より効果的なQ熱治療薬につながる可能性のある研究(Research could lead to more effective Q fever therapeutics)

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2024-05-14 ワシントン州立大学(WSU)

Q熱を引き起こす高感染性の細菌に対する人間の免疫システムの防御方法を研究した結果、新しい効果的な治療法やワクチンの開発が期待されます。コクシエラ・ブルネッティ(C. burnetii)は動物と人間に重大な健康リスクをもたらし、潜在的なバイオテロの脅威とされています。ワシントン州立大学の研究では、STING(インターフェロン遺伝子の刺激因子)と呼ばれるタンパク質が感染後期において重要な役割を果たすことが明らかになりました。STINGが活性化されると炎症反応が引き起こされ、アポトーシス(プログラムされた細胞死)を誘導し、細菌の拡散を防ぎます。STINGの有無で細菌の負荷が大きく変わることが確認され、STINGの理解は新しいワクチンや抗生物質の開発に役立つとされています。この発見は、抗生物質耐性が増加している結核菌などの他の病原体の対策にも応用できる可能性があります。

<関連情報>

STING依存的なBAX-IRF3シグナルがCoxiella burnetii感染後期のアポトーシスをもたらす STING dependent BAX-IRF3 signaling results in apoptosis during late-stage Coxiella burnetii infection

Manish Chauhan,Chelsea A. Osbron,Heather S. Koehler & Alan G. Goodman
Cell Death & Disease  Published:08 March 2024
DOI:https://doi.org/10.1038/s41419-024-06573-1

より効果的なQ熱治療薬につながる可能性のある研究(Research could lead to more effective Q fever therapeutics)

Abstract

STING (STimulator of Interferon Genes) is a cytosolic sensor for cyclic dinucleotides (CDNs) and initiates an innate immune response upon binding to CDNs. Coxiella burnetii is a Gram-negative obligate intracellular bacterium and the causative agent of the zoonotic disease Q fever. The ability of C. burnetii to inhibit host cell death is a critical factor in disease development. Previous studies have shown that C. burnetii inhibits host cell apoptosis at early stages of infection. However, during the late-stages of infection, there is host cell lysis resulting in the release of bacteria to infect bystander cells. Thus, we investigated the role of STING during late-stages of C. burnetii infection and examined STING’s impact on host cell death. We show that the loss of STING results in higher bacterial loads and abrogates IFNβ and IL6 induction at 12 days post-infection. The absence of STING during C. burnetii infection significantly reduces apoptosis through decreased caspase-8 and -3 activation. During infection, STING activates IRF3 which interacts with BAX. BAX then translocates to the mitochondria, which is followed by mitochondrial membrane depolarization. This results in increased cytosolic mtDNA in a STING-dependent manner. The presence of increased cytosolic mtDNA results in greater cytosolic 2′-3′ cGAMP, creating a positive feedback loop and leading to further increases in STING activation and its downstream signaling. Taken together, we show that STING signaling is critical for BAX-IRF3-mediated mitochondria-induced apoptosis during late-stage C. burnetii infection.

有機化学・薬学
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