Table_5_Innovation in Nucleotide-Binding Oligomerization-Like Receptor and Toll-Like Receptor Sensing Drives the Major Histocompatibility Complex-II Free Atlantic Cod Immune System.xlsx

The absence of MHC class II antigen presentation and multiple pathogen recognition receptors in the Atlantic cod has not impaired its immune response however how underlying mechanisms have adapted remains largely unknown. In this study, ex vivo cod macrophages were challenged with various bacterial and viral microbe-associated molecular patterns (MAMP) to identify major response pathways. Cytosolic MAMP-PRR pathways based upon the NOD-like receptors (NLRs) and RIG-I-like receptors (RLRs) were identified as the critical response pathways. Our analyses suggest that internalization of exogenous ligands through scavenger receptors drives both pathways activating transcription factors like NF-kB (Nuclear factor-kappa B) and interferon regulatory factors (IRFs). Further, ligand-dependent differential expression of a unique TLR25 isoform and multiple NLR paralogues suggests (sub)neofunctionalization toward specific immune defensive strategies. Our results further demonstrate that the unique immune system of the Atlantic cod provides an unprecedented opportunity to explore the evolutionary history of PRR-based signaling in vertebrate immunity.

大西洋鳕（Atlantic cod）缺失主要组织相容性复合体II类（MHC class II）抗原呈递功能与多种病原体识别受体（pathogen recognition receptors，PRR），却未削弱其免疫应答，但其潜在的适应性调控机制仍鲜为人知。本研究中，研究人员以多种细菌、病毒来源的微生物相关分子模式（microbe-associated molecular patterns，MAMP）刺激离体大西洋鳕巨噬细胞，以鉴定其主要免疫应答通路。研究发现，基于核苷酸结合寡聚化结构域样受体（NOD-like receptors，NLRs）与视黄酸诱导基因I样受体（RIG-I-like receptors，RLRs）的胞质MAMP-PRR通路为关键应答通路。分析结果显示，清道夫受体介导的外源性配体内吞可激活上述两条通路，并激活核因子κB（Nuclear factor-kappa B，NF-κB）与干扰素调节因子（interferon regulatory factors，IRFs）等转录因子。此外，独特的TLR25亚型与多种NLR旁系同源基因的配体依赖性差异表达，提示其（亚）新功能化朝向特定免疫防御策略演化。本研究结果进一步表明，大西洋鳕独特的免疫系统为探索脊椎动物免疫中基于PRR的信号通路演化历史提供了前所未有的研究契机。