Rahman Mohammad Arif, Goldfarbmuren Katherine C, Sarkis Sarkis, Bissa Massimiliano, Gutowska Anna, Schifanella Luca, Moles Ramona, Doster Melvin N, Andersen Hanne, Jethmalani Yogita, Serebryannyy Leonid, Cardozo Timothy, Lewis Mark G, Franchini Genoveffa
Animal Models and Retroviral Vaccines Section, Basic Research Laboratory, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
JCI Insight. 2025 Aug 8;10(15). doi: 10.1172/jci.insight.194633.
Exposure to Bacillus Calmette-Guérin (BCG) or Canarypox ALVAC/Alum vaccine elicits pro- or antiinflammatory innate responses, respectively. We tested whether prior exposure of macaques to these immunogens protected against SARS-CoV-2 replication in lungs and found more efficient replication control after the pro-inflammatory immunity elicited by BCG. The decreased virus level in lungs was linked to early infiltrates of classical monocytes producing IL-8 with systemic neutrophils, Th2 cells, and Ki67+CD95+CD4+ T cells producing CCR7. At the time of SARS-CoV-2 exposure, BCG-treated animals had higher frequencies of lung infiltrating neutrophils and higher CD14+ cells expressing efferocytosis marker MERTK, responses correlating with decreased SARS-CoV-2 replication in lung. At the same time point, plasma IL-18, TNF-α, TNFSF-10, and VEGFA levels were also higher in the BCG group and correlated with decreased virus replication. Finally, after SARS-CoV-2 exposure, decreased virus replication correlated with neutrophils producing IL-10 and CCR7 preferentially recruited to the lungs of BCG-vaccinated animals. These data point to the importance of the spatiotemporal distribution of functional monocytes and neutrophils in controlling SARS-CoV-2 levels and suggest a central role of monocyte efferocytosis in curbing replication.
接触卡介苗（BCG）或金丝雀痘病毒安卡拉疫苗/铝佐剂疫苗分别引发促炎或抗炎固有反应。我们测试了猕猴预先接触这些免疫原是否能预防SARS-CoV-2在肺部的复制，结果发现，在卡介苗引发的促炎免疫后，病毒复制的控制更为有效。肺部病毒水平的降低与产生白细胞介素-8的经典单核细胞早期浸润有关，这些单核细胞与全身的中性粒细胞、Th2细胞以及产生趋化因子受体7（CCR7）的Ki67+CD95+CD4+ T细胞有关。在接触SARS-CoV-2时，接受卡介苗治疗的动物肺部浸润的中性粒细胞频率更高，且表达胞葬作用标志物MERTK的CD14+细胞更多，这些反应与肺部SARS-CoV-2复制减少相关。在同一时间点，卡介苗组血浆中的白细胞介素-18、肿瘤坏死因子-α、肿瘤坏死因子配体超家族成员10（TNFSF-10）和血管内皮生长因子A（VEGFA）水平也更高，且与病毒复制减少相关。最后，在接触SARS-CoV-2后，病毒复制减少与产生白细胞介素-10的中性粒细胞以及优先募集到接种卡介苗动物肺部的CCR7相关。这些数据表明功能性单核细胞和中性粒细胞的时空分布在控制SARS-CoV-2水平方面的重要性，并提示单核细胞胞葬作用在抑制病毒复制中起核心作用。
