Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature. 2013 Sep 5;501(7465):52-7. doi: 10.1038/nature12479. Epub 2013 Aug 21.
Nociceptor sensory neurons are specialized to detect potentially damaging stimuli, protecting the organism by initiating the sensation of pain and eliciting defensive behaviours. Bacterial infections produce pain by unknown molecular mechanisms, although they are presumed to be secondary to immune activation. Here we demonstrate that bacteria directly activate nociceptors, and that the immune response mediated through TLR2, MyD88, T cells, B cells, and neutrophils and monocytes is not necessary for Staphylococcus aureus-induced pain in mice. Mechanical and thermal hyperalgesia in mice is correlated with live bacterial load rather than tissue swelling or immune activation. Bacteria induce calcium flux and action potentials in nociceptor neurons, in part via bacterial N-formylated peptides and the pore-forming toxin α-haemolysin, through distinct mechanisms. Specific ablation of Nav1.8-lineage neurons, which include nociceptors, abrogated pain during bacterial infection, but concurrently increased local immune infiltration and lymphadenopathy of the draining lymph node. Thus, bacterial pathogens produce pain by directly activating sensory neurons that modulate inflammation, an unsuspected role for the nervous system in host-pathogen interactions.
伤害感受器感觉神经元专门用于检测潜在的有害刺激，通过引发疼痛感觉和引发防御行为来保护机体。细菌感染通过未知的分子机制产生疼痛，尽管它们被认为是免疫激活的次要原因。在这里，我们证明细菌可以直接激活伤害感受器，而 TLR2、MyD88、T 细胞、B 细胞和中性粒细胞和单核细胞介导的免疫反应对于金黄色葡萄球菌诱导的小鼠疼痛不是必需的。小鼠的机械性和热痛觉过敏与活细菌负荷相关，而与组织肿胀或免疫激活无关。细菌通过不同的机制诱导伤害感受器神经元中的钙通量和动作电位，部分通过细菌 N-甲酰化肽和形成孔的毒素α-溶血素。Nav1.8 谱系神经元（包括伤害感受器）的特异性消融消除了细菌感染期间的疼痛，但同时增加了引流淋巴结的局部免疫浸润和淋巴结病。因此，细菌病原体通过直接激活感觉神经元来产生疼痛，这些神经元调节炎症，这是神经系统在宿主-病原体相互作用中的一个意想不到的作用。
