尿路感染加剧创伤性脑损伤后的认知缺陷和区域特异性神经炎症

摘要(中文译文)

创伤性脑损伤（TBI）增加感染风险，尿路感染（UTI）在需要额外医疗干预的患者群体中常被报道。UTI是全球最常见的细菌感染之一，反映了重大的公共卫生威胁，且对女性的影响尤为显著。UTI最常由尿路致病性大肠杆菌（UPEC）引起，可在易感患者中引发谵妄样症状，但损伤后UTI的特异性神经免疫和认知效应仍研究不足。为填补这一知识空白，我们采用TBI和UTI临床前模型的独特组合，以明确脑损伤后膀胱感染的生物学效应。我们假设TBI后UTI会恶化脑损伤的长期结局。雌性小鼠接受假损伤或侧方液体冲击性脑损伤，损伤后3天（DPI），经尿道接种赋形剂或UPEC以模拟损伤后感染。分别于6 DPI和8 DPI进行Y迷宫和旷场行为学测试。6 DPI时从部分小鼠采集脑组织和血液用于流式细胞术和酶联免疫吸附测定。10 DPI时从剩余小鼠采集脑组织和膀胱用于免疫组织化学。TBI小鼠表现出空间记忆缺陷，UTI后进一步加重；然而，TBI或UTI后未观察到探索行为的差异。TBI显著升高血浆白细胞介素-6，但引人注目的是，TBI后UTI在6 DPI时抑制了该反应。流式细胞术显示6 DPI时循环免疫细胞无显著差异，但证实TBI升高了小胶质细胞反应性和单核细胞向脑内浸润，且独立于感染。TBI和UTI对海马和皮层中胶质纤维酸性蛋白（GFAP）和离子钙结合衔接分子1（Iba1）的表达产生差异性调节，反映了叠加效应和交互效应。TBI后UTI以脑区特异性方式升高小胶质细胞CD68表达，进一步表明损伤后感染改变了神经免疫格局。总之，这些数据为TBI后UTI的效应提供了新见解，表明TBI后UTI对整体结局不利，值得进一步研究膀胱感染与神经炎症之间的信号机制。

Abstract

Traumatic brain injury (TBI) increases the risk for infection, and urinary tract infection (UTI) is commonly reported in patient populations that require additional medical intervention. UTIs are one of the most prevalent bacterial infections worldwide, reflecting a significant public health threat that disproportionately affects females. UTIs are most often caused by uropathogenic (UPEC) and can cause delirium-like symptoms in vulnerable patients, but the specific neuroimmune and cognitive effects of post-injury UTI remain underexplored. To address this gap in knowledge, we present a unique combination of pre-clinical models of TBI and UTI to define the biological effects of bladder infection after brain injury. We hypothesize that UTI after TBI worsens the long-term outcome of brain injury. Female mice received either a sham injury or lateral fluid percussion TBI, and 3 days post-injury (DPI), mice were inoculated transurethrally with vehicle or UPEC to recapitulate a post-injury infection. Y-maze and open-field behavioral tests were administered 6 DPI and 8 DPI, respectively. Brains and blood were collected for flow cytometry and enzyme-linked immunosorbent assay from a subset of mice 6 DPI. Brains and urinary bladders were collected for immunohistochemistry from the remaining mice 10 DPI. TBI mice displayed spatial memory deficits, which were exacerbated following UTI; however, no differences in exploratory behavior were observed after TBI or UTI. TBI significantly elevated plasma interleukin-6, but strikingly, UTI following TBI dampened this response 6 DPI. Flow cytometry revealed no significant differences in circulating immune cells 6 DPI but confirmed that TBI elevated microglial reactivity and monocyte infiltration to the brain, independent of infection. TBI and UTI differentially modulated Glial Fibrillary Acidic Protein (GFAP) and Ionized Calcium-binding Adapter Molecule 1 (Iba1) expression in the hippocampus and cortex, reflecting additive and interaction-based effects. UTI after TBI elevated microglia CD68 expression in a brain region-specific manner further demonstrating that post-injury infection alters the neuroimmune landscape. Together, these data offer novel insight into the effects of UTI after TBI, showing that UTI after TBI is detrimental to overall outcome and warrant further investigation into the signaling mechanisms between bladder infection and neuroinflammation.

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