毒力调节因子AbsR对禽致病性大肠杆菌细菌生理具有多重作用

Journal of Integrative Agriculture ›› 2024, Vol. 23 ›› Issue (2): 649-668.DOI: 10.1016/j.jia.2023.07.035

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毒力调节因子AbsR对禽致病性大肠杆菌细菌生理具有多重作用

收稿日期:2023-04-09 接受日期:2023-06-19 出版日期:2024-02-20 发布日期:2024-01-30

The virulence regulator AbsR in avian pathogenic Escherichia coli has pleiotropic effects on bacterial physiology

Dongfang Zhao^{1, 2*}, Haobo Zhang^3*, Xinyang Zhang^{1, 2}, Fengwei Jiang¹, Yijing Li², Wentong Cai^1#, Ganwu Li^{1, 4#}

¹State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China
²College of Veterinary Medicine, Northeast Agricultural University, Harbin 150038, China
³National Animal Tuberculosis Reference Laboratory, Division of Zoonoses Surveillance, China Animal Health and Epidemiology Center, Qingdao 266032, China
⁴Department of Veterinary Diagnostic and Production Animal Medicine, College of Veterinary Medicine, Iowa State University, Ames, Iowa 50011-1134, the United States

Received:2023-04-09 Accepted:2023-06-19 Online:2024-02-20 Published:2024-01-30
About author:Dongfang Zhao, E-mail: zhaodongfang1104@163.com; Haobo Zhang, E-mail: zhanghaobo@cahec.cn; #Correspondence Wentong Cai, E-mail: caiwentong@caas.cn; Ganwu Li, E-mail: liganwu@iastate.edu * These authors contributed equally to this study
Supported by:
This work was supported by the National Natural Science Foundation of China Young Scholars Project (31902242) and the Agricultural Science and Technology Innovation Program (ASTIP) of Chinese Academy of Agricultural Sciences (2017–2020).

摘要/Abstract

摘要：

禽致病性大肠杆菌（Avian pathogenic Escherichia coli ,APEC）是一种肠外致病性大肠杆菌（Extraintestinal pathogenic E. coli , ExPEC），可引起禽类和人类肠道以外组织的严重感染。MprA（microcin production regulation, locus A，现更名为AbsR，a blood survival regulator）是MarR（multiple antibiotic resistance regulator）转录调节因子家族的成员。它调控人源ExPEC中荚膜生物合成基因的表达，并且具有作为药物靶标的潜力。然而，目前的研究尚未完全阐明AbsR的靶基因及其调控机制。本研究利用ChIP-Seq和RNA-Seq技术对APEC AbsR调节子进行了系统分析，结果表明，AbsR直接调控99个基因，间接调控667个基因。接下来通过实时荧光定量PCR和体外实验证实了AbsR对靶基因转录水平和功能的影响。研究发现，AbsR在APEC XM中直接调控K1荚膜基因簇的表达，从而使菌株能够抵抗巨噬细胞的吞噬、血清杀伤，并发挥毒力作用。此外，AbsR还直接激活酸感应信号系统基因evgAS及耐酸相关基因hdeBAD和gadE，从而发挥体外耐酸能力。它还通过直接激活T2SS基因簇的表达，进而影响SslE蛋白的表达和分泌促进生物膜形成。此外，AbsR还间接调控I-F CRISPR系统基因的表达。在小鼠模型中，我们探索了AbsR及其靶基因对APEC XM毒力的影响，证实AbsR主要通过荚膜基因簇发挥毒力。在另外三株不同来源的ExPEC分离株中，AbsR可以抑制1型菌毛基因和I-F CRISPR系统相关基因的表达，同时激活酸感应信号系统基因evgAS、Group 2荚膜基因的表达；表明这些调控对于ExPEC共同的靶基因具有普适性。本研究首次系统梳理了MarR家族转录调控因子AbsR在肠道外致病性大肠杆菌的调控网络及其调控机制，明确了AbsR作为一类调控蛋白的调控方式及其致病机制。研究还首次证实AbsR对肠道外致病性大肠杆菌中的共同靶基因的调控具有普适性，这大大增进了我们对AbsR调控和功能的理解，并拓展了AbsR调控网络的广度。这对于预防及治疗大肠杆菌病的药物选择及维持宿主共生菌群稳态提供了重要参考。此外，该研究结果也为将来基于AbsR的药物筛选和研发提供理论依据。

Abstract:

Avian pathogenic Escherichia coli (APEC) belonging to extraintestinal pathogenic E. coli (ExPEC) can cause severe infections in extraintestinal tissues in birds and humans, such as the lungs and blood. MprA (microcin production regulation, locus A, herein renamed AbsR, a blood survival regulator), a member of the MarR (multiple antibiotic resistance regulator) transcriptional regulator family, governs the expression of capsule biosynthetic genes in human ExPEC and represents a promising druggable target for antimicrobials. However, a deep understanding of the AbsR regulatory mechanism as well as its regulon is lacking. In this study, we present a systems-level analysis of the APEC AbsR regulon using ChIP-Seq (chromatin immunoprecipitation sequencing) and RNA-Seq (RNA sequencing) methods. We found that AbsR directly regulates 99 genes and indirectly regulates 667 genes. Furthermore, we showed that: 1) AbsR contributes to antiphagocytotic effects by macrophages and virulence in a mouse model for systemic infection by directly activating the capsular gene cluster; 2) AbsR positively impacts biofilm formation via direct regulation of the T2SS (type II secretion system) but plays a marginal role in virulence; and 3) AbsR directly upregulates the acid tolerance signaling system EvgAS to withstand acid stress but is dispensable in ExPEC virulence. Finally, our data indicate that the role of AbsR in virulence gene regulation is relatively conserved in ExPEC strains. Altogether, this study provides a comprehensive analysis of the AbsR regulon and regulatory mechanism, and our data suggest that AbsR likely influences virulence primarily through the control of capsule production. Interestingly, we found that AbsR severely represses the expression of the type I-F CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR associated) systems, which could have implications in CRISPR biology and application.

Key words: Avian pathogenic Escherichia coli (APEC) , Extraintestinal pathogenic Escherichia coli (ExPEC) , AbsR , RNA-Seq , ChIP-Seq , Gene regulation

. 毒力调节因子AbsR对禽致病性大肠杆菌细菌生理具有多重作用[J]. Journal of Integrative Agriculture, 2024, 23(2): 649-668.

Dongfang Zhao, Haobo Zhang, Xinyang Zhang, Fengwei Jiang, Yijing Li, Wentong Cai, Ganwu Li.

The virulence regulator AbsR in avian pathogenic Escherichia coli has pleiotropic effects on bacterial physiology [J]. Journal of Integrative Agriculture, 2024, 23(2): 649-668.

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