Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
Department of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, USA.
J Infect Dis. 2021 Dec 15;224(12):2073-2084. doi: 10.1093/infdis/jiab274.
Staphylococcus aureus (SA) bacterial pneumonia is a common cause of sepsis in intensive care units. Immune checkpoint inhibitors (CPIs) that target programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have been proposed for the treatment of sepsis. However, in our systematic review of sepsis preclinical models, none of the models examined CPIs in pneumonia.
Mice were inoculated intratracheally with vehicle control, low dose (LD)- or high dose (HD)-SA. Immune cell recruitment and checkpoint molecule expression were examined at 4, 24, and 48 hours after infection. Infected animals, treated with control or anti-PD-L1 antibodies, were assessed for survival, bacterial burden, lung immunophenotypes, and mediator production.
LD-SA and HD-SA produced lethality of 15% and 70%, respectively, by 168 hours. At 24 hours, LD-infected animals exhibited increased lung monocyte PD-L1 expression (P = .0002) but lower bacterial counts (P = .0002) compared with HD animals. By 48 hours, either infection induced lung neutrophil and macrophage PD-L1 expression (P < .0001). Anti-PD-L1 treatment at the time of infection and at 24 hours following infection with low to high doses of SA reduced PD-L1 detection but did not affect survival or bacterial clearance.
Anti-PD-L1 therapy did not alter survival in this pneumonia model. Preclinical studies of additional common pathogens and septic foci are needed.
金黄色葡萄球菌（SA）细菌性肺炎是重症监护病房脓毒症的常见病因。针对程序性细胞死亡蛋白 1（PD-1）及其配体（PD-L1）的免疫检查点抑制剂（CPIs）已被提议用于脓毒症的治疗。然而，在我们对脓毒症临床前模型的系统评价中，没有一个模型检查过肺炎中的 CPIs。
通过气管内接种向小鼠接种载剂对照、低剂量（LD）或高剂量（HD）SA。在感染后 4、24 和 48 小时检查免疫细胞募集和检查点分子表达。用对照或抗 PD-L1 抗体治疗感染动物，评估其存活率、细菌负荷、肺免疫表型和介质产生。
LD-SA 和 HD-SA 在 168 小时时分别产生 15%和 70%的致死率。在 24 小时时，LD 感染的动物表现出肺单核细胞 PD-L1 表达增加（P=0.0002），但与 HD 动物相比，细菌计数减少（P=0.0002）。在 48 小时时，任何一种感染都诱导了肺中性粒细胞和巨噬细胞 PD-L1 表达（P<0.0001）。在感染低剂量至高剂量 SA 时以及在感染后 24 小时给予抗 PD-L1 治疗，减少了 PD-L1 的检测，但没有影响存活率或细菌清除。
在这个肺炎模型中，抗 PD-L1 治疗并没有改变存活率。需要进行针对其他常见病原体和脓毒症灶的临床前研究。
