JAK/STAT Signaling Predominates in Human and Murine Fungal Post-infectious Inflammatory Response Syndrome.
JAK/STAT Signaling Predominates in Human and Murine Fungal Post-infectious Inflammatory Response Syndrome.
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JAK/STAT 信号传导在人类和小鼠真菌感染后炎症反应综合征中占主导地位。
DOI：
10.1101/2024.01.18.24301483
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Williamson,PeterR
中科院分区：
文献类型：
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作者：
Hargarten,JessicaC;Ssebambulidde,Kenneth;Anjum,SeherH;Vaughan,MalcolmJ;Xu,Jintao;Song,Brian;Ganguly,Anutosh;Park,Yoon-Dong;Scott,Terri;Hammoud,DimaA;Olszewski,MichalA;Williamson,PeterR
感染后炎症综合征已被越来越多地认为是多种传染病（包括结核病、细菌性脑膜炎和COVID-19）中宿主损伤的原因。最近，一种感染后炎症反应综合征（PIIRS）被描述为非hiv感染的隐球菌真菌性脑膜脑炎（CM）的主要死亡原因。由于颅骨的刚性结构限制了炎症性水肿导致的不受控制的组织扩张，因此炎症综合征在神经系统感染中尤为严重。在本研究中，利用小鼠PIIRS模型的神经转录途径分析表明，Janus激酶/信号换能器和转录激活因子（JAK/STAT）的激活占主导地位。JAK/STAT抑制剂治疗可改善CNS损伤标志物，减少鞘内CD44hiCD62lo CD4+效应CD4+ t细胞和MHC II+炎性骨髓细胞，并使小鼠体重增加，后者在抗真菌药物治疗后增加。基于这些数据，使用JAK/STAT抑制剂ruxolitinib的短期疗程，启动了途径驱动的类固醇保留人类治疗类固醇难治性PIIRS。这些药物耐受性良好，减少了活化的HLA-DR+ CD4+和CD8+细胞和炎症单核细胞，并改善了脑成像。总之，这些发现支持JAK/STAT在PIIRS中的作用，以及JAK/STAT抑制剂作为PIRS和其他神经炎症综合征的潜在辅助治疗的进一步研究。
Post-infection inflammatory syndromes have been increasingly recognized as a cause of host damage in a variety of infectious diseases including tuberculosis, bacterial meningitis, and COVID-19. Recently, a post-infectious inflammatory response syndrome (PIIRS) was described in non-HIV-infected cryptococcal fungal meningoencephalitis (CM) as a major cause of mortality. Inflammatory syndromes are particularly severe in neurological infections due to the skull’s rigid structure which limits unchecked tissue expansion from inflammatory-induced edema. In the present studies, neurologic transcriptional pathway analysis utilizing a murine PIIRS model demonstrated a predominance of Janus kinase/signal transducer and activator of transcription (JAK/STAT) activation. JAK/STAT inhibitor treatment resulted in improvements in CNS damage markers, reductions in intrathecal CD44hiCD62lo CD4+ effector CD4+ T-cells and MHC II+ inflammatory myeloid cells, and weight gains in mice, the latter after treatment with antifungals. Based on these data, pathway-driven steroid-sparing human treatment for steroid-refractory PIIRS was initiated using short courses of the JAK/STAT inhibitor ruxolitinib. These were well tolerated and reduced activated HLA-DR+ CD4+ and CD8+ cells and inflammatory monocytes as well as improved brain imaging. Together, these findings support the role of JAK/STAT in PIIRS as well as further study of JAK/STAT inhibitors as potential adjunctive therapy for PIRS and other neural inflammatory syndromes.