Department of Microbiology and Molecular Genetics, Faculty of Medicine, The Institute for Medical Research - Israel-Canada, The Hebrew University, Jerusalem 91120, Israel.
J Immunol. 2011 Dec 1;187(11):6022-31. doi: 10.4049/jimmunol.1101385. Epub 2011 Oct 24.
Group A Streptococcus (GAS) causes diverse infections in humans, ranging from mild to life-threatening invasive diseases, such as necrotizing fasciitis (NF), a rapidly progressing deep tissue infection. Despite prompt treatments, NF remains a significant cause of morbidity and mortality, even in previously healthy individuals. The early recruitment of leukocytes is crucial to the outcome of NF; however, although the role of polymorphonuclear neutrophils (PMNs) in host defense against NF is well established, the role of recruited macrophages remains poorly defined. Using a cutaneous murine model mimicking human NF, we found that mice deficient in TNF-α were highly susceptible to s.c. infections with GAS, and a paucity of macrophages, but not PMNs, was demonstrated. To test whether the effects of TNF-α on the outcome of infection are mediated by macrophages/monocytes, we systemically depleted C57BL/6 mice of monocytes by pharmacological and genetic approaches. Systemic monocyte depletion substantially increased bacterial dissemination from soft tissues without affecting the number of recruited PMNs or altering the bacterial loads in soft tissues. Enhanced GAS dissemination could be reverted by either i.v. injection of monocytes or s.c. administration of peritoneal macrophages. These experiments demonstrated that recruited macrophages play a key role in defense against the extracellular pathogen GAS by limiting its spread from soft tissues.
A 组链球菌（GAS）可引起人类多种感染，从轻症到危及生命的侵袭性疾病，如坏死性筋膜炎（NF），这是一种迅速进展的深部组织感染。尽管进行了及时治疗，NF 仍然是发病率和死亡率的重要原因，即使在以前健康的个体中也是如此。白细胞的早期募集对于 NF 的结果至关重要；然而，尽管多形核粒细胞（PMN）在宿主防御 NF 中的作用已得到充分证实，但募集的巨噬细胞的作用仍未得到明确界定。使用模拟人类 NF 的皮肤小鼠模型，我们发现 TNF-α 缺陷小鼠对 GAS 的皮下感染高度敏感，并且缺乏巨噬细胞，但PMN 数量未受影响。为了测试 TNF-α 对感染结果的影响是否通过巨噬细胞/单核细胞介导，我们通过药理学和遗传学方法系统地耗尽 C57BL/6 小鼠的单核细胞。系统的单核细胞耗竭可显著增加从软组织传播的细菌，而不影响募集的 PMN 数量或改变软组织中的细菌负荷。通过静脉内注射单核细胞或皮下给予腹腔巨噬细胞可逆转增强的 GAS 传播。这些实验表明，募集的巨噬细胞通过限制 GAS 从软组织扩散，在抵御细胞外病原体 GAS 的防御中发挥关键作用。
