mLife最新文献 - Book学术

z-VAD-FMK triggers macrophage necroptosis during mycobacterial infection via a non-canonical off-target mechanism. z-VAD-FMK通过非规范脱靶机制触发分枝杆菌感染期间巨噬细胞坏死。

IF 6.7

mLife Pub Date : 2026-10-01 DOI: 10.1002/mlf2.70101

Rong Hu, Pei Li, Jie Han, Jiamin Huang, Guoyi Huang, Xiuju Jiang, Daniel Pfau, Guobao Li, Yi-Nan Gong, Carl F Nathan, Li Zhang

{"title":"z-VAD-FMK triggers macrophage necroptosis during mycobacterial infection via a non-canonical off-target mechanism.","authors":"Rong Hu, Pei Li, Jie Han, Jiamin Huang, Guoyi Huang, Xiuju Jiang, Daniel Pfau, Guobao Li, Yi-Nan Gong, Carl F Nathan, Li Zhang","doi":"10.1002/mlf2.70101","DOIUrl":"https://doi.org/10.1002/mlf2.70101","url":null,"abstract":"Macrophages are the predominant cell type infected by Mycobacterium tuberculosis (Mtb) in tuberculosis (TB). Death of Mtb-infected macrophages promotes tissue pathology and releases Mtb to infect other cells, suggesting that inhibiting the death of Mtb-infected macrophages could be an adjunctive treatment of TB. Prospects for such an intervention depend on identifying the molecular pathways leading to cell death. We previously reported that the death of Mtb-infected mouse macrophages in vitro depends on type I interferons (IFNs) and lysosomal membrane permeabilization contributes to cell death. Here, we report that the death of Mtb-infected primary mouse macrophages in vitro became necroptotic in the presence of a pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-FMK, hereafter called z-VAD) acting on a target other than caspase-8. Macrophages infected with Mycobacterium kansasii or Rhodococcus equi likewise underwent z-VAD-dependent necroptosis. In TB-resistant C57BL/6 mice, the deficiency of the key necroptosis executioner, mixed lineage kinase domain-like (MLKL), did not affect bacterial burden or pulmonary pathology. In contrast, in mice lacking the IFN repressor SP140, which express high levels of type I IFNs after Mtb infection and develop necrotic pulmonary lesions, MLKL-deficiency reduced bacterial burden and pathology after high-dose infection. This report illustrates that off-target action(s) of a caspase-8 inhibitor can switch the cell death pathway to necroptosis in macrophages infected with several Gram-positive pathogens and highlights that necroptosis can exacerbate TB. Identifying the target of z-VAD may help to delineate how necrotic lesions form in TB.","PeriodicalId":94145,"journal":{"name":"mLife","volume":" ","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13628176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149121252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Establishment of a genome editing system and expression of heterologous proteins in the nonconventional yeast Pichia kudriavzevii. 非常规酵母毕赤酵母基因组编辑系统的建立及异源蛋白的表达。

IF 6.7

mLife Pub Date : 2026-09-29 DOI: 10.1002/mlf2.70104

Jiayin Ma, Yifan Cui, Binru Yin, Cheng Jin

引用次数: 0

Targeting homologous recombination repair to potentiate fluoroquinolone efficacy in Mycobacterium abscessus. 靶向同源重组修复增强氟喹诺酮治疗脓肿分枝杆菌的疗效。

IF 6.7

mLife Pub Date : 2026-09-22 DOI: 10.1002/mlf2.70103

Shuai Wang, Md Shah Alam, Buhari Yusuf, Jingran Zhang, Ziwen Lu, Xiaofan Zhang, H M Adnan Hameed, Mst Sumaia Khatun, Chunyu Li, Lijie Li, Aleksey A Vatlin, Aweke M Belachew, Xirong Tian, Yamin Gao, Cuiting Fang, Rogers P Zhang, Jun Li, Xinyue Wang, Liqiang Feng, Li Wan, Tianyu Zhang

{"title":"Targeting homologous recombination repair to potentiate fluoroquinolone efficacy in Mycobacterium abscessus.","authors":"Shuai Wang, Md Shah Alam, Buhari Yusuf, Jingran Zhang, Ziwen Lu, Xiaofan Zhang, H M Adnan Hameed, Mst Sumaia Khatun, Chunyu Li, Lijie Li, Aleksey A Vatlin, Aweke M Belachew, Xirong Tian, Yamin Gao, Cuiting Fang, Rogers P Zhang, Jun Li, Xinyue Wang, Liqiang Feng, Li Wan, Tianyu Zhang","doi":"10.1002/mlf2.70103","DOIUrl":"10.1002/mlf2.70103","url":null,"abstract":"Fluoroquinolones (FQs) are important for treating fast-growing mycobacterial infections; however, their efficacy can be limited by intrinsic resistance and the emergence of acquired resistance. FQs induce lethal DNA double-strand breaks (DSBs) by targeting topoisomerases. Through a transposon screen in Mycobacterium abscessus, we identified that disruption of adnB, a homologous recombination (HR) gene, markedly sensitized the pathogen to FQs. Subsequent study showed that deleting core HR components (adnB, recO, recA, recR, and ruvB) increased FQs' susceptibility, while other DSB repair pathways (single-strand annealing or non-homologous end joining) had no effect, demonstrating a unique reliance on HR for FQs' tolerance. Complementation with native or its homolog genes restored the resistance phenotype, indicating a conserved HR-dependent tolerance mechanism in M. abscessus. In a murine model, genetic HR abrogation significantly improved FQs' therapeutic efficacy. These results highlight HR repair as a potential therapeutic target to potentiate FQs' activity and combat drug resistance in M. abscessus infections.","PeriodicalId":94145,"journal":{"name":"mLife","volume":" ","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13595048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149027309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genome reduction in marine ammonia-oxidizing archaea driven by elevated temperature. 海洋氨氧化古菌基因组在高温驱动下的减少。

IF 6.7

mLife Pub Date : 2026-09-21 DOI: 10.1002/mlf2.70099

Minglei Ren, Jianjun Wang

引用次数: 0

Mechanistic insights into HipA-mediated bacterial persistence: Role of initial cellular states and toxin expression kinetics. hipa介导的细菌持久性的机制见解：初始细胞状态和毒素表达动力学的作用。

IF 6.7

mLife Pub Date : 2026-09-16 DOI: 10.1002/mlf2.70095

Jing Zhao, Yixiao Xiong, Hongxia Zhao, Jin Wang, Xiaona Fang

{"title":"Mechanistic insights into HipA-mediated bacterial persistence: Role of initial cellular states and toxin expression kinetics.","authors":"Jing Zhao, Yixiao Xiong, Hongxia Zhao, Jin Wang, Xiaona Fang","doi":"10.1002/mlf2.70095","DOIUrl":"https://doi.org/10.1002/mlf2.70095","url":null,"abstract":"Persistent bacteria subpopulations showing multidrug tolerance pose significant challenges to antibiotic therapy. While the HipBA toxin-antitoxin (TA) system is known to play a role in persister formation, existing studies predominantly focus on its kinase activity and intracellular regulatory pathways, with limited attention to the environmental or conditional factors. In this study, we administered controlled induction of HipA across varied growth conditions in Escherichia coli, establishing that conditional constraints fundamentally modulate HipA's capacity to induce persistence. We demonstrated that cells in the lag phase, rather than in the exponential or stationary phase, were more likely to enter the persistent state upon HipA upregulation. Moreover, our results indicated that the accumulation rate of HipA, rather than the absolute HipA level, was a crucial determinant of persister frequency. Finally, we confirmed the essential role of RelA in HipA-mediated formation of persistent bacteria. These findings highlight the importance of previously unexplored conditional factors and expression kinetics in HipA-mediated persistence, providing mechanistic insights that link toxin kinetics, growth phase regulation, and stringent response signaling in bacterial antibiotic tolerance.","PeriodicalId":94145,"journal":{"name":"mLife","volume":" ","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13579642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148993353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

ISAba1-mediated crp-osmC amplification enhances host-associated fitness in Acinetobacter baumannii. isaba1介导的crp-osmC扩增增强鲍曼不动杆菌宿主相关适应度

IF 6.7

mLife Pub Date : 2026-09-14 DOI: 10.1002/mlf2.70105

Da-Wei Wei, Jiangqing Huang, Hailing Fang, Xinyu Wang, Gang Zhang, Chao Wang, Yuqin Song, Jie Feng

{"title":"ISAba1-mediated crp-osmC amplification enhances host-associated fitness in Acinetobacter baumannii.","authors":"Da-Wei Wei, Jiangqing Huang, Hailing Fang, Xinyu Wang, Gang Zhang, Chao Wang, Yuqin Song, Jie Feng","doi":"10.1002/mlf2.70105","DOIUrl":"10.1002/mlf2.70105","url":null,"abstract":"Acinetobacter baumannii is a pathogen, highly adaptable to both hospital- and host-associated environments. Understanding the genetic mechanisms underlying its adaptability is critical for controlling its persistence. Our study identified the crp-osmC gene cluster, flanked by ISAba1 elements, as a significant genetic structure undergoing amplification in A. baumannii. By experimentally mimicking the amplification of this gene cluster, we found that it substantially enhanced bacterial growth and competitive fitness, promoted survival in mouse serum, and improved colonization in murine infection models. Mechanistically, transcriptomic analysis suggested that crp-osmC amplification may enhance host-associated fitness by promoting pathways related to metabolic flexibility and nutrient acquisition, including phenylalanine metabolism, siderophore biosynthesis, and sulfur metabolism. It is noteworthy that this amplification was largely limited to the epidemic ST2 lineage clinical isolates. Intriguingly, gene amplification was also accompanied by reduced biofilm formation and heightened susceptibility to several antibiotics. Overall, ISAba1-mediated amplification of the crp-osmC cluster enhances host-associated fitness in A. baumannii, while the accompanying increase in antibiotic sensitivity reflects a trade-off between survival and resistance.","PeriodicalId":94145,"journal":{"name":"mLife","volume":" ","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13574567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148979116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Coxiella burnetii inhibits host cell death by ubiquitination-induced inactivation of an apoptosis nuclease. 伯纳氏杆菌通过泛素化诱导细胞凋亡核酸酶失活抑制宿主细胞死亡。

IF 6.7

mLife Pub Date : 2026-08-27 eCollection Date: 2026-08-01 DOI: 10.1002/mlf2.70093

Yong Zhang, Jun Jiao, Shuxin Liu, Jingya Yuan, Siyao Liu, Tao-Tao Chen, Songying Ouyang, Jiaqi Fu, Zhao-Qing Luo

引用次数: 0

Functional characterization of a pore-forming effector TseMt from the H4 type VI secretion system of Pseudomonas aeruginosa. 铜绿假单胞菌H4型分泌系统成孔效应因子TseMt的功能表征

IF 6.7

mLife Pub Date : 2026-08-27 eCollection Date: 2026-08-01 DOI: 10.1002/mlf2.70108

Liwen Wu, Yong Liu, Ruolin Huang, Ying Zhao, Junbo Liu, Ying An, Yiqiu Zhang, Xingyu Wang, Haoyu Zheng, Tongtong Pei, Xiaoye Liang, Xiaotian Liu, Min Zheng, Ronghui Liu, Yi Li, Jiuxin Qu, Yingxia Liu, Liang Yang, Mingjie Zhang, Tao Dong

{"title":"Functional characterization of a pore-forming effector TseMt from the H4 type VI secretion system of Pseudomonas aeruginosa.","authors":"Liwen Wu, Yong Liu, Ruolin Huang, Ying Zhao, Junbo Liu, Ying An, Yiqiu Zhang, Xingyu Wang, Haoyu Zheng, Tongtong Pei, Xiaoye Liang, Xiaotian Liu, Min Zheng, Ronghui Liu, Yi Li, Jiuxin Qu, Yingxia Liu, Liang Yang, Mingjie Zhang, Tao Dong","doi":"10.1002/mlf2.70108","DOIUrl":"10.1002/mlf2.70108","url":null,"abstract":"Pseudomonas aeruginosa is a major nosocomial pathogen in which the type VI secretion system (T6SS) contributes to interbacterial competition and virulence. While most strains encode three T6SSs, additional T6SS clusters have been identified in clinical isolates through comparative genomics, but their functions and effector biology remain undefined. Here, we identify TseMt as a major antibacterial effector associated with an H4-T6SS in a clinical P. aeruginosa isolate LYSZa7. TseMt is a periplasmically active toxin whose activity is neutralized by a cognate immunity protein, TsiMt. Biochemical assays show that TseMt binds membranes and forms ion-conducting pores, establishing it as a pore-forming effector. A 3.0 Å cryo-electron microscopy structure reveals a distinct three-domain architecture comprising an N-terminal MIX-like domain, a central α-helical scaffold, and a C-terminal toxin domain. Genetic analysis and structural modeling indicate that TseMt is delivered through a dedicated PAAR-VgrG-chaperone pathway. Together, these findings define the structural basis, functional mechanism, and delivery pathway of the H4-T6SS effector TseMt from a clinical P. aeruginosa isolate and reveal its role in mediating bacterial competition.","PeriodicalId":94145,"journal":{"name":"mLife","volume":" ","pages":"417-431"},"PeriodicalIF":6.7,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13520059/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148842711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Functionally cured chronic hepatitis B: A cure-related occult HBV infection state. 功能性治愈的慢性乙型肝炎：一种与治愈相关的隐性HBV感染状态。

IF 6.7

mLife Pub Date : 2026-08-27 eCollection Date: 2026-08-01 DOI: 10.1002/mlf2.70102

Fengmin Lu, Xin Zheng, Xinyu Du, Xianlin Ye, Yongzhen Liu, Jinfeng Zeng, Ying Yan

{"title":"Functionally cured chronic hepatitis B: A cure-related occult HBV infection state.","authors":"Fengmin Lu, Xin Zheng, Xinyu Du, Xianlin Ye, Yongzhen Liu, Jinfeng Zeng, Ying Yan","doi":"10.1002/mlf2.70102","DOIUrl":"10.1002/mlf2.70102","url":null,"abstract":"Occult HBV infection (OBI) is characterized by the presence of replication-competent hepatitis B virus (HBV) DNA (covalently closed circular DNA [cccDNA] and/or relaxed circular DNA [rcDNA]) in the liver and/or HBV DNA in the blood, despite negative hepatitis B surface antigen (HBsAg) serology. The potential risks associated with OBI include HBV blood transmission, diagnostic challenges, and viral reactivation under immunosuppressive therapy. Some patients with OBI may face a higher risk of liver fibrosis compared to those who have achieved complete clearance of the virus. Functional cure is defined as the clearance of HBsAg, with or without hepatitis B surface antibody (anti-HBs) seroconversion, and undetectable serum HBV DNA after finite therapy. It has been recommended as the optimal goal of antiviral treatment for chronic hepatitis B (CHB) by major guidelines. We highlight that patients achieving functional cure represent a distinct form of cure-related OBI, with unique virological features and potential clinical implications. Furthermore, although direct epidemiological evidence remains limited, accumulating studies have demonstrated that OBI cases with undetectable HBV DNA and negative HBsAg serology retain the potential for transfusion transmission. Accordingly, the transfusion-related risk associated with functional cure should not be overlooked. Here, we discuss the definition, virological and immunological basis, prevalence, diagnosis, and clinical significance of OBI, highlighting its link to cccDNA persistence and immune suppression of viral replication. Finally, we emphasize regular follow-up to mitigate the risks of transfusion-related transmission, HBV reactivation, and disease progression. Further research is warranted to elucidate the viral and immune status of functionally cured patients, thereby optimizing treatment strategies and ensuring blood safety.","PeriodicalId":94145,"journal":{"name":"mLife","volume":" ","pages":"393-400"},"PeriodicalIF":6.7,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13519582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148842639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Thirteen-year genomic analysis (2010-2022) reveals high-risk ICU Pseudomonas aeruginosa in China. 13年基因组分析（2010-2022）揭示中国ICU铜绿假单胞菌高危人群

IF 6.7

mLife Pub Date : 2026-08-27 eCollection Date: 2026-08-01 DOI: 10.1002/mlf2.70097

Jiadai Huang, Kaichao Chen, Miaomiao Xie, Weiyi Shen, Xiaoyang Ju, Yuchen Wu, Jiaping Li, Hongwei Zhou, Yonglu Huang, Yizhou Zhang, Yuanfeng Zhang, Tianmin Li, Letong Xu, Yue Sun, Fang Chen, Sheng Chen, Xin Deng, Rong Zhang, Yanyan Hu

{"title":"Thirteen-year genomic analysis (2010-2022) reveals high-risk ICU Pseudomonas aeruginosa in China.","authors":"Jiadai Huang, Kaichao Chen, Miaomiao Xie, Weiyi Shen, Xiaoyang Ju, Yuchen Wu, Jiaping Li, Hongwei Zhou, Yonglu Huang, Yizhou Zhang, Yuanfeng Zhang, Tianmin Li, Letong Xu, Yue Sun, Fang Chen, Sheng Chen, Xin Deng, Rong Zhang, Yanyan Hu","doi":"10.1002/mlf2.70097","DOIUrl":"10.1002/mlf2.70097","url":null,"abstract":"Pseudomonas aeruginosa is a significant opportunistic pathogen, particularly prevalent in intensive care units (ICUs). Through a comprehensive genomic and phenotypic analysis of 518 ICU and healthy isolates collected over a 13-year period (2010-2022), we found that ICU strains, despite reduced sequence type (ST) diversity, are dominated by persistent high-risk clones, notably ST463 and ST1076. Despite possessing a lower overall prophage content, ICU isolates show a broader and more diverse repertoire of anti-phage defense systems. This strengthened defense capacity correlates with ICU strains, demonstrating heightened resistance to phage challenge and contributing to lower historical phage exposure. Concurrently, ICU isolates harbor a significantly higher antimicrobial resistance (AMR) gene burden. Our detailed genomic analysis shows that this increased AMR is primarily driven by plasmid acquisition. Importantly, AMR genes associated with prophage elements are exclusively found in ICU isolates, highlighting their selective retention and functional contribution to resistance in this high-pressure environment. Furthermore, specific virulence genes, including exoU, pilA, and rhsP2, are more prevalent in ICU strains, indicating enhanced pathogenicity. Collectively, these findings underscore a qualitative distinction in ICU P. aeruginosa: their dominance and persistence stem from highly adapted clones, robust anti-phage defenses, rapid plasmid-mediated AMR acquisition, and clinically selected prophage-borne AMR.","PeriodicalId":94145,"journal":{"name":"mLife","volume":" ","pages":"459-472"},"PeriodicalIF":6.7,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13519588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148842652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0