人类表面活性蛋白 A 变体的免疫调节差异决定了 SARS-CoV-2 引起的肺病的严重程度

Ikechukwu B Jacob, Akinkunmi O Lawal, Salma S Mahmoud, Emerson M Kopsack, Erin S Reynolds, Qinghe Meng, HongKuan Fan, Paul T Massa, Saravanan Thangamani, Hongpeng Jia, Guirong Wang
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引用次数: 0

摘要

COVID-19 仍是全球公共卫生的重大威胁。一些易感人群感染后会导致危及生命的急性肺损伤(ALI/ARDS)和/或死亡。人类表面活性蛋白 A(SP-A)是一种在肺部和其他粘膜组织中表达的 C 型凝集素,在宿主抵御各种病原体的过程中发挥着关键作用。人类 SP-A 基因(SFTPA1 和 SFTPA2)具有高度的多态性,包括几个常见的基因变体,即 SP-A1(变体 6A2、6A4)和 SP-A2(变体 1A0、1A3)。在这里,我们阐明了SP-A变体在体内应对SARS-CoV-2感染时的不同抗病毒和免疫调节作用。六种基因改造的小鼠品系同时表达 hACE2(SARS-CoV-2 受体)和单个 SP-A 变体:(小鼠(hACE2/6A2 (6A2)、hACE2/6A4 (6A4)、hACE2/1A0 (1A0)和 hACE2/1A3 (1A3))、一种 SP-A 基因敲除小鼠(hACE2/SP-A KO (KO))和一种 hACE2/小鼠 SP-A (K18))经鼻内注射 103 PFU SARS-CoV-2 或生理盐水(Sham)。与其他小鼠品系相比,受感染的 KO 和 1A0 小鼠体重下降和死亡率更高。与其他受感染的小鼠品系相比,KO、1A0 和 6A2 小鼠的 ALI 更严重。与 KO 小鼠相比,在受感染的 SP-A 小鼠肺部普遍观察到病毒滴度降低。转录组分析显示,在 KO 和 1A0 小鼠的肺中,MyD88、Stat3、IL-18 和 Jak2 等在免疫反应中起核心作用的基因上调。然而,与 1A0 小鼠相比,6A2 小鼠的 Mapk1 基因明显下调。生物通路分析确定了参与肺宿主防御和先天性免疫的通路,包括病原体诱导的细胞因子、NOD1/2 和 Trem1 信号通路。与转录组数据一致的是,在死亡率最高的 KO 和 1A0 小鼠的肺部和血清中,细胞因子和趋化因子(如 G-CSF、TNF-α、IL-6 和 IL-1β 及 IL-10)的水平相对较高。这些研究结果表明,人类SP-A变体通过抑制病毒的感染性和调节免疫相关基因的表达,对SARS-CoV-2诱发的肺损伤和疾病严重程度有不同的调节作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Differential Immunoregulation by Human Surfactant Protein A Variants Determines Severity of SARS-CoV-2-induced Lung Disease
COVID-19 remains a significant threat to public health globally. Infection in some susceptible individuals causes life-threatening acute lung injury (ALI/ARDS) and/or death. Human surfactant protein A (SP-A) is a C-type lectin expressed in the lung and other mucosal tissues, and it plays a critical role in host defense against various pathogens. The human SP-A genes (SFTPA1 and SFTPA2) are highly polymorphic and comprise several common genetic variants, i.e., SP-A1 (variants 6A2, 6A4) and SP-A2 (variants 1A0, 1A3). Here, we elucidated the differential antiviral and immunoregulatory roles of SP-A variants in response to SARS-CoV-2 infection in vivo. Six genetically-modified mouse lines, expressing both hACE2 (SARS-CoV-2 receptor) and individual SP-A variants: (hACE2/6A2 (6A2), hACE2/6A4 (6A4), hACE2/1A0 (1A0), and hACE2/1A3 (1A3), one SP-A knockout (hACE2/SP-A KO (KO) and one hACE2/mouse SP-A (K18) mice, were challenged intranasally with 103 PFU SARS-CoV-2 or saline (Sham). Infected KO and 1A0 mice had more weight loss and mortality compared to other mouse lines. Relative to other infected mouse lines, a more severe ALI was observed in KO, 1A0, and 6A2 mice. Reduced viral titers were generally observed in the lungs of infected SP-A mice relative to KO mice. Transcriptomic analysis revealed an upregulation in genes that play central roles in immune responses such as MyD88, Stat3, IL-18, and Jak2 in the lungs of KO and 1A0 mice. However, Mapk1 was significantly downregulated in 6A2 versus 1A0 mice. Analysis of biological pathways identified those involved in lung host defense and innate immunity, including pathogen-induced cytokine, NOD1/2, and Trem1 signaling pathways. Consistent with the transcriptomic data, levels of cytokines and chemokines such as G-CSF, TNF-α, IL-6 and, IL-1β, and IL-10 were comparatively higher in the lungs and sera of KO and 1A0 mice with the highest mortality rate. These findings demonstrate that human SP-A variants differentially modulate SARS-CoV-2-induced lung injury and disease severity by differentially inhibiting viral infectivity and regulating immune-related gene expressions.
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