Bhattacharya Ilina, Kadam Rashmi, Yadavalli Tejabhiram, Patil Chandrashekhar D, Borase Hemant, Volety Ipsita, Kalinin Sergey, Feinstein Douglas L, Tseng Henry C, Shukla Deepak
Department of Ophthalmology and Visual Sciences, University of Illinois Chicago, Chicago, Illinois, USA.
Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, Illinois, USA.
Clin Transl Med. 2025 Jun;15(6):e70353. doi: 10.1002/ctm2.70353.
Herpes simplex virus-1 (HSV-1) infections are lifelong and linked to neurological diseases such as multiple sclerosis (MS), yet the underlying mechanisms in the host remain poorly understood.
This study investigates new molecular dynamics following HSV-1 infection, uncovering the pivotal role of the mixed lineage kinase domain-like (MLKL) protein. Beyond its known function in necroptosis, MLKL was found to control HSV-1 transport into the nucleus, tightly regulated by Optineurin (OPTN). We evidenced an essential regulatory interaction between MLKL and OPTN, governing MLKL's activity in both necroptosis-dependent and independent pathways. In vivo, studies using Optn knockout mice demonstrated how this MLKL-OPTN axis contributes to demyelination and neurological symptoms mimicking MS. This axis critically prevents oligodendrocyte death and the associated demyelination during HSV-1 infection. Furthermore, pharmacological interventions with Necrosulfonamide (NSA), an MLKL inhibitor, showed therapeutic potential in preserving myelin integrity and reducing neurological deficits in HSV-1-infected models, suggesting a viable strategy for managing virus-induced neurodegeneration.
Our findings highlight the significant role of MLKL in HSV-1 pathogenesis and suggest that MLKL dysregulation is a key mechanism behind severe neurological damage.
MLKL plays a significant role in regulating endosomal transport of HSV-1 to nucleus during early stages of infection. Formation of p-MLKL bodies during HSV-1 infection leads to death of oligodendrocyte and subsequent demyelination. OPTN can negatively modulate MLKL levels to restrict infection and consequential oligodendrocyte death during HSV-1 infection.
单纯疱疹病毒1型（HSV-1）感染是终身性的，且与诸如多发性硬化症（MS）等神经疾病相关，但宿主中的潜在机制仍知之甚少。
本研究调查了HSV-1感染后的新分子动力学，揭示了混合谱系激酶结构域样（MLKL）蛋白的关键作用。除了其在坏死性凋亡中的已知功能外，还发现MLKL可控制HSV-1向细胞核的转运，这一过程受视黄醛结合蛋白（OPTN）的严格调控。我们证明了MLKL与OPTN之间存在重要的调节相互作用，该相互作用在坏死性凋亡依赖和非依赖途径中均调控MLKL的活性。在体内，使用Optn基因敲除小鼠的研究表明了这种MLKL-OPTN轴如何导致模仿MS的脱髓鞘和神经症状。在HSV-1感染期间，该轴至关重要地防止了少突胶质细胞死亡及相关的脱髓鞘。此外，使用MLKL抑制剂坏死磺酰胺（NSA）的药物干预显示出在HSV-1感染模型中保护髓鞘完整性和减少神经功能缺损的治疗潜力，这表明这是一种应对病毒诱导的神经变性的可行策略。
我们的数据突出了MLKL在HSV-1发病机制中的重要作用，并表明MLKL失调是严重神经损伤背后的关键机制。
MLKL在感染早期调节HSV-至细胞核的内体转运中起重要作用。HSV-1感染期间p-MLKL小体的形成导致少突胶质细胞死亡及随后的脱髓鞘。OPTN可负向调节MLKL水平，以在HSV-1感染期间限制感染及随之而来的少突胶质细胞死亡。
