Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, KS, United States.
Hafion LLC, Lawrence, KS, United States.
Front Immunol. 2020 Nov 17;11:583008. doi: 10.3389/fimmu.2020.583008. eCollection 2020.
Infections caused by the opportunistic pathogen can be difficult to treat due to innate and acquired antibiotic resistance and this is exacerbated by the emergence of multi-drug resistant strains. Unfortunately, no licensed vaccine yet exists to prevent infections. Here we describe a novel subunit vaccine that targets the type III secretion system (T3SS). This vaccine is based on the novel antigen PaF (Pa Fusion), a fusion of the T3SS needle tip protein, PcrV, and the first of two translocator proteins, PopB. Additionally, PaF is made self-adjuvanting by the N-terminal fusion of the A1 subunit of the mucosal adjuvant double-mutant heat-labile enterotoxin (dmLT). Here we show that this triple fusion, designated L-PaF, can activate dendritic cells and elicits strong IgG and IgA titers in mice when administered intranasally. This self-adjuvanting vaccine expedites the clearance of from the lungs of challenged mice while stimulating host expression of IL-17A, which may be important for generating a protective immune response in humans. L-PaF's protective capacity was recapitulated in a rat pneumonia model, further supporting the efficacy of this novel fusion vaccine.
由于固有和获得性抗生素耐药性，机会性病原体引起的感染很难治疗，而多药耐药株的出现则加剧了这种情况。不幸的是，目前还没有许可的疫苗来预防 感染。在这里，我们描述了一种针对 III 型分泌系统（T3SS）的新型亚单位疫苗。这种疫苗基于新型抗原 PaF（Pa 融合），它是 T3SS 针头蛋白 PcrV 与两个转位蛋白 PopB 之一的融合。此外，PaF 通过黏膜佐剂双突变不耐热肠毒素（dmLT）A1 亚基的 N 端融合而具有自佐剂活性。在这里，我们表明，这种三重融合体，称为 L-PaF，可激活树突状细胞，并在经鼻内给药时在小鼠中引发强烈的 IgG 和 IgA 滴度。这种自佐剂疫苗可加快 challenged 小鼠肺部的清除速度，同时刺激宿主表达 IL-17A，这对于在人类中产生保护性免疫反应可能很重要。L-PaF 在大鼠肺炎模型中的保护能力得到了重现，进一步支持了这种新型融合疫苗的功效。
