G-CSF and IL-6 drive myeloid dysregulation during severe viral infection

Kimberly Kajihara, Donghong Yan, Gretchen Seim, Hannah Little-Hooy, Jing Kang, Cynthia Chen, Marco De Simone, Tim Delemarre, Spyros Darmanis, Haridha Shivram, Rebecca Bauer, Carrie M Rosenberger, Sharookh Kapadia, Min Xu, Miguel Reyes
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Abstract

Dysregulated myeloid states are associated with disease severity in both sepsis and COVID-19. However, their relevance in non-COVID-19 viral infection, the factors driving their induction, and their role in tissue injury remain poorly understood. We performed a meta-analysis of 1,622,180 myeloid cells from 890 COVID-19 or sepsis patients and controls across 19 published blood scRNA-seq datasets, which revealed severity-associated gene programs in both neutrophils and monocytes pointing to emergency myelopoiesis (EM). Using published bulk transcriptional data from 562 individuals with non-COVID-19 viral disease, we show that these signatures are similarly upregulated during severe influenza and RSV infection. Analysis of transcriptional and proteomic responses in tocilizumab-treated COVID-19 patients show that IL-6 signaling blockade results in a partial reduction of EM signatures and a compensatory increase in the growth factor G-CSF. Using a cellular model of human myelopoiesis, we show that both IL-6 and G-CSF stimulate the production of myeloid cells that express EM signatures in vitro. Using a mouse model of severe influenza infection, we demonstrate the effect of IL-6 and G-CSF signaling blockade on EM-associated myeloid cells, and highlight the opposing effects of EM-induced neutrophils and monocytes on tissue injury. Our study demonstrates the link between systemic cytokines and myeloid dysregulation during severe infection in humans, and highlights the cooperative role of IL-6 and G-CSF signaling in driving infection-induced myelopoiesis.
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G-CSF 和 IL-6 驱动严重病毒感染期间的髓细胞失调
在败血症和 COVID-19 病毒感染中,失调的骨髓状态与疾病的严重程度有关。然而,人们对其与非 COVID-19 病毒感染的相关性、诱导因素及其在组织损伤中的作用仍知之甚少。我们对 19 个已发表的血液 scRNA-seq 数据集中 890 名 COVID-19 或败血症患者和对照组的 1,622,180 个髓系细胞进行了荟萃分析,结果显示,中性粒细胞和单核细胞中与严重程度相关的基因程序都指向紧急骨髓造血(EM)。利用已发表的来自 562 名非 COVID-19 病毒性疾病患者的大量转录数据,我们发现这些特征在严重流感和 RSV 感染期间也有类似的上调。对托珠单抗治疗的 COVID-19 患者的转录和蛋白质组反应的分析表明,IL-6 信号传导阻断导致 EM 特征部分减少,生长因子 G-CSF 补偿性增加。利用人类骨髓造血细胞模型,我们发现IL-6和G-CSF都能刺激体外表达EM特征的骨髓细胞的生成。我们利用小鼠严重流感感染模型证明了 IL-6 和 G-CSF 信号传导阻断对 EM 相关髓系细胞的影响,并强调了 EM 诱导的中性粒细胞和单核细胞对组织损伤的相反作用。我们的研究证明了人类重症感染期间全身细胞因子与骨髓失调之间的联系,并强调了 IL-6 和 G-CSF 信号在驱动感染诱导的骨髓造血过程中的合作作用。
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