Division of Innate and Comparative Immunology, Center for Human Systems Immunology, Duke University School of Medicine, Durham, North Carolina, United States of America.
Department of Infectious Diseases and Global Health, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, United States of America.
PLoS Pathog. 2024 Aug 12;20(8):e1012439. doi: 10.1371/journal.ppat.1012439. eCollection 2024 Aug.
Natural killer (NK) cells play a critical role in virus control. However, it has remained largely unclear whether NK cell mobilization in SARS-CoV-2 infections is beneficial or pathologic. To address this deficit, we employed a validated experimental NK cell depletion non-human primate (NHP) model with SARS-CoV-2 Delta variant B.1.617.2 challenge. Viral loads (VL), NK cell numbers, activation, proliferation, and functional measures were evaluated in blood and tissues. In non-depleted (control) animals, infection rapidly induced NK cell expansion, activation, and increased tissue trafficking associated with VL. Strikingly, we report that experimental NK cell depletion leads to higher VL, longer duration of viral shedding, significantly increased levels of pro-inflammatory cytokines in the lungs, and overt lung damage. Overall, we find the first significant and conclusive evidence for NK cell-mediated control of SARS-CoV-2 virus replication and disease pathology. These data indicate that adjunct therapies for infection could largely benefit from NK cell-targeted approaches.
自然杀伤 (NK) 细胞在病毒控制中发挥着关键作用。然而，NK 细胞在 SARS-CoV-2 感染中的动员是有益还是病理性的，在很大程度上仍不清楚。为了解决这一不足，我们采用了经过验证的实验性 NK 细胞耗竭非人类灵长类动物 (NHP) 模型，并用 SARS-CoV-2 Delta 变体 B.1.617.2 进行了挑战。在血液和组织中评估了病毒载量 (VL)、NK 细胞数量、激活、增殖和功能指标。在未耗竭（对照）动物中，感染迅速诱导 NK 细胞扩增、激活，并增加与 VL 相关的组织迁移。引人注目的是，我们报告说，实验性 NK 细胞耗竭导致更高的 VL、更长时间的病毒脱落、肺部促炎细胞因子水平显著增加以及明显的肺部损伤。总的来说，我们发现了 NK 细胞介导的 SARS-CoV-2 病毒复制和疾病病理学控制的第一个重要和明确的证据。这些数据表明，感染的辅助治疗可能会从 NK 细胞靶向治疗中受益。
