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METTL3 aggravates lung injury in neonatal mice with Streptococcus pneumoniae-induced pneumonia via the circ_0001239/KLF10 axis. METTL3通过circ_0001239/KLF10轴加重肺炎链球菌诱导肺炎新生小鼠的肺损伤。
IF 2.8 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-11-11 Epub Date: 2025-10-17 DOI: 10.1128/iai.00288-25
Liping Yang, Yufei Xie, Panpan Yan, Mei Liu, Jingjing Zhang, Caixia Ma

As a leading causative agent of pneumonia infection worldwide, Streptococcus pneumoniae (Spn) induces lung injury and presents substantial therapeutic challenges. To elucidate the role of methyltransferase-like 3 (METTL3) in modulating circular RNA_0001239 (circ_0001239), YTH domain containing protein 2 (YTHDC2), and Krüppel-like factor 10 (KLF10) through m6A modification, we established Spn-induced neonatal mouse models. The survival rates, bacterial load in bronchoalveolar lavage fluid, and METTL3 expression in pulmonary tissue were evaluated. After METTL3 downregulation, lung wet-to-dry ratio, myeloperoxidase activity, and inflammatory markers were assessed. Methylated RNA immunoprecipitation detected enriched m6A modification on circ_0001239, while RNA immunoprecipitation validated the bindings of circ_0001239 to YTHDC2 and YTHDC2 to KLF10. The KLF10 mRNA stability was analyzed via actinomycin D treatment. METTL3 and circ_0001239 were upregulated in pneumonic lungs, while KLF10 was downregulated. METTL3 knockdown improved survival, alleviated lung injury, increased superoxide dismutase levels, and suppressed interleukin (IL)-6, IL-1β, and malondialdehyde levels. METTL3 promoted the binding of circ_0001239 to YTHDC2 via m6A modification, destabilizing KLF10 mRNA. Circ_0001239 overexpression or KLF10 knockdown reversed the protective effects of low expression of METTL3 on lung damage in neonatal mice with pneumonia. In conclusion, METTL3 aggravates Spn-induced lung injury via m6A-dependent circ_0001239/YTHDC2/KLF10 axis, thereby providing potential therapeutic targets for severe pneumonia.

作为世界范围内肺炎感染的主要病原体,肺炎链球菌(Spn)引起肺损伤,并提出了实质性的治疗挑战。为了阐明甲基转移酶样3 (METTL3)通过m6A修饰调控环状RNA_0001239 (circ_0001239)、含YTH结构域蛋白2 (YTHDC2)和kr pell样因子10 (KLF10)的作用,我们建立了spn诱导的新生小鼠模型。观察生存率、支气管肺泡灌洗液细菌载量及肺组织METTL3表达情况。METTL3下调后,评估肺干湿比、髓过氧化物酶活性和炎症标志物。甲基化RNA免疫沉淀检测到circ_0001239上富集的m6A修饰,而RNA免疫沉淀证实了circ_0001239与YTHDC2和YTHDC2与KLF10的结合。通过放线菌素D处理分析KLF10 mRNA的稳定性。METTL3和circ_0001239在肺中上调,而KLF10下调。METTL3基因敲低可提高生存率,减轻肺损伤,增加超氧化物歧化酶水平,抑制白细胞介素(IL)-6、IL-1β和丙二醛水平。METTL3通过m6A修饰促进circ_0001239与YTHDC2结合,破坏KLF10 mRNA的稳定。Circ_0001239过表达或KLF10敲低可逆转METTL3低表达对新生肺炎小鼠肺损伤的保护作用。综上所述,METTL3通过m6a依赖性circ_0001239/YTHDC2/KLF10轴加重spn诱导的肺损伤,从而为重症肺炎提供潜在的治疗靶点。
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引用次数: 0
Cell death pathways in response to Mycobacterium tuberculosis and other mycobacterial infections. 响应结核分枝杆菌和其他分枝杆菌感染的细胞死亡途径。
IF 2.8 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-10-14 Epub Date: 2025-09-09 DOI: 10.1128/iai.00401-25
Md Atik Faysal, Mostafa Hanafy, Denise K Zinniel, Fatema Yeasmin Tanni, Ezhumalai Muthukrishnan, Govardhan Rathnaiah, Raul G Barletta

Cell death mechanisms play a fundamental role in mycobacterial pathogenesis. We critically reviewed 94 research manuscripts, 44 review articles, and 4 book chapters to analyze important discoveries, background literature, and potential shortcomings in the field. The focus of this review is the pathogen Mycobacterium tuberculosis (Mtb) and other Mtb and Mycobacterium avium complex microorganisms. Virulent strains hijack cell death processes by inhibiting autophagy, apoptosis, and pyroptosis while eliciting necrosis and ferroptosis to multiply intracellularly and spread within and between hosts. In addition, virulent strains may induce apoptosis in epithelial cells or secondary infected macrophages to spread. Autophagy does not control Mtb intracellular replication in vivo but suppresses macrophage and T cell responses in Mtb infections, with a predominant role in preventing neutrophil infiltration. In contrast, attenuated vaccine strains promote apoptosis in macrophages, leading to the activation of innate immunity and, eventually, the acquired immune response. Although Mtb infection activates necroptosis, studies with mutant cell lines have indicated that this process is not essential for cell lysis and that Mtb promotes unprogrammed necrosis. Ferroptosis is discussed in the context of necrotic processes involving lipid peroxidation. Recent research indicated that pyroptosis is more akin to apoptosis as Mtb proteins induce cell membrane repair to prevent inflammasome activation. In the supplementary tables, homologs of mycobacterial cell death pathways and virulence factors were identified using a basic local alignment search tool protein followed by a conserved domain database search to determine the presence of functional domains. Finally, prospects for therapeutic interventions are discussed.

细胞死亡机制在分枝杆菌的发病机制中起着重要作用。我们批判性地回顾了94篇研究手稿、44篇综述文章和4本书章节,以分析该领域的重要发现、背景文献和潜在缺陷。本文综述的重点是病原体结核分枝杆菌(Mtb)和其他结核分枝杆菌和鸟分枝杆菌复合微生物。毒株通过抑制细胞自噬、细胞凋亡和焦亡来劫持细胞死亡过程,同时诱导坏死和铁亡在细胞内繁殖并在宿主内部和宿主之间传播。此外,毒株可诱导上皮细胞凋亡或继发性感染的巨噬细胞扩散。在体内,自噬不控制结核分枝杆菌的细胞内复制,但在结核分枝杆菌感染中抑制巨噬细胞和T细胞的反应,主要作用是防止中性粒细胞浸润。相反,减毒疫苗株促进巨噬细胞凋亡,导致先天免疫激活,最终获得性免疫应答。虽然结核分枝杆菌感染会激活坏死坏死,但对突变细胞系的研究表明,这一过程对细胞溶解不是必需的,结核分枝杆菌促进非程序性坏死。在涉及脂质过氧化的坏死过程的背景下讨论铁下垂。最近的研究表明,Mtb蛋白诱导细胞膜修复以阻止炎症小体的激活,从而导致细胞焦亡更类似于细胞凋亡。在补充表中,分枝杆菌细胞死亡途径和毒力因子的同源物是使用基本的局部比对搜索工具蛋白,然后使用保守结构域数据库搜索以确定功能结构域的存在。最后,对治疗干预的前景进行了讨论。
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引用次数: 0
Genetic transformation of Gardnerella species and characterization of vaginolysin and sialidase mutants. 加德纳菌种的遗传转化及阴道溶素和唾液酸酶突变体的鉴定。
IF 2.8 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-10-14 Epub Date: 2025-08-21 DOI: 10.1128/iai.00299-25
Amy K Klimowicz, Erin M Garcia, Kimberly K Jefferson, Joseph P Dillard

Bacterial vaginosis (BV) is the most prevalent vaginal disorder in women of childbearing age and causes pregnancy complications, including preterm birth, amnionitis, and postpartum endometritis. BV also interferes with sexual health and increases stress. BV is a vaginal dysbiosis that occurs when Lactobacillus species are displaced by facultative and anaerobic bacterial species, including Gardnerella, Prevotella, Fannyhessea, Sneathia, Megasphaera, Mycoplasma, and others. Species of Gardnerella increase just prior to the onset of symptoms and are considered to play major roles in the development and transmission of BV. However, Gardnerella species have remained genetically intractable, limiting investigations of their virulence mechanisms. Here, we describe methods for genetic manipulation of Gardnerella. Through trial and error, we optimized methods for electrotransformation of Gardnerella and created methods for making mutations and complements. We mutated the gene for the toxin vaginolysin (vly) in G. vaginalis and the gene for sialidase nanH3 in G. pickettii. A vly point mutant was tested in human cervix tissue and found to lack lytic activity. The nanH3 mutant lost sialidase and mucus degradation activity. Overall, this genetic toolkit opens a door for molecular characterization of Gardnerella and its mechanisms in BV.

细菌性阴道病(BV)是育龄妇女中最常见的阴道疾病,可引起妊娠并发症,包括早产、羊膜炎和产后子宫内膜炎。细菌性阴道炎还会干扰性健康,增加压力。细菌性阴道炎是一种阴道生态失调,发生在乳杆菌种被兼性和厌氧细菌种取代时,包括加德纳菌、普雷沃氏菌、范尼赫西菌、Sneathia菌、Megasphaera菌、支原体等。加德纳菌的种类在出现症状之前增加,被认为在细菌性阴道炎的发展和传播中起主要作用。然而,加德纳菌种类仍然难以遗传,限制了对其毒力机制的研究。在这里,我们描述了加德纳菌的遗传操作方法。通过反复试验,我们优化了加德纳菌电转化的方法,并创造了突变和补体的制备方法。我们突变了阴道革螨毒素阴道溶素(vly)基因和皮氏革螨唾液酸酶nanH3基因。在人宫颈组织中测试了一个vly点突变体,发现缺乏裂解活性。nanH3突变体丧失了唾液酸酶和粘液降解活性。总的来说,这个遗传工具箱为加德纳菌的分子特征及其在细菌性脑膜炎中的机制打开了一扇门。
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引用次数: 0
Modulation of group B Streptococcus infection and vaginal cell inflammatory signaling in vitro by Lactobacillus crispatus-loaded electrospun fibers. 负载马铃薯乳杆菌的静电纺丝纤维对B群链球菌感染和阴道细胞炎症信号的体外调节。
IF 2.8 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-10-14 Epub Date: 2025-08-27 DOI: 10.1128/iai.00170-25
Nagwa El-Baz, Anthony Kyser, Mohamed Y Mahmoud, Christopher Z Farrell, Sierra Ginocchio, Hermann B Frieboes, Ryan S Doster

Vaginal colonization by Streptococcus agalactiae, also known as Group B Streptococcus (GBS), is a major risk factor for ascending infections, preterm birth, and neonatal sepsis. Current GBS prevention efforts include routine GBS perinatal screening and intrapartum antibiotic prophylaxis, which decrease the rate of early-onset neonatal sepsis, but have drawbacks that include impacting the infant's developing microbiome. Lactobacillus-dominant vaginal microbiomes provide protection against pathogens such as GBS, and using probiotics as an antibiotic-free approach to limit GBS colonization is of increasing interest. In this study, we investigated the ability of Lactobacillus crispatus-loaded electrospun fibers to deliver live L. crispatus cells in an in vitro vaginal epithelial cell model, modulate GBS infection establishment and persistence, and alter vaginal cell inflammatory signaling. Our data demonstrate that electrospun fibers deliver viable L. crispatus to the surface of vaginal epithelial cells and that L. crispatus modulates vaginal cell inflammatory signaling by decreasing inflammatory IL-8 release and increasing anti-inflammatory IL-1RA secretion during established GBS infection. Treatment of pre-established GBS infection with electrospun fibers with or without L. crispatus decreased GBS burden at 24 hours, suggesting L. crispatus-dependent and -independent anti-GBS activity, and L. crispatus elicited an anti-inflammatory response via IL-1RA release. Overall, the data highlight the potential of electrospun fibers as a feasible probiotic delivery platform with antibacterial activity against GBS and which provides commensal lactobacilli capable of modulating host-pathogen interactions and inflammatory signaling of the vaginal epithelium.

无乳链球菌,也被称为B群链球菌(GBS),阴道定殖是上升感染、早产和新生儿败血症的主要危险因素。目前的GBS预防措施包括常规的GBS围产期筛查和产时抗生素预防,这可以降低早发性新生儿败血症的发生率,但也存在影响婴儿微生物群发育的缺点。乳酸菌为主的阴道微生物群提供了对GBS等病原体的保护,使用益生菌作为一种无抗生素的方法来限制GBS的定植越来越受到关注。在这项研究中,我们研究了负载crispatus乳杆菌的电纺丝纤维在体外阴道上皮细胞模型中传递活的crispatus细胞的能力,调节GBS感染的建立和持续,并改变阴道细胞炎症信号。我们的数据表明,在已建立的GBS感染过程中,电纺丝纤维将活的crispatus传递到阴道上皮细胞表面,并且crispatus通过减少炎性IL-8释放和增加抗炎IL-1RA分泌来调节阴道细胞炎症信号。用含有或不含crispatus的电纺丝纤维治疗预先建立的GBS感染24小时后,GBS负荷降低,表明crispatus依赖和独立抗GBS活性,并且crispatus通过IL-1RA释放引起抗炎反应。总的来说,这些数据强调了电纺丝纤维作为一种可行的益生菌输送平台的潜力,它具有抗GBS的抗菌活性,并提供能够调节宿主-病原体相互作用和阴道上皮炎症信号的共生乳酸菌。
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引用次数: 0
The emerging view on the roles of butyrate in Clostridioides difficile pathogenesis. 关于丁酸盐在艰难梭菌发病机制中的作用的新观点。
IF 2.8 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-10-14 Epub Date: 2025-09-24 DOI: 10.1128/iai.00047-25
Horia A Dobrila, Andrew J Hryckowian

The Centers for Disease Control and Prevention classifies Clostridioides difficile as an urgent threat to the nation's health, as it causes 450,000 infections, 15,000 deaths, and 1 billion dollars in excess healthcare costs per year in the United States. Current treatments for C. difficile infections (CDIs) are antibiotics and, in recurrent cases, microbiome restoration therapy (MRT). Antibiotics contribute to antibiotic resistance and recurrent CDIs. Although MRTs (e.g., defined consortia of microbes or fecal transplant) are increasingly accessible, the long-term sustainability and accessibility of these treatments remain to be determined. These limitations highlight the need for more precise strategies for coping with CDI. Because a disrupted (dysbiotic) gut microbiome is the primary risk factor for CDI, a better understanding of the interactions between C. difficile, the microbiome, and the host will aid the development of such treatments. Butyrate is a prominent microbiome-host co-metabolite that is influenced by host dietary fiber intake and differentiates healthy from dysbiotic gut ecosystems. Emerging evidence supports that butyrate is a key determinant of C. difficile fitness and pathogenesis. Here, we review the current literature and gaps in knowledge about how butyrate-rich gut environments exclude C. difficile, and how butyrate impacts C. difficile growth, metabolism, toxin production/release, and sporulation. We further discuss the implications of continued study of butyrate's impacts on CDI, including the eventual development of new strategies to mitigate CDI in at-risk human populations.

美国疾病控制与预防中心(Centers for Disease Control and Prevention)将艰难梭菌(clostridiides difficile)列为对美国健康的紧急威胁,因为它每年在美国导致45万人感染,1.5万人死亡,并造成10亿美元的额外医疗费用。目前艰难梭菌感染(cdi)的治疗方法是抗生素,在复发病例中,微生物组恢复治疗(MRT)。抗生素有助于抗生素耐药性和复发性cdi。尽管mrt(例如,定义的微生物群或粪便移植)越来越容易获得,但这些治疗的长期可持续性和可及性仍有待确定。这些限制突出了需要更精确的策略来应对CDI。由于肠道微生物群紊乱(生态失调)是CDI的主要危险因素,因此更好地了解艰难梭菌、微生物群和宿主之间的相互作用将有助于开发此类治疗方法。丁酸盐是一种重要的微生物群-宿主共代谢物,受宿主膳食纤维摄入量的影响,并能区分健康肠道生态系统和益生菌生态系统。新出现的证据支持丁酸盐是艰难梭菌适应性和发病机制的关键决定因素。在这里,我们回顾了目前的文献和关于富含丁酸盐的肠道环境如何排除艰难梭菌的知识空白,以及丁酸盐如何影响艰难梭菌的生长、代谢、毒素产生/释放和孢子形成。我们进一步讨论了丁酸盐对CDI影响的持续研究的意义,包括最终制定新的策略来减轻高危人群的CDI。
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引用次数: 0
The host calcium system contributes to intracellular Rickettsia pathogenesis. 宿主钙系统参与细胞内立克次体发病。
IF 2.8 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-10-14 Epub Date: 2025-08-21 DOI: 10.1128/iai.00363-25
Jinyi C Zhu, Jack H Cook, Mustapha Dahmani, Sean P Riley

Bacteria in the genus Rickettsia are obligate intracellular parasites of the eukaryotic cytoplasm. Pathogenic Rickettsia species are exquisitely evolved to only proliferate within eukaryotic host cells, particularly within endothelial cells of the mammalian vasculature. Through evolution in this very specific niche, Rickettsia have developed an inextricable dependence on multiple host functions. This absolute dependence on host cell biology offers a potential strategy for antibacterial development called host-targeted therapeutics. A previous screen of compounds that specifically target mammalian cell biology indicated that host-targeted calcium channel blockers (CCBs) inhibit Rickettsia conorii proliferation within human cells. CCBs are routinely prescribed to human patients as antihypertensives or antianginals that function by disrupting the calcium ion equilibrium in vesicula/cardiac smooth muscle cells. To further investigate the potential anti-Rickettsia activities of CCBs, we sought to define the interaction between pathogenic Rickettsia and the host Ca2+ system. Achieved data demonstrate that CCBs inhibit Rickettsia proliferation within endothelial cells, and that physical disruption of the host Ca2+ ion gradient also disrupts Rickettsia growth. Additional analyses reveal that Rickettsia infection leads to a rapid and persistent disruption of the host Ca2+ equilibrium. By querying Rickettsia pathogenesis, we demonstrate that some CCBs marginally disrupt rickettsial adherence to the host cell or induce apoptosis. However, all tested CCBs universally and significantly disrupt the ability of Rickettsia to polymerize actin. Together, these data demonstrate that CCBs possess anti-Rickettsia properties that function by disrupting rickettsial actin polymerization, and these results highlight the complex interdependence of Rickettsia and host cell biology.

立克次体属细菌是真核细胞质的专性细胞内寄生虫。致病性立克次体经过精心进化,只在真核宿主细胞内增殖,特别是在哺乳动物血管内皮细胞内。通过在这个非常特殊的生态位的进化,立克次体已经发展出对多种宿主功能的不可分割的依赖。这种对宿主细胞生物学的绝对依赖为抗菌开发提供了一种潜在的策略,称为宿主靶向治疗。先前对特异性靶向哺乳动物细胞生物学的化合物的筛选表明,宿主靶向钙通道阻滞剂(CCBs)可抑制人类细胞内的康氏立克次体增殖。CCBs通常作为抗高血压药或抗心绞痛药开给人类患者,其作用是破坏囊泡/心脏平滑肌细胞中的钙离子平衡。为了进一步研究CCBs潜在的抗立克次体活性,我们试图确定致病性立克次体与宿主Ca2+系统之间的相互作用。已获得的数据表明,CCBs抑制立克次体在内皮细胞内的增殖,并且宿主Ca2+离子梯度的物理破坏也会破坏立克次体的生长。另外的分析表明,立克次体感染导致宿主Ca2+平衡的快速和持续的破坏。通过查询立克次体的发病机制,我们证明了一些CCBs轻微地破坏立克次体对宿主细胞的粘附或诱导细胞凋亡。然而,所有测试的CCBs普遍且显著地破坏立克次体聚合肌动蛋白的能力。总之,这些数据表明,CCBs具有抗立克次体的特性,其功能是通过破坏立克次体肌动蛋白聚合,这些结果突出了立克次体和宿主细胞生物学之间复杂的相互依赖关系。
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引用次数: 0
Host-directed therapeutic targets in macrophages and their ligands against mycobacteria tuberculosis. 巨噬细胞及其配体抗结核分枝杆菌的宿主靶向治疗靶点。
IF 2.8 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-10-14 Epub Date: 2025-08-25 DOI: 10.1128/iai.00063-25
Jin Li, Yanmei Wang, Lei He, Luchuan Yang, Tao Tao, Lang Bai, Youfu Luo

Although current combination regimens of antibiotics have significantly improved tuberculosis (TB) cure rates, substantial challenges persist in the global effort to end TB. These include poor patient compliance, the emergence of drug-resistant strains due to prolonged treatments, and the persistence of latent TB infections. Host-directed therapies (HDTs) have emerged as a promising complementary strategy, leveraging the modulation of host immune responses to combat Mycobacterium tuberculosis (Mtb). Unlike conventional antibiotics, HDTs can enhance therapeutic outcomes by boosting host defense mechanisms, reducing treatment duration and dosage, and minimizing the risk of resistance development. Notably, several HDTs have shown significant efficacy against multidrug-resistant (MDR) Mtb strains, while also mitigating excessive inflammation and lowering relapse rates-achievements that remain elusive with antibiotic regimens alone. This review provides a comprehensive overview of recent advancements in HDTs, focusing on druggable targets and the mechanisms by which these therapies restore or enhance immune functions disrupted by Mtb. By integrating insights into macrophage polarization, metabolic modulation, autophagy promotion, and cell death regulation, HDTs offer innovative and multifaceted approaches to TB treatment. Furthermore, the potential for HDTs to synergize with existing antibiotics underscores their relevance in overcoming current therapeutic limitations. This synthesis aims to inspire further research and development, with the ultimate goal of advancing HDTs as a transformative solution for TB management.

尽管目前的抗生素联合治疗方案显著提高了结核病治愈率,但在全球终止结核病的努力中仍然存在重大挑战。这些问题包括患者依从性差,由于长期治疗而出现耐药菌株,以及潜伏性结核感染的持续存在。宿主定向疗法(HDTs)已成为一种有希望的补充策略,利用宿主免疫反应的调节来对抗结核分枝杆菌(Mtb)。与传统抗生素不同,HDTs可以通过增强宿主防御机制、缩短治疗时间和剂量以及最大限度地降低耐药性风险来提高治疗效果。值得注意的是,一些HDTs对耐多药(MDR) Mtb菌株显示出显著的疗效,同时还能减轻过度炎症和降低复发率——这些成就仅用抗生素方案仍然难以实现。本文综述了HDTs的最新进展,重点是可药物靶点和这些疗法恢复或增强被结核分枝杆菌破坏的免疫功能的机制。通过整合巨噬细胞极化、代谢调节、自噬促进和细胞死亡调控的见解,HDTs为结核病治疗提供了创新和多方面的方法。此外,HDTs与现有抗生素协同作用的潜力强调了它们在克服当前治疗局限性方面的相关性。这一综合研究旨在激励进一步的研究与开发,最终目标是推动高强度结核病作为结核病管理的变革性解决方案。
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引用次数: 0
Acquired tick resistance in Peromyscus leucopus alters Ixodes scapularis infection. 获得性蜱抗药性改变肩胛骨硬蜱感染。
IF 2.8 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-10-14 Epub Date: 2025-09-03 DOI: 10.1128/iai.00246-25
Elis A Fisk, Cassie J Leonard, Kristin L Rosche, Elisabeth Ramirez-Zepp, Jeffrey R Abbott, Jeb P Owen, Dana K Shaw

Ticks are obligate hematophagous parasites and pathogen vectors responsible for morbidity and mortality worldwide. Ixodes scapularis is a vector for at least seven pathogens relevant to human and animal health, including the Lyme disease microbe, Borrelia burgdorferi, and the causative agent of anaplasmosis, Anaplasma phagocytophilum. Tick-host interactions affect the maintenance of tick-borne pathogens in a population. Here, we report that repeated I. scapularis larval infestations on the wild host species Peromyscus leucopus lead to immune-mediated rejection of the tick, a phenomenon termed acquired tick resistance (ATR). On previously infested mice, we observed that larval feeding success was reduced by over 50%, and fed larvae had decreased blood meal weights compared to larvae fed on naïve hosts. Over sequential infestations, mice exhibited increasingly severe inflammation at tick bite sites characterized by an influx of basophils, eosinophils, neutrophils, and T lymphocytes. Larvae fed on sensitized mice ingested higher quantities of host leukocytes when compared to ticks fed on naïve hosts, which rarely ingested nucleated cells. When challenged with B. burgdorferi or A. phagocytophilum, larvae fed on sensitized mice ingested more bacteria. Altogether, we demonstrate that reservoir host species develop ATR against larval I. scapularis, which reduces tick feeding success and affects pathogen ingestion by larvae. These results indicate that ATR could impact Ixodes population dynamics, prevalence of infected ticks, and pathogen circulation in the wild.

蜱是专性吸血寄生虫和病原体媒介,在世界范围内造成发病率和死亡率。肩胛棘虫是至少七种与人类和动物健康相关的病原体的媒介,包括莱姆病微生物、伯氏疏螺旋体和无形体病的病原体、嗜吞噬细胞无形体。蜱与宿主的相互作用影响种群中蜱传病原体的维持。在这里,我们报告了反复的肩胛骨蜱幼虫对野生宿主白斑过omyscus leucopus的侵害导致免疫介导的对蜱的排斥,这种现象被称为获得性蜱抗性(ATR)。在先前被感染的小鼠中,我们观察到幼虫的取食成功率降低了50%以上,并且与以naïve宿主为食的幼虫相比,被喂食的幼虫的血粉重量降低了。在连续的感染中,小鼠在蜱叮咬部位表现出越来越严重的炎症,其特征是嗜碱性粒细胞、嗜酸性粒细胞、中性粒细胞和T淋巴细胞的涌入。与以naïve宿主为食的蜱虫相比,以致敏小鼠为食的幼虫摄入了更多的宿主白细胞,而naïve宿主很少摄入有核细胞。当被伯氏疏螺旋体或嗜吞噬细胞芽胞杆菌攻击时,以致敏小鼠为食的幼虫摄入了更多的细菌。综上所述,我们证明了宿主物种对肩胛骨蜱幼虫产生ATR,这降低了蜱的取食成功率,并影响了幼虫对病原体的摄入。这些结果表明,ATR可能会影响野外伊蚊种群动态、感染蜱流行和病原体循环。
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引用次数: 0
Complete deletion of the Chlamydia muridarum putative cytotoxin locus reveals contributions during invasion in tissue culture and oviduct pathology during murine genital tract infection. muridarum衣原体假定的细胞毒素位点的完全缺失揭示了在组织培养和小鼠生殖道感染期间的输卵管病理侵袭过程中的贡献。
IF 2.8 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-10-14 Epub Date: 2025-09-22 DOI: 10.1128/iai.00419-25
Lucie H Berclaz, Gracie Eicher, Grace Wieselquist, Akosua Frimpong, Aria Mallare, Rebeccah S Lijek, Kenneth A Fields

Chlamydiaceae is a family of obligate intracellular bacteria that infect a wide range of human and animal hosts. Chlamydia muridarum is a murine-specific species that has been leveraged as an efficacious model of disease mediated by human-specific Chlamydia trachomatis. Genes within the plasticity zone, a region of the chromosome with increased genetic variation across species and serovars, are speculated to contribute to species-specific pathogenesis. C. muridarum expresses three homologous proteins (TC0437-0439) that show similarity to large clostridial cytotoxins. The putative chlamydial cytotoxins have been proposed to mediate immediate toxicity in highly infected epithelial cells by interfering with actin polymerization. We utilized FRAEM mutagenesis to delete all three putative cytotoxins (tc0437-0439). The null strain retained immediate cytotoxicity but exhibited decreased invasion efficiency in tissue culture. During murine infections of the female genital tract, the absence of the putative cytotoxins caused decreased oviduct pathology and did not impact bacterial burden in the upper genital tract. These results indicate that the putative cytotoxins contribute to infection at the cellular level and in the female genital tract of mice.

衣原菌科是一类专性细胞内细菌,广泛感染人类和动物宿主。沙眼衣原体是一种小鼠特异性物种,已被利用作为人类特异性沙眼衣原体介导的疾病的有效模型。可塑性区是染色体上的一个区域,在物种和血清型中遗传变异增加,据推测,可塑性区内的基因有助于物种特异性发病。C. muridarum表达三个同源蛋白(TC0437-0439),显示出与大型梭状芽胞杆菌细胞毒素相似。假设的衣原体细胞毒素通过干扰肌动蛋白聚合介导高度感染上皮细胞的立即毒性。我们利用FRAEM诱变法删除了所有三种假定的细胞毒素(tc0437-0439)。空白菌株在组织培养中保留了立即的细胞毒性,但表现出较低的侵袭效率。在雌性生殖道感染的小鼠中,假定的细胞毒素的缺失导致输卵管病理减少,并且不影响上生殖道的细菌负荷。这些结果表明,假定的细胞毒素在细胞水平和小鼠雌性生殖道中参与感染。
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引用次数: 0
Elevated glucose increases Staphylococcus aureus antibiotic resistance in a cystic fibrosis airway epithelial cell infection model. 在囊性纤维化气道上皮细胞感染模型中,葡萄糖升高会增加金黄色葡萄球菌的抗生素耐药性。
IF 2.8 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-10-14 Epub Date: 2025-09-22 DOI: 10.1128/iai.00178-25
Emily M Hughes, Meghan J Hirsch, Joshua T Huffines, Stefanie Krick, Megan R Kiedrowski

In a healthy lung, the airway epithelium regulates glucose transport to maintain low glucose concentrations in the airway surface liquid (ASL). However, hyperglycemia and chronic lung diseases, such as cystic fibrosis (CF), can result in increased glucose in bronchial aspirates. People with CF are also at increased risk of lung infections caused by bacterial pathogens, including methicillin-resistant Staphylococcus aureus. Yet, it is not known how increased airway glucose availability affects bacteria in chronic CF lung infections or impacts treatment outcomes. To model the CF airways, we cultured immortalized CF (CFBE41o-) and non-CF (16HBE) human bronchial epithelial cells at the air-liquid interface (ALI). Glucose concentrations in the basolateral media were maintained at 5.5 or 12.5 mM to mimic a normal and hyperglycemic milieu, respectively. We found that glucose concentrations in the ASL of ALI cultures maintained in normal or high glucose mimicked levels measured in breath condensate assays from people with CF and hyperglycemia. Additionally, we found hyperglycemia increased S. aureus aggregation and antibiotic resistance during infection of cells maintained in high glucose compared to normal glucose conditions. Heightened antibiotic resistance was not observed during in vitro growth with elevated glucose. Limiting glucose with 2-deoxyglucose both decreased aggregation and reduced antibiotic resistance back to levels comparable to non-hyperglycemic conditions. These data indicate that hyperglycemia alters S. aureus growth during infection and may reduce efficacy of antibiotic treatment. Glucose restriction is a potential option that could be explored to limit bacterial growth and improve treatment outcomes in chronic airway infections.

在健康的肺中,气道上皮调节葡萄糖转运以维持气道表面液体(ASL)中的低葡萄糖浓度。然而,高血糖和慢性肺部疾病,如囊性纤维化(CF),可导致支气管吸入物中葡萄糖升高。CF患者还面临由细菌性病原体(包括耐甲氧西林金黄色葡萄球菌)引起的肺部感染风险增加。然而,尚不清楚气道葡萄糖可用性增加如何影响慢性CF肺部感染的细菌或影响治疗结果。为了建立CF气道模型,我们在气液界面(ALI)处培养永生化CF (cfbe410 -)和非CF (16HBE)人支气管上皮细胞。将基底外侧培养基中的葡萄糖浓度分别维持在5.5或12.5 mM,以模拟正常和高血糖环境。我们发现ALI培养的ASL中的葡萄糖浓度维持在正常或高葡萄糖水平,与CF和高血糖患者的呼吸凝结水测定的水平相似。此外,我们发现与正常葡萄糖条件相比,高血糖增加了金黄色葡萄球菌在高葡萄糖条件下维持的细胞感染期间的聚集和抗生素耐药性。在葡萄糖升高的体外生长过程中,没有观察到抗生素耐药性的增强。用2-脱氧葡萄糖限制葡萄糖既可以减少聚集,又可以将抗生素耐药性降低到与非高血糖状况相当的水平。这些数据表明,高血糖会改变金黄色葡萄球菌在感染期间的生长,并可能降低抗生素治疗的疗效。葡萄糖限制是一种潜在的选择,可以探索限制细菌生长和改善慢性气道感染的治疗效果。
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引用次数: 0
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Infection and Immunity
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