Interferon signaling drives epithelial metabolic reprogramming to promote secondary bacterial infection.
Interferon signaling drives epithelial metabolic reprogramming to promote secondary bacterial infection.
复制标题
DOI：
10.1371/journal.ppat.1011719
复制
发表时间：
2023-11
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
临床研究报告，病毒感染促进多个宿主部位的急性或慢性细菌感染。这些病毒-细菌共感染与更严重的临床结果广泛相关。在体外和体内的实验模型中，病毒诱导的干扰素反应可以增加宿主对继发性细菌感染的易感性。在这里，我们使用基于细胞的筛选来评估389个干扰素刺激基因（ISGs）诱导慢性铜绿假单胞菌感染的能力。我们鉴定并验证了5种足以促进细菌感染的isg。此外，我们剖析了己糖激酶2 （HK2）的作用机制，这是一种参与诱导有氧糖酵解的基因，通常被称为Warburg效应。我们报道HK2上调介导Warburg效应和l -乳酸分泌，从而增强慢性铜绿假单胞菌感染。这些发现阐明了抗病毒免疫反应如何使宿主易受继发性细菌感染，揭示了病毒-细菌联合感染治疗的潜在策略。病毒感染可使宿主易受继发性细菌感染。越来越多的证据表明，病毒-细菌合并感染会导致更严重的临床表现，并导致危及生命的急性或慢性细菌感染。宿主对病毒感染的免疫反应促进继发性细菌感染；然而，我们对抗病毒反应如何有利于随后的细菌感染的理解是有限的。在这里，我们的目的是评估由抗病毒反应诱导的一组基因，即干扰素刺激基因（ISGs），在增强铜绿假单胞菌感染中的作用，这种感染常见于免疫功能低下个体呼吸道的病毒-细菌共感染。我们发现，ISG己糖激酶2 （HK2）驱动代谢重编程并介导呼吸上皮分泌代谢物乳酸，促进慢性铜绿假单胞菌感染。这些发现提高了我们对抗病毒反应如何改变宿主粘膜环境，从而导致随后的细菌感染的理解。
Clinical studies report that viral infections promote acute or chronic bacterial infections at multiple host sites. These viral-bacterial co-infections are widely linked to more severe clinical outcomes. In experimental models in vitro and in vivo, virus-induced interferon responses can augment host susceptibility to secondary bacterial infection. Here, we used a cell-based screen to assess 389 interferon-stimulated genes (ISGs) for their ability to induce chronic Pseudomonas aeruginosa infection. We identified and validated five ISGs that were sufficient to promote bacterial infection. Furthermore, we dissected the mechanism of action of hexokinase 2 (HK2), a gene involved in the induction of aerobic glycolysis, commonly known as the Warburg effect. We report that HK2 upregulation mediates the induction of Warburg effect and secretion of L-lactate, which enhances chronic P. aeruginosa infection. These findings elucidate how the antiviral immune response renders the host susceptible to secondary bacterial infection, revealing potential strategies for viral-bacterial co-infection treatment. Viral infections can make the host susceptible to secondary bacterial infections. Increasing evidence indicates that viral-bacterial co-infections cause worse clinical manifestations and lead to life-threatening acute or chronic bacterial infections. The host immune response against a viral infection promotes secondary bacterial infection; however, our understanding of how the antiviral response favors a subsequent bacterial infection is limited. Here, we aimed to assess the role of a suite of genes induced by the antiviral response, known as interferon-stimulated genes (ISGs), in the enhancement of Pseudomonas aeruginosa infection, which is frequently found in viral-bacterial co-infections in the airways of immunocompromised individuals. We found that the ISG hexokinase 2 (HK2), which drives metabolic reprogramming and mediates the secretion of the metabolite lactate by the respiratory epithelium, promotes chronic P. aeruginosa infection. These findings improve our understanding of how the antiviral response changes the host mucosal environment, enabling a subsequent bacterial infection.
登录
查看更多内容
影响因子：
3.1
作者：
Exley, RM;Goodwin, L;Tang, CM
通讯作者：
Tang, CM
影响因子：
3.7
作者：
Empey, Kerry M.;Orend, Jacob G.;Kolls, Jay K.
通讯作者：
Kolls, Jay K.
影响因子：
30.5
作者：
Jochems SP;Marcon F;Carniel BF;Holloway M;Mitsi E;Smith E;Gritzfeld JF;Solórzano C;Reiné J;Pojar S;Nikolaou E;German EL;Hyder-Wright A;Hill H;Hales C;de Steenhuijsen Piters WAA;Bogaert D;Adler H;Zaidi S;Connor V;Gordon SB;Rylance J;Nakaya HI;Ferreira DM
通讯作者：
Ferreira DM
影响因子：
6.7
作者：
Hosmer J;Nasreen M;Dhouib R;Essilfie AT;Schirra HJ;Henningham A;Fantino E;Sly P;McEwan AG;Kappler U
通讯作者：
Kappler U
影响因子：
8
作者：
Finelli, Lyn;Fiore, Anthony;Uyeki, Timothy
通讯作者：
Uyeki, Timothy