Khan Arshad, Bakhru Pearl, Saikolappan Sankaralingam, Das Kishore, Soudani Emily, Singh Christopher R, Estrella Jaymie L, Zhang Dekai, Pasare Chandrashekhar, Ma Yue, Sun Jianjun, Wang Jin, Hunter Robert L, Tony Eissa N, Dhandayuthapani Subramanian, Jagannath Chinnaswamy
1Department of Pathology and Laboratory Medicine, University of Texas Health Sciences Center, Houston, TX USA.
2Molecular and Translational Medicine, Paul L. Foster School of Medicine Texas Tech University Health Sciences Center, El Paso, TX USA.
NPJ Vaccines. 2019 Aug 5;4:34. doi: 10.1038/s41541-019-0122-8. eCollection 2019.
BCG is widely used as a vaccine against tuberculosis due to (Mtb), which kills millions of people each year. BCG variably protects children, but not adults against tuberculosis. BCG evades phagosome maturation, autophagy, and reduces MHC-II expression of antigen-presenting cells (APCs) affecting T-cell activation. To bypass these defects, an autophagy-inducing, TLR-2 activating C5 peptide from Mtb-derived CFP-10 protein was overexpressed in BCG in combination with Ag85B. Recombinant BCG induced a robust MHC-II-dependent antigen presentation to CD4 T cells in vitro, and elicited stronger T1 cytokines (IL-12, IL-1β, and TNFα) from APCs of C57Bl/6 mice increasing phosphorylation of p38MAPK and ERK. BCG also enhanced MHC-II surface expression of MΦs by inhibiting MARCH1 ubiquitin ligase that degrades MHC-II. BCG infected APCs from MyD88 or TLR-2 knockout mice showed decreased antigen presentation. Furthermore, BCG induced LC3-dependent autophagy in macrophages increasing antigen presentation. Consistent with in vitro effects, BCG markedly expanded both effector and central memory T cells in C57Bl/6 mice protecting them against both primary aerosol infection with Mtb and reinfection, but was less effective among TLR-2 knockout mice. Thus, BCG induces stronger and longer lasting immunity, and is better than BCG against tuberculosis of mice.
卡介苗（BCG）作为一种抗结核分枝杆菌（Mtb）的疫苗被广泛使用，结核分枝杆菌每年导致数百万人死亡。卡介苗对儿童的保护作用不一，但对成人没有抗结核作用。卡介苗可逃避吞噬体成熟、自噬，并降低抗原呈递细胞（APC）的MHC-II表达，从而影响T细胞活化。为了克服这些缺陷，一种来自结核分枝杆菌衍生的CFP-10蛋白的自噬诱导、TLR-2激活的C5肽与Ag85B一起在卡介苗中过表达。重组卡介苗在体外诱导了强大的依赖MHC-II的抗原呈递给CD4 T细胞，并从C57Bl/6小鼠的APC中引发了更强的T1细胞因子（IL-12、IL-1β和TNFα），增加了p38MAPK和ERK的磷酸化。卡介苗还通过抑制降解MHC-II的MARCH1泛素连接酶来增强巨噬细胞的MHC-II表面表达。来自MyD88或TLR-2基因敲除小鼠的卡介苗感染的APC显示抗原呈递减少。此外，卡介苗在巨噬细胞中诱导LC3依赖性自噬，增加抗原呈递。与体外效应一致，卡介苗在C57Bl/6小鼠中显著扩增了效应T细胞和中央记忆T细胞，保护它们免受结核分枝杆菌的原发性气溶胶感染和再感染，但在TLR-2基因敲除小鼠中效果较差。因此，卡介苗诱导更强、更持久的免疫，并且比卡介苗更能抵抗小鼠的结核病。
