Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, USA.
Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA.
Sci Rep. 2021 Apr 27;11(1):9040. doi: 10.1038/s41598-021-88291-8.
The nontuberculous mycobacteria (NTM) Mycobacterium avium is a clinically significant pathogen that can cause a wide range of maladies, including tuberculosis-like pulmonary disease. An immunocompromised host status, either genetically or acutely acquired, presents a large risk for progressive NTM infections. Due to this quietly emerging health threat, we evaluated the ability of a recombinant fusion protein ID91 combined with GLA-SE [glucopyranosyl lipid adjuvant, a toll like receptor 4 agonist formulated in an oil-in-water stable nano-emulsion] to confer protection in both C57BL/6 (wild type) and Beige (immunocompromised) mouse models. We optimized an aerosol challenge model using a clinical NTM isolate: M. avium 2-151 smt, observed bacterial growth kinetics, colony morphology, drug sensitivity and histopathology, characterized the influx of pulmonary immune cells, and confirmed the immunogenicity of ID91 in both mouse models. To determine prophylactic vaccine efficacy against this M. avium isolate, mice were immunized with either ID91 + GLA-SE or bacillus Calmette-Guérin (BCG). Immunocompromised Beige mice displayed a delayed influx of innate and adaptive immune cells resulting in a sustained and increased bacterial burden in the lungs and spleen compared to C57BL/6 mice. Importantly, both ID91 + GLA-SE and BCG vaccines significantly reduced pulmonary bacterial burden in both mouse strains. This work is a proof-of-concept study of subunit vaccine-induced protection against NTM.
非结核分枝杆菌（NTM）中的鸟分枝杆菌是一种具有临床意义的病原体，可引起多种疾病，包括类似肺结核的肺部疾病。无论是遗传还是急性获得的免疫功能低下宿主状态，都会使进展性 NTM 感染的风险大大增加。由于这种悄然出现的健康威胁，我们评估了重组融合蛋白 ID91 与 GLA-SE（葡糖苷脂佐剂，一种在水包油稳定纳米乳液中配制的 toll 样受体 4 激动剂）联合使用，能否在 C57BL/6（野生型）和 Beige（免疫功能低下）两种小鼠模型中提供保护。我们使用临床 NTM 分离株：M. avium 2-151 smt 优化了气溶胶挑战模型，观察了细菌生长动力学、菌落形态、药物敏感性和组织病理学，分析了肺部免疫细胞的流入情况，并在两种小鼠模型中证实了 ID91 的免疫原性。为了确定针对这种 M. avium 分离株的预防性疫苗疗效，我们用 ID91+GLA-SE 或卡介苗（BCG）免疫小鼠。与 C57BL/6 小鼠相比，免疫功能低下的 Beige 小鼠先天和适应性免疫细胞的流入延迟，导致肺部和脾脏中的细菌负荷持续增加。重要的是，ID91+GLA-SE 和 BCG 疫苗都显著降低了两种小鼠品系的肺部细菌负荷。这项工作是针对 NTM 的亚单位疫苗诱导保护的概念验证研究。
