中国病毒学英文版
IF:4.7
公众号ID:virologica
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作者
唐康,庄楷,赵祖逸,张炳松,刘欣,李诗斯,唐静,陈绎霖,杜向军
单位
广东医科大学公共卫生学院
中山大学公共卫生学院(深圳)
北京师范大学数学科学学院
深圳市宝安区慢性病防治院
广东医科大学生物医学工程学院
摘要
病毒性感染病一直以来威胁着人类的生存健康,而基于动物模型的生物医学研究成果在临床应用上的转化率较低。然而对造成这种结果的原因却缺少系统的探索。这里,我们整合构建了包括人类在内的7个物种的蛋白互作组,并发现对这些物种的研究程度呈现巨大差异。使用一个随机采样策略分别获得与6个物种具有相同网络规模的人类互作组,发现病毒靶向蛋白在互作组上的聚集程度(LCC比例),及这些靶点从互作组上移除后网络碎片化程度(IC值)与互作组的网络大小(即网络密度)相关。与人类相比,不同病毒对其他物种的扰动具有复杂性,然而整体呈现出聚集程度降低及病毒靶点相对IC值小于0的趋势。病毒靶向蛋白(VTPs)的相对IC值大小与网络局部结构的保守性(ICC值)相关,而与序列相似性无关,表明在病毒与宿主相互作用过程中,是局部网络结构受到选择,并进一步维系网络韧性。进一步结果发现,相对IC值及LCC比例差异与病毒性传染病的非疫苗药物治疗批准率呈正比,表明我们的发现将有助于理解跨物种病毒扰动的差异并指导后续模式动物的选择。
Fig. 1. Estimation of the human interactome size. (A) Overview of network-based framework for analysis of evolutionary divergence in virus–host interactions. (B) Describing the process of human interactome size estimation. (C) Human interactome size estimated by comparison to different species with respect to the number of protein-coding genes and PPIs. The circle area is proportional to the PPI number. Ns, the number of starting nodes in the human interactome; Ms, the edge number in the human interactome corresponding to Ns = 18,101 nodes; Ne, the node number within the largest connected component; Me, the edge number in the human interactome corresponding to Ne nodes; ph, the probability of each possible PPI in humans; PPI, protein-protein interaction.
Fig. 2. Two metrics for assessing the evolutionary conservation of proteins.(A) The relative number of 1:1 orthologous proteins between humansand other species. The point size represents the absolute number of 1:1 orthologs. (B)ICC measures the proportion of conserved PPIs between protein v in humans and its orthologous protein v'. (C) The correlation between ICC and sequence similarity in orthologous protein pairs between humans and mice. Statistical results of gene set enrichment analysis based on sequence similarity scores(D)and ICC values (E). Dot size represents the number of pathways within the enriched pathway categories. Red and blue colors indicate conserved and divergent pathways, respectively. ICC, interaction conservation coefficient.
Fig. 3. Heterogeneity in the LCC proportion across species. Correlation between LCC proportion and network density (A)and divergence timebetween six species and humans (B). (C)The linear relationship between the mean LCC proportion and network density for 6,000 randomized human interactomes. Lines show the generalized linear model of LCC proportion values, and the colored bands indicate 95% confidence band for the linear fit. (D) Comparison of LCC proportions in the mouse interactome versus size-matched human interactomes. The blue vectors signify reduced connectivity conservation. (E) Correlation between host carrier number and LCC proportion differences for viruses. LCC, largest connected component; AIC, Akaike information criterion.
Fig. 4. Perturbations exerted by viruses on host interactomes. (A) The relative IC measures the change in topological fragmentation between protein v in humans and its orthologous protein v'. (B) The ranking of viruses by mean relative IC values in each comparator species (in descending order), followed by aggregation of their average ranks across all six species. The correlation between relative IC and sequence similarity (C) and ICC (D) in orthologous gene pairs of three classifications (non-, specific- and pan-VTP) between humans and mice. (E)The correlation between mean relative IC and LCC proportion differences for 29 viruses between humans and mice. (F)The linear relationship between the mean IC and network density for 6,000 randomized human interactomes. Lines show the generalized linear model of mean IC values, and the colored bands indicate 95% confidence band for the linear fit. IC, isolated components; LCC, largest connected component; ICC, interaction conservation coefficient; AIC, Akaike information criterion.
Fig.5. The correlation between network metrics and the approval rates of antiviral therapeutics.The correlation between mean relative IC (A), LCC proportion differences (B), and sequence similarity (C) and the probabilities of success from phase 1 trials to approval (PoS1A) of vaccine and non-vaccine anti-infective drug development programs. IC, isolated components; LCC, largest connected component.
本文亮点
采用了一种随机抽样策略,从完整的人类互作组中抽取边子集,生成与每个参考物种网络规模相匹配的“大小匹配版”人类互作组
人类的蛋白质互作网络在面对病毒攻击时表现出更强的韧性。这可能是人类与病毒长期“军备竞赛”的进化结果——即使病毒倾向于攻击网络中的核心节点,人类网络依然演化出了更强的抗干扰能力
进化选择压力作用在局部网络结构层面,而非单个蛋白质序列层面——维持网络结构的稳定性,可能比维持个别氨基酸序列的保守性更为重要
网络指标(LCC比例差异和相对IC值)与抗病毒非疫苗药物的临床成功率显著相关,表明无法用序列相似性解释的转化失败,可能恰恰隐含在网络结构的差异之中
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VS 往期直达
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期刊简介
《中国病毒学(英文)》Virologica Sinica, 是中国科学院武汉病毒研究所和中国微生物学会共同主办的病毒学领域的专业学术期刊。聚焦病毒发现及流行规律、病毒致病机理、病毒-宿主互作、疫苗及抗病毒药物研发、病毒相关生物技术等领域,覆盖病毒学全链条研究。本刊最新影响因子4.7,5年影响因子4.6, 均位于病毒学领域前15%(JCR2025), CiteScore 2025 7.3, 连续十二年入选“中国最具国际影响力学术期刊” (TOP 5%)。期刊于2022年变更为以金色开放获取模式出版的开源期刊(Open Access Journal),与科爱出版社合作全球出版传播。本刊为中国科技核心期刊,且被SCI、PubMed/Medline、PubMed Central、Scopus等数据库收录。