Khan Arshad, Singh Vipul K, Mishra Abhishek, Soudani Emily, Bakhru Pearl, Singh Christopher R, Zhang Dekai, Canaday David H, Sheri Anjaneyulu, Padmanabhan Seetharamaiyer, Challa Sreerupa, Iyer Radhakrishnan P, Jagannath Chinnaswamy
Department of Pathology and Genomic Medicine, Center for Human Infectious Diseases, Houston Methodist Research Institute, Weill Cornell Medicine, Houston, TX, United States.
Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, United States.
Front Immunol. 2020 Dec 7;11:592333. doi: 10.3389/fimmu.2020.592333. eCollection 2020.
Tuberculosis (TB) caused by (MTB) kills about 1.5 million people each year and the widely used Bacille Calmette-Guérin (BCG) vaccine provides a partial protection against TB in children and adults. Because BCG vaccine evades lysosomal fusion in antigen presenting cells (APCs), leading to an inefficient production of peptides and antigen presentation required to activate CD4 T cells, we sought to boost its efficacy using novel agonists of RIG-I and NOD2 as adjuvants. We recently reported that the dinucleotide SB 9200 (Inarigivir) derived from our small molecule nucleic acid hybrid (SMNH) platform, activated RIG-I and NOD2 receptors and exhibited a broad-spectrum antiviral activity against hepatitis B and C, Norovirus, RSV, influenza and parainfluenza. Inarigivir increased the ability of BCG-infected mouse APCs to secrete elevated levels of IL-12, TNF-α, and IFN-β, and Caspase-1 dependent IL-1β cytokine. Inarigivir also increased the ability of macrophages to kill MTB in a Caspase-1-, and autophagy-dependent manner. Furthermore, Inarigivir led to a Capsase-1 and NOD2- dependent increase in the ability of BCG-infected APCs to present an Ag85B-p25 epitope to CD4 T cells . Consistent with an increase in immunogenicity of adjuvant treated APCs, the Inarigivir-BCG vaccine combination induced robust protection against tuberculosis in a mouse model of MTB infection, decreasing the lung burden of MTB by 1-log10 more than that afforded by BCG vaccine alone. The Inarigivir-BCG combination was also more efficacious than a muramyl-dipeptide-BCG vaccine combination against tuberculosis in mice, generating better memory T cell responses supporting its novel adjuvant potential for the BCG vaccine.
由结核分枝杆菌（MTB）引起的结核病每年导致约150万人死亡，广泛使用的卡介苗（BCG）疫苗为儿童和成人提供了部分抗结核保护。由于卡介苗疫苗可避免在抗原呈递细胞（APC）中发生溶酶体融合，导致激活CD4 T细胞所需的肽产生效率低下以及抗原呈递不足，我们试图使用新型的RIG-I和NOD2激动剂作为佐剂来提高其效力。我们最近报道，源自我们的小分子核酸杂交（SMNH）平台的二核苷酸SB 9200（Inarigivir）可激活RIG-I和NOD2受体，并对乙型和丙型肝炎、诺如病毒、呼吸道合胞病毒、流感和副流感表现出广谱抗病毒活性。Inarigivir增强了受卡介苗感染的小鼠APC分泌高水平白细胞介素-12、肿瘤坏死因子-α和干扰素-β以及半胱天冬酶-1依赖性白细胞介素-1β细胞因子的能力。Inarigivir还以半胱天冬酶-1和自噬依赖性方式增强了巨噬细胞杀死MTB的能力。此外，Inarigivir导致受卡介苗感染的APC呈递Ag85B-p25表位给CD4 T细胞的能力以半胱天冬酶-1和NOD2依赖性方式增加。与经佐剂处理的APC免疫原性增加一致，Inarigivir-卡介苗疫苗组合在MTB感染的小鼠模型中诱导了强大的抗结核保护作用，使MTB的肺部负担比单独使用卡介苗疫苗降低了1个对数级以上。在小鼠中，Inarigivir-卡介苗组合在抗结核方面也比胞壁酰二肽-卡介苗疫苗组合更有效，产生了更好的记忆T细胞反应，支持其作为卡介苗疫苗新型佐剂的潜力。
