol, 2004, 113(3): 278-284.
23. Mizukami T, Kanai T, Mikami Y, et al. CCR9⁺ macrophages are required for eradication of peritoneal bacterial infections and prevention of polymicrobial sepsis. Immunol Lett, 2012, 147(1-2): 75-79.
24. Benvenga MJ, Chaney SF, Baez M, et al. Metabotropic glutamate2 receptors play a key role in modulating head twitches induced by a serotonergic hallucinogen in mice. Front Pharmacol, 2018, 9: 208.
25. Taylor DL, Jones F, Kubota ESFCS, et al. Stimulation of microglial metabotropic glutamate receptor mGlu2 triggers tumor necrosis factor α-induced neurotoxicity in concert with microglial-derived Fas ligand. J Neurosci, 2005, 25(11): 2952-2964.
26. Gohar EY. G protein-coupled estrogen receptor 1 as a novel regulator of blood pressure. Am J Physiol Renal Physiol, 2020, 319(4): F612-F617.
27. Waghulde H, Cheng X, Galla S, et al. Attenuation of microbiotal dysbiosis and hypertension in a CRISPR/Cas9 gene ablation rat model of GPER1. Hypertension, 2018, 72(5): 1125-1132.
28. Pei SJ, Zhu HY, Guo JH, et al. Knockout of CNR1 prevents metabolic stress-induced cardiac injury through improving insulin resistance (IR) injury and endoplasmic reticulum (ER) stress by promoting AMPK-alpha activation. Biochem Biophys Res Commun, 2018, 503(2): 744-751.
29. Van Wyngene L, Vandewalle J, Libert C. Reprogramming of basic metabolic pathways in microbial sepsis: therapeutic targets at last?. EMBO Mol Med, 2018, 10(8): e8712.
30. Dejean AS, Joulia E, Walzer T. The role of Eomes in human CD4 T cell differentiation: a question of context. Eur J Immunol, 2019, 49(1): 38-41.
31. Kong DH, Kim YK, Kim MR, et al. Emerging roles of vascular cell adhesion molecule-1 (VCAM-1) in immunological disorders and cancer. Int J Mol Sci. 2018, 19(4): 1057.
32. Urbahn MA, Kaup SC, Reusswig F, et al. Phospholipase D1 regulation of TNF-alpha protects against responses to LPS. Sci Rep, 2018, 8(1): 10006.
33. Lee SK, Kim SD, Kook M, et al. Phospholipase D2 drives mortality in sepsis by inhibiting neutrophil extracellular trap formation and down-regulating CXCR2. J Exp Med, 2015, 212(9): 1381-1390.

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