Intracellular replication of Streptococcus pneumoniae inside splenic macrophages serves as a reservoir for septicaemia.
Intracellular replication of Streptococcus pneumoniae inside splenic macrophages serves as a reservoir for septicaemia.
复制标题
DOI：
10.1038/s41564-018-0147-1
复制
发表时间：
2018-05
影响因子：
28.3
通讯作者：
Oggioni MR
中科院分区：
文献类型：
--
作者：
Ercoli G;Fernandes VE;Chung WY;Wanford JJ;Thomson S;Bayliss CD;Straatman K;Crocker PR;Dennison A;Martinez-Pomares L;Andrew PW;Moxon ER;Oggioni MR
细菌性败血症是死亡的主要原因，但其发病机制仍然知之甚少。在实验性肺炎球菌小鼠静脉内感染中，血液中细菌最初减少，数小时后发生致命的败血症。这些事件代表了脾巨噬细胞和中性粒细胞对肺炎球菌的有效清除所驱动的群体瓶颈，但正如我们在这里所显示的，伴随着偶尔的细菌细胞内复制，这些细菌被CD 169阳性脾巨噬细胞的子集吸收。在该模型中，这些隔离细菌的增殖为肺炎球菌向血流中的传播提供了储存库，如使用抗CD 169 mAb治疗的预防所证明的。在离体猪脾中也观察到CD 169+脾巨噬细胞内肺炎球菌的细胞内复制，其中显微解剖结构与人类相当。我们还表明，大环内酯类，有效地渗透巨噬细胞，防止败血症，而β-内酰胺类，与低效的细胞内渗透，未能防止传播到血液中。我们的研究结果定义了一个转变，我们的理解从一个专门的细胞外病原体的肺炎球菌与细胞内阶段。这些发现为开发针对这种早期、以前未被认识到的细菌性脓毒症细胞内阶段的治疗方法打开了大门。
Bacterial septicaemia is a major cause of mortality, but its pathogenesis remains poorly understood. In experimental pneumococcal murine intravenous infection, an initial reduction of bacteria in the blood is followed hours later by a fatal septicaemia. These events represent a population-bottleneck driven by efficient clearance of pneumococci by splenic macrophages and neutrophils, but as we show here, accompanied by occasional intracellular replication of bacteria that are taken up by a sub-set of CD169-positive splenic macrophages. In this model, proliferation of these sequestered bacteria provides a reservoir for dissemination of pneumococci into the bloodstream, as demonstrated by its prevention using an anti-CD169 mAb treatment. Intracellular replication of pneumococci within CD169+ splenic macrophages was also observed in an ex vivo porcine spleen, where the microanatomy is comparable to humans. We also showed that macrolides, that effectively penetrate macrophages, prevented septicaemia whereas beta-lactams, with inefficient intracellular penetration, failed to prevent dissemination to the blood. Our findings define a shift in our understanding of the pneumococcus from an exclusively extracellular pathogen to one with an intracellular phase. These findings open the door to the development of treatments that target this early, previously unrecognized intracellular phase of bacterial sepsis.
登录
查看更多内容
DOI：
10.4049/jimmunol.1200776
发表时间：
2012-09-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Klaas M;Oetke C;Lewis LE;Erwig LP;Heikema AP;Easton A;Willison HJ;Crocker PR
通讯作者：
Crocker PR
影响因子：
9.8
作者：
Grant AJ;Restif O;McKinley TJ;Sheppard M;Maskell DJ;Mastroeni P
通讯作者：
Mastroeni P
DOI：
10.1084/jem.20161621
发表时间：
2017-05-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Deniset JF;Surewaard BG;Lee WY;Kubes P
通讯作者：
Kubes P
DOI：
10.1073/pnas.0909541107
发表时间：
2010-01-05
影响因子：
11.1
作者：
Backer, Ronald;Schwandt, Timo;den Haan, Joke M. M.
通讯作者：
den Haan, Joke M. M.
影响因子：
3.6
作者：
Jones, C;Virji, M;Crocker, PR
通讯作者：
Crocker, PR