Hayes Megan I, Ravishankar Sumedha, Qayum Tariq, Nizet Victor, Madigan Cressida A
School of Biological Sciences, University of California, San Diego, La Jolla, United States of America.
Department of Pediatrics, University of California, San Diego, La Jolla, United States of America.
PLoS One. 2025 Sep 12;20(9):e0332161. doi: 10.1371/journal.pone.0332161. eCollection 2025.
Mycobacterial brain infection, for example tuberculous meningitis (TBM), caused by Mycobacterium tuberculosis, is a severe manifestation of tuberculosis that occurs when the bacteria invade the brain. In addition to extensive inflammation, vascular complications such as stroke frequently arise, significantly increasing the risk of disability and death. However, the mechanisms underlying these vascular complications remain poorly understood, as current knowledge is derived exclusively from human studies. To date, no animal model has been established to investigate the onset and progression of vascular pathology in TBM. Here, we use transparent zebrafish larvae to investigate vascular pathology during the early stages of TBM, establishing a model for studying vascular complications from mycobacterial brain infection. We find that mycobacteria preferentially attach to the lumen of vessel bifurcations and induce vessel enlargement. These attached microcolonies are sufficient to occlude brain blood vessels in the absence of an organized thrombus. The majority of microcolony-associated occlusions are transient and contribute to global hypoperfusion of the brain. These vascular disruptions lead to accumulation of oxidative stress and cell death in both the vasculature and neurons. Taken together, these findings demonstrate the occurrence of ischemic events during the early stages of mycobacterial brain infection and establish an animal model for studying vascular complications in TBM.
分枝杆菌脑部感染，例如由结核分枝杆菌引起的结核性脑膜炎（TBM），是结核病的一种严重表现，当细菌侵入大脑时就会发生。除了广泛的炎症外，血管并发症如中风也经常出现，显著增加了残疾和死亡的风险。然而，这些血管并发症的潜在机制仍知之甚少，因为目前的知识完全来自人体研究。迄今为止，尚未建立动物模型来研究TBM中血管病变的发生和发展。在这里，我们使用透明的斑马鱼幼虫来研究TBM早期阶段的血管病变，建立了一个研究分枝杆菌脑部感染引起的血管并发症的模型。我们发现分枝杆菌优先附着在血管分叉处的管腔内并导致血管扩张。这些附着的微菌落足以在没有有组织血栓的情况下阻塞脑血管。大多数与微菌落相关的阻塞是短暂的，并导致大脑整体灌注不足。这些血管破坏导致血管系统和神经元中氧化应激的积累和细胞死亡。综上所述，这些发现证明了分枝杆菌脑部感染早期阶段缺血事件的发生，并建立了一个研究TBM中血管并发症的动物模型。
