Pathogenomics Laboratory, ICAR-National Institute of High-Security Animal Diseases, OIE Reference lab for Avian Influenza, Bhopal, 462021, Madhya Pradesh, India.
Veterinary College and Research Institute, Tamil Nadu Veterinary and Animal Sciences University, Orathanadu, 614625, Tamil Nadu, India.
Arch Virol. 2022 Jan;167(1):141-152. doi: 10.1007/s00705-021-05287-5. Epub 2021 Nov 16.
Elucidation of the molecular pathogenesis underlying virus-host interactions is important for the development of new diagnostic and therapeutic strategies against highly pathogenic avian influenza (HPAI) virus infection in chickens. However, the pathogenesis of HPAI virus in chickens is not completely understood. To identify the intracellular signaling pathways and critical host proteins associated with influenza pathogenesis, we analyzed the lung proteome of a chicken infected with HPAI H5N1 virus (A/duck/India/02CA10/2011/Agartala). Mass spectrometry data sets were searched against the chicken UniProt reference database. At the local false discovery rate level of 5%, a total of 3313 proteins with the presence of at least one unique peptide were identified in the chicken lung proteome datasets. Differential expression analysis of these proteins showed that 247 and 1754 proteins were downregulated at 12 h and 48 h postinfection, respectively. We observed expression of proteins of the predominant signaling pathways, including Toll-like receptors (TLRs), retinoic acid-inducible gene I-like receptors (RLRs), NOD-like receptors (NLRs), and JAK-STAT signaling. Activation of these pathways is associated with the cytokine storm effect and thus may be the cause of the severity of HPAI H5N1 infection in chickens. We also observed the expression of myeloid differentiation primary response protein (MyD88), inhibitor of nuclear factor kappa B kinase subunit beta (IKBKB), interleukin 1 receptor associated kinase 4 (IRAK4), RELA proto-oncogene NF-κB subunit (RELA), and mitochondrial antiviral signaling protein (MAVS), which are involved in critical signaling pathways, as well as other, less-commonly identified proteins such as hepatocyte nuclear factor 4 alpha (HNF4A), ELAV-like RNA binding protein 1 (ELAVL1), fibronectin 1 (FN1), COP9 signalosome subunit 5 (COPS5), cullin 1 (CUL1), breast cancer type 1 susceptibility protein (BRCA1), and the FYN proto-oncogene Src family tyrosine kinase (FYN) as main hub proteins that might play important roles in influenza pathogenesis in chickens. In summary, we identified the signaling pathways and the proteomic determinants associated with disease pathogenesis in chickens infected with HPAI H5N1 virus.
阐明病毒-宿主相互作用的分子发病机制对于开发针对高致病性禽流感（HPAI）病毒感染鸡的新的诊断和治疗策略非常重要。然而，HPAI 病毒在鸡中的发病机制尚不完全清楚。为了鉴定与流感发病机制相关的细胞内信号通路和关键宿主蛋白，我们分析了感染 HPAI H5N1 病毒（A/duck/India/02CA10/2011/Agartala）的鸡的肺蛋白质组。质谱数据集针对鸡 UniProt 参考数据库进行了搜索。在局部假发现率水平为 5%时，鸡肺蛋白质组数据集中共鉴定到 3313 种存在至少一个独特肽的蛋白质。这些蛋白质的差异表达分析表明，分别在感染后 12 小时和 48 小时下调了 247 种和 1754 种蛋白质。我们观察到主要信号通路（包括 Toll 样受体（TLRs）、视黄酸诱导基因 I 样受体（RLRs）、NOD 样受体（NLRs）和 JAK-STAT 信号）的蛋白表达。这些途径的激活与细胞因子风暴效应有关，因此可能是 HPAI H5N1 感染鸡的严重程度的原因。我们还观察到髓样分化原初反应蛋白（MyD88）、核因子 kappa B 激酶亚基 beta（IKBKB）抑制剂、白细胞介素 1 受体相关激酶 4（IRAK4）、RELA 原癌基因 NF-κB 亚基（RELA）和线粒体抗病毒信号蛋白（MAVS）的表达，这些蛋白参与关键信号通路，以及其他不太常见的鉴定蛋白，如肝细胞核因子 4 alpha（HNF4A）、ELAV 样 RNA 结合蛋白 1（ELAVL1）、纤维连接蛋白 1（FN1）、COP9 信号体亚基 5（COPS5）、Cullin 1（CUL1）、乳腺癌 1 型易感性蛋白（BRCA1）和 FYN 原癌基因Src 家族酪氨酸激酶（FYN），这些蛋白可能作为主要枢纽蛋白在鸡的流感发病机制中发挥重要作用。总之，我们鉴定了与 HPAI H5N1 病毒感染鸡的疾病发病机制相关的信号通路和蛋白质组决定因素。
