发现慢性尿路感染背后隐藏的表观遗传机制
![The culture of USCs of juvenile C3H/HeN mice regenerates differentiated urothelium in vitro. a, USCs isolated from 8-week-old C3H/HeN mice were expanded by spheroidal culture in matrigel with 50% L-WRN conditioned media (CM) including Y-27632, a ROCK inhibitor, and SB431542, a TGF β type 1 inhibitor. After 3 d of spheroid culture, cells were dissociated into a single-cell suspension and 3–4 × 105 cells were seeded onto transwell membranes. The cells were cultured in 50% CM for 3–5 d, then cultured in 5% CM for 2–3 weeks until full differentiation. b, Cell cultures with a TER value >4,000 ohm × cm2 were then analyzed (5 transwells cultured from one juvenile C3H/HeN cell line). For consistency, TER was measured 1 d after media change. c,d, Differentiated urothelia on the transwells were fixed and imaged via (c) confocal microscopy and (d) SEM to show a top-down view of the urothelium at magnification 500× (top panel) and 10,000× (bottom panel). In c, samples were stained for F-actin, the terminal differentiation marker K20 and nuclei (DAPI). e–h, The urothelia were also paraffin-embedded, sectioned and stained with hematoxylin and eosin (H&E) (e) and immunostained for K20, Ecad and DAPI (f), Upk3a, p63 and DAPI (g) or K5, K14 and DAPI (h). Representative images are shown. Data are from 2–3 independent experiments using USCs from 5 different juvenile C3H/HeN mice. Credit: Nature Microbiology (2023). DOI: 10.1038/s41564-023-01346-6 发现慢性尿路感染背后隐藏的表观遗传机制](https://scx1.b-cdn.net/csz/news/800a/2023/hidden-epigenetic-mech.jpg)
发表在微生物学性质,一项在老鼠身上进行的研究发现,尿路感染的微生物基础可能包括局部的表观遗传改变,这些改变更有可能导致额外的感染。
以前的尿路感染众所周知,尿路感染会使患者易受未来感染,但其复发背后的机制尚不清楚。来自圣路易斯华盛顿大学医学院的研究人员对他们之前的研究进行了跟进,他们发现小鼠膀胱尿路感染后上皮细胞发生了不同的变化,导致了不同的结果。
目前的研究“尿路致病性大肠杆菌”感染诱导的上皮细胞训练免疫影响尿路疾病的预后,”比较了从患有解决或慢性尿路致病性大肠杆菌(UPEC)感染史的小鼠中分离的尿路上皮干细胞(USC)系,发现了表观遗传变化,包括染色质可及性、DNA甲基化和组蛋白修饰的差异。《新闻与观点》杂志发表了一篇关于这项研究的文章。
研究人员遵循的一条线索是,先前的感染导致尿路上皮干细胞的变化,这种变化在细胞培养的许多代中持续存在,表明这些细胞中可能存在表观遗传修饰。表观遗传修饰不是改变细胞的DNA序列,而是改变DNA的获取方式,从而改变哪些基因被表达。这些变化可以改变正常的细胞功能,在这种情况下,会改变免疫反应。
他们发现UPEC感染作为一种表皮突变原,重新编程尿路上皮细胞的功能活性,导致重塑和改变或训练先天反应,以应对随后的感染。本研究证实了粘膜细菌感染在诱发特异性免疫反应中的直接作用表观遗传变化粘膜上皮干细胞。
虽然没有提出解决方案,但对小鼠的研究确实确定了以前未知的机制,为未来设计慢性尿路感染解决方案的研究提供了信息。这可能是我们对这一主题知识的一个重要且可行的提升,目前我们只提供了关于如何在上完厕所后擦拭的建议,保持生殖器干燥的建议,以及鼓励大量饮用蔓越莓汁作为预防再感染的策略。
即使没有目前的治疗方法,这项研究可能对那些患有慢性复发性感染的人来说是一个好消息,因为它证实了这个问题是基于表观基因组的免疫问题,而不是因为他们没有遵守基本卫生指导或摄入足够的蔓越莓汁。
更多信息:Seongmi K. Russell等,尿路致病性大肠杆菌感染诱导的上皮训练免疫影响尿路疾病的预后,微生物学性质(2023)。DOI: 10.1038 / s41564 - 023 - 01346 - 6
Soumitra Mohanty, John Kerr White和Annelie Brauner,表观遗传修饰影响尿路感染结果,微生物学性质(2023)。DOI: 10.1038 / s41564 - 023 - 01371 - 5
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