Department of Biology, Lund University, Sölvegatan 35, 223 62, Lund, Sweden.
Division of Infectious Diseases, Boston Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, USA.
Nat Commun. 2023 Jul 6;14(1):4008. doi: 10.1038/s41467-023-39771-0.
Variability in disease severity caused by a microbial pathogen is impacted by each infection representing a unique combination of host and pathogen genomes. Here, we show that the outcome of invasive Streptococcus pyogenes infection is regulated by an interplay between human STING genotype and bacterial NADase activity. S. pyogenes-derived c-di-AMP diffuses via streptolysin O pores into macrophages where it activates STING and the ensuing type I IFN response. However, the enzymatic activity of the NADase variants expressed by invasive strains suppresses STING-mediated type I IFN production. Analysis of patients with necrotizing S. pyogenes soft tissue infection indicates that a STING genotype associated with reduced c-di-AMP-binding capacity combined with high bacterial NADase activity promotes a 'perfect storm' manifested in poor outcome, whereas proficient and uninhibited STING-mediated type I IFN production correlates with protection against host-detrimental inflammation. These results reveal an immune-regulating function for bacterial NADase and provide insight regarding the host-pathogen genotype interplay underlying invasive infection and interindividual disease variability.
病原体引起的疾病严重程度的变异性受到每个感染的影响，每个感染代表宿主和病原体基因组的独特组合。在这里，我们表明，侵袭性化脓性链球菌感染的结果受到人类 STING 基因型和细菌 NADase 活性之间相互作用的调节。化脓性链球菌衍生的 c-di-AMP 通过链球菌溶血素 O 孔扩散到巨噬细胞中，在那里它激活 STING，随后引发 I 型 IFN 反应。然而，侵袭性菌株表达的 NADase 变体的酶活性抑制 STING 介导的 I 型 IFN 产生。对患有坏死性化脓性链球菌软组织感染的患者的分析表明，与结合 c-di-AMP 的能力降低相关的 STING 基因型与高细菌 NADase 活性相结合，导致“完美风暴”表现为不良结局，而高效且不受抑制的 STING 介导的 I 型 IFN 产生与宿主有害炎症的保护相关。这些结果揭示了细菌 NADase 的免疫调节功能，并提供了有关侵袭性感染和个体间疾病变异性的宿主-病原体基因型相互作用的见解。
