2023-05-04 ペンシルベニア州立大学(PennState)
◆血吸虫は、水生の寄生虫であり、全世界で2億5,000万人以上の感染症の原因である。住血吸虫症の症状は、かゆみ、発熱、寒気、咳、筋肉痛から、重度の腹痛、肝臓や脾臓の拡大、最も重度の場合には死亡に至る。血吸虫症の予防法は存在せず、治療法としてはプラジカンテルという薬があるが、耐性株が存在するため効果がない場合がある。また、症状は軽度な場合が多いが、5-10%の重症で致命的な場合もある。
◆これに対し、免疫学者たちは、なぜ一部の人が軽度の病気しか発症しないのか、そして、重度の病気を発症する人がいるのかを理解しようと努力している。免疫学者たちは、この研究により、住血吸虫症の治療法を開発するための戦略を見出すことができると期待している。
<関連情報>
- https://www.psu.edu/news/agricultural-sciences/story/newly-discovered-immune-system-mechanism-suppresses-parasitic-infection/
- https://www.pnas.org/doi/10.1073/pnas.2211047120
ガスデルミンDとSTINGシグナルのバランスが、住血吸虫の免疫病理の重篤度を形成する The balance between gasdermin D and STING signaling shapes the severity of schistosome immunopathology
Parisa Kalantari, Andrea Pilotta Gois, Yoelkys Morales, Bijan F. Harandi, Shruti Sharma and Miguel J. Stadecker
Proceedings of the National Academy of Sciences Published:March 21, 2023
DOi:https://doi.org/10.1073/pnas.2211047120
Significance
Schistosomes cause widespread disease in vertebrates and are responsible for over 200 million human infections worldwide. Most schistosome-infected patients develop a mild form of the disease; however, for 5 to 10% of the patients, the disease is severe and life threatening. To date, the molecular mechanisms resulting in such widely dissimilar pathology remain poorly understood. We now report that in low-pathology setting, cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING)-dependent type I interferon (IFN-I) down-regulates dendritic cell (DC) expression of CD209a, with consequent dampening of IL-1β, IL-23, and Th17 cell activation, as well as increased Th2 cytokines, resulting in the amelioration of immunopathology. Additionally, Gsdmd, which is highly expressed in high-pathology setting, reduces egg-mediated IFN-I responses via induction of pore formation and enhanced pyroptosis.
Abstract
There is significant disease heterogeneity among mouse strains infected with the helminth Schistosoma mansoni. Here, we uncover a unique balance in two critical innate pathways governing the severity of disease. In the low-pathology setting, parasite egg-stimulated dendritic cells (DCs) induce robust interferon (IFN)β production, which is dependent on the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) cytosolic DNA sensing pathway and results in a Th2 response with suppression of proinflammatory cytokine production and Th17 cell activation. IFNβ induces signal transducer and activator of transcription (STAT)1, which suppresses CD209a, a C-type lectin receptor associated with severe disease. In contrast, in the high-pathology setting, enhanced DC expression of the pore-forming protein gasdermin D (Gsdmd) results in reduced expression of cGAS/STING, impaired IFNβ, and enhanced pyroptosis. Our findings demonstrate that cGAS/STING signaling represents a unique mechanism inducing protective type I IFN, which is counteracted by Gsdmd.
