Peptide methionine sulfoxide reductases (Msrs) are enzymes that repair ROS-damage to sulfur-containing amino acids such as methionine, ensuring functional integrity of cellular proteins. Here we have shown that unlike the majority of pro- and eukaryotic Msrs, the peptide methionine sulfoxide reductase (MsrAB) from the human pathobiont Haemophilus influenzae (Hi) is required for the repair of hypochlorite damage to cell envelope proteins, but more importantly, we were able to demonstrate that MsrAB plays a role in modulating the host immune response to Hi infection. Loss of MsrAB resulted in >1000-fold increase in sensitivity of Hi to HOCl-mediated killing, and also reduced biofilm formation and in-biofilm survival. Expression of msrAB was also induced by hydrogen peroxide and paraquat, but a Hi2019^ΔmsrAB strain was not susceptible to killing by these ROS in vitro. Hi2019^ΔmsrAB fitness in infection models was low, with a 3-fold reduction in intracellular survival in bronchial epithelial cells, increased susceptibility to neutrophil killing, and a 10-fold reduction in survival in a mouse model of lung infection. Interestingly, infection with Hi2019^ΔmsrAB led to specific changes in the antibacterial response of human host cells, with genes encoding antimicrobial peptides (BPI, CAMP) upregulated between 4 and 9 fold compared to infection with Hi2019^WT, and reduction in expression of two proteins with antiapoptotic functions (BIRC3, XIAP). Modulation of host immune responses is a novel role for an enzyme of this type and provides first insights into mechanisms by which MsrAB supports Hi survival in vivo.

中文翻译：

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流感嗜血杆菌的肽蛋氨酸亚砜还原酶是必需的，可防止HOCl的侵染，并影响宿主对感染的反应。

肽甲硫氨酸亚砜还原酶（Msrs）是将ROS损伤修复为含硫氨基酸如甲硫氨酸的酶，从而确保细胞蛋白质的功能完整性。在这里，我们已经表明，与大多数原核和真核Msrs不同，人类病原体流感嗜血杆菌（Hi）的肽蛋氨酸亚砜还原酶（MsrAB ）是修复次氯酸盐对细胞包膜蛋白的修复所必需的，但更重要的是，我们能够证明MsrAB在调节宿主对Hi感染的免疫反应中起作用。MsrAB的丢失导致Hi对HOCl介导的杀伤的敏感性增加> 1000倍，并且还减少了生物膜的形成和生物膜的存活。msrAB的表达也诱导过氧化氢和百草枯，但Hi2019 ^{Δ msrAB}菌株不容易通过体外这些ROS杀死。Hi2019 ^{Δ msrAB}在感染模型适合度较低，在细胞内生存了3倍的减少支气管上皮细胞，易感性增加嗜中性粒细胞杀死，并在存活10倍减少肺部感染的小鼠模型。有趣的是，感染Hi2019 ^{Δ msrAB}导致人类宿主细胞的抗菌响应的具体变化，用编码4和9之间上调抗微生物肽（BPI，CAMP）基因倍相比感染Hi2019 ^WT，并降低两种具有抗凋亡功能的蛋白质（BIRC3，XIAP）的表达。宿主免疫应答的调节是这种酶的新作用，它为MsrAB在体内支持Hi存活的机制提供了初步见识。