Department of Microbiology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
J Bacteriol. 2024 Aug 22;206(8):e0009824. doi: 10.1128/jb.00098-24. Epub 2024 Jul 17.
The innate immune system employs a variety of antimicrobial oxidants to control and kill host-associated bacteria. Hypothiocyanite/hypothiocyanous acid (OSCN/HOSCN) is one such antimicrobial oxidant that is synthesized by lactoperoxidase, myeloperoxidase, and eosinophil peroxidase at sites throughout the human body. HOSCN has potent antibacterial activity while being largely non-toxic toward human cells. The molecular mechanisms by which bacteria sense and defend themselves against HOSCN have only recently begun to be elaborated, notably by the discovery of bacterial HOSCN reductase (RclA), an HOSCN-degrading enzyme widely conserved among bacteria that live on epithelial surfaces. In this paper, I show that Ni sensitizes to HOSCN by inhibiting glutathione reductase and that inorganic polyphosphate protects against this effect, probably by chelating Ni ions. I also found that RclA is very sensitive to inhibition by Cu and Zn, metals that are accumulated to high levels by innate immune cells, and that, surprisingly, thioredoxin and thioredoxin reductase are not involved in HOSCN stress resistance in . These results advance our understanding of the contribution of different oxidative stress responses and redox buffering pathways to HOSCN resistance in and illustrate important interactions between metal ions and the enzymes bacteria use to defend themselves against oxidative stress.
Hypothiocyanite (HOSCN) is an antimicrobial oxidant produced by the innate immune system. The molecular mechanisms by which host-associated bacteria defend themselves against HOSCN have only recently begun to be understood. The results in this paper are significant because they show that the low molecular weight thiol glutathione and enzyme glutathione reductase are critical components of the HOSCN response, working by a mechanism distinct from that of the HOSCN-specific defenses provided by the RclA, RclB, and RclC proteins and that metal ions (including nickel, copper, and zinc) may impact the ability of bacteria to resist HOSCN by inhibiting specific defensive enzymes (e.g., glutathione reductase or RclA).
先天免疫系统采用多种抗菌氧化剂来控制和杀死与宿主相关的细菌。次碘酸盐/次碘酸（OSCN/HOSCN）是一种这样的抗菌氧化剂，它由乳过氧化物酶、髓过氧化物酶和嗜酸性粒细胞过氧化物酶在人体各处合成。HOSCN 具有很强的抗菌活性，而对人体细胞的毒性则相对较低。细菌感知并防御 HOSCN 的分子机制最近才开始被详细阐述，特别是通过发现细菌 HOSCN 还原酶（RclA），这是一种广泛存在于生活在上皮表面的细菌中的 HOSCN 降解酶。在本文中，我表明 Ni 通过抑制谷胱甘肽还原酶使 对 HOSCN 敏感，而无机多磷酸盐通过螯合 Ni 离子来保护 免受这种影响。我还发现 RclA 对 Cu 和 Zn 的抑制非常敏感，这两种金属在先天免疫细胞中积累到很高水平，令人惊讶的是，硫氧还蛋白和硫氧还蛋白还原酶不参与 对 HOSCN 应激的抗性。这些结果提高了我们对不同氧化应激反应和氧化还原缓冲途径对 中 HOSCN 抗性的贡献的理解，并说明了金属离子与细菌用来防御氧化应激的酶之间的重要相互作用。
次碘酸（HOSCN）是先天免疫系统产生的一种抗菌氧化剂。宿主相关细菌防御自身免受 HOSCN 的分子机制最近才开始被理解。本文的结果意义重大，因为它们表明，低分子量硫醇谷胱甘肽和酶谷胱甘肽还原酶是 中 HOSCN 反应的关键组成部分，其作用机制与 RclA、RclB 和 RclC 蛋白提供的 HOSCN 特异性防御机制不同，金属离子（包括镍、铜和锌）可能通过抑制特定的防御酶（如谷胱甘肽还原酶或 RclA）来影响细菌抵抗 HOSCN 的能力。
