Cairns Dana M, Smiley Brooke M, Smiley Jordan A, Khorsandian Yasaman, Kelly Marilyn, Itzhaki Ruth F, Kaplan David L
Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA.
Institute of Population Ageing, University of Oxford, Oxford OX2 6PR, UK.
Sci Signal. 2025 Jan 7;18(868):eado6430. doi: 10.1126/scisignal.ado6430.
Infection with herpes simplex virus type 1 (HSV-1) in the brains of carriers increases the risk of Alzheimer's disease (AD). We previously found that latent HSV-1 in a three-dimensional in vitro model of -heterozygous human brain tissue was reactivated in response to neuroinflammation caused by exposure to other pathogens. Because traumatic brain injury also causes neuroinflammation, we surmised that brain injury might similarly reactivate latent HSV-1. Here, we examined the effects of one or more controlled blows to our human brain model in the absence or presence of latent HSV-1 infection. After repeated, mild controlled blows, latently infected tissues showed reactivation of HSV-1; the production and accumulation of β amyloid and phosphorylated tau (which promotes synaptic dysfunction and neurodegeneration); and activated gliosis, which is associated with destructive neuroinflammation. These effects are collectively associated with AD, dementia, and chronic traumatic encephalopathy (CTE) and were increased with additional injury but were absent in mock-infected tissue. Blocking the cytokine IL-1β prevented the induction of amyloid and gliosis in latently infected monolayer cultures after scratch wounding. We thus propose that after repeated mechanical injuries to the brain, such as from direct blows to the head or jarring motions of the head, the resulting reactivation of HSV-1 in the brain may contribute to the development of AD and related diseases in some individuals.
单纯疱疹病毒1型（HSV-1）感染携带者的大脑会增加患阿尔茨海默病（AD）的风险。我们之前发现，在三维体外杂合人类脑组织模型中，潜伏的HSV-1会因暴露于其他病原体引发的神经炎症而重新激活。由于创伤性脑损伤也会导致神经炎症，我们推测脑损伤可能同样会激活潜伏的HSV-1。在此，我们研究了在存在或不存在潜伏HSV-1感染的情况下，对我们的人类脑模型进行一次或多次可控打击的影响。在反复进行轻度可控打击后，潜伏感染的组织出现了HSV-1的重新激活；β淀粉样蛋白和磷酸化tau蛋白（其促进突触功能障碍和神经退行性变）的产生和积累；以及激活的胶质增生，这与破坏性神经炎症有关。这些影响共同与AD、痴呆和慢性创伤性脑病（CTE）相关，并且随着额外损伤而增加，但在模拟感染的组织中不存在。在划痕损伤后，阻断细胞因子IL-1β可防止潜伏感染的单层培养物中淀粉样蛋白和胶质增生的诱导。因此，我们提出，在大脑反复受到机械损伤后，如头部直接受到打击或头部剧烈晃动，大脑中由此引发的HSV-1重新激活可能会在一些个体中导致AD及相关疾病的发展。
