Vashishta Mohit, Khan Naeem, Mehto Subhash, Sehgal Devinder, Natarajan Krishnamurthy
Infectious Disease Immunology Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, India.
Molecular Immunology Laboratory, National Institute of Immunology, New Delhi, India.
PLoS One. 2015 Jul 27;10(7):e0133601. doi: 10.1371/journal.pone.0133601. eCollection 2015.
Pneumonia leads to high mortality in children under the age of five years worldwide, resulting in close to 20 percent of all deaths in this age group. Therefore, investigations into host-pathogen interactions during Streptococcus pneumoniae infection are key in devising strategies towards the development of better vaccines and drugs. To that end, in this study we investigated the role of S. pneumoniae and its surface antigen Pneumococcal surface protein A (PspA) in modulating the expression of co-stimulatory molecule Programmed Death Ligand 1 (PD-L1) expression on dendritic cells (DCs) and the subsequent effects of increased PD-L1 on key defence responses. Our data indicate that stimulation of DCs with PspA increases the surface expression of PD-L1 in a time and dose dependent manner. Characterization of mechanisms involved in PspA induced expression of PD-L1 indicate the involvement of Toll-Like Receptor 2 (TLR2) and calcium homeostasis. While calcium release from intracellular stores positively regulated PD-L1 expression, calcium influx from external milieu negatively regulated PD-L1 expression. Increase in PD-L1 expression, when costimulated with PspA and through TLR2 was higher than when stimulated with PspA or through TLR2. Further, knockdown of TLR2 and the intermediates in the TLR signaling machinery pointed towards the involvement of a MyD88 dependent pathway in PspA induced PD-L1 expression. Incubation of DCs with S. pneumoniae resulted in the up-regulation of PD-L1 expression, while infection with a strain lacking surface PspA failed to do so. Our data also suggests the role of PspA in ROS generation. These results suggest a novel and specific role for PspA in modulating immune responses against S. pneumoniae by regulating PD-L1 expression.
在全球范围内，肺炎导致五岁以下儿童的死亡率很高，占该年龄组所有死亡人数的近20%。因此，研究肺炎链球菌感染期间宿主与病原体的相互作用是设计开发更好疫苗和药物策略的关键。为此，在本研究中，我们调查了肺炎链球菌及其表面抗原肺炎球菌表面蛋白A（PspA）在调节树突状细胞（DCs）上共刺激分子程序性死亡配体1（PD-L1）表达中的作用，以及PD-L1增加对关键防御反应的后续影响。我们的数据表明，用PspA刺激DCs会以时间和剂量依赖的方式增加PD-L1的表面表达。对PspA诱导PD-L1表达所涉及机制的表征表明，Toll样受体2（TLR2）和钙稳态参与其中。虽然细胞内储存释放的钙正向调节PD-L1表达，但细胞外环境流入的钙负向调节PD-L1表达。当与PspA共刺激并通过TLR2刺激时，PD-L1表达的增加高于仅用PspA刺激或仅通过TLR2刺激时。此外，TLR2及TLR信号传导机制中的中间体的敲低表明，MyD88依赖性途径参与了PspA诱导的PD-L1表达。用肺炎链球菌孵育DCs会导致PD-L1表达上调，而用缺乏表面PspA的菌株感染则不会。我们的数据还表明PspA在活性氧生成中的作用。这些结果表明，PspA通过调节PD-L1表达在调节针对肺炎链球菌的免疫反应中具有新的特定作用。
