Neutrophils drive pulmonary vascular leakage in MHV-1 infection of susceptible A/J mice.
Neutrophils drive pulmonary vascular leakage in MHV-1 infection of susceptible A/J mice.
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DOI：
10.3389/fimmu.2022.1089064
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
肺部炎症、中性粒细胞浸润和肺血管渗漏是急性呼吸窘迫综合征（ARDS）的病理标志，ARDS可导致呼吸道病毒感染的致命并发症。然而，尽管有类似的合并症，但一些患者的感染可能无症状，而另一些患者则会出现急性呼吸窘迫综合征，例如严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）感染。在这项研究中，我们用小鼠肝炎病毒1株（MHV-1）感染耐药的C57BL/6和易感的A/J小鼠，以确定呼吸道冠状病毒感染模型中肺血管渗漏易感性的机制。A/J动物在感染早期表现出肺损伤参数增加、肺中性粒细胞内流和其他白细胞募集不足。此外，在基础条件下，A/J中性粒细胞过表达髓过氧化物酶和多种丝氨酸蛋白酶的原代颗粒蛋白基因。感染期间，与C57BL/6小鼠相比，脊髓过氧化物酶和弹性蛋白酶蛋白在支气管肺泡间隙释放的浓度更高。而其他颗粒型的基因在两株间表达无差异。我们发现中性粒细胞的消耗导致感染A/J小鼠的肺损伤减轻，而在C57BL/6小鼠中没有影响，这表明中性粒细胞表型和募集谱的改变是易感小鼠肺免疫病理的主要驱动因素。这些结果表明，宿主对肺冠状病毒感染的易感性可能部分由中性粒细胞表型的潜在差异所控制，而中性粒细胞表型在小鼠品系之间可能存在差异，其机制涉及原代颗粒蛋白作为中性粒细胞驱动的肺损伤介质。
Lung inflammation, neutrophil infiltration, and pulmonary vascular leakage are pathological hallmarks of acute respiratory distress syndrome (ARDS) which can lethally complicate respiratory viral infections. Despite similar comorbidities, however, infections in some patients may be asymptomatic while others develop ARDS as seen with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections for example. In this study, we infected resistant C57BL/6 and susceptible A/J strains of mice with pulmonary administration of murine hepatitis virus strain 1 (MHV-1) to determine mechanisms underlying susceptibility to pulmonary vascular leakage in a respiratory coronavirus infection model. A/J animals displayed increased lung injury parameters, pulmonary neutrophil influx, and deficient recruitment of other leukocytes early in the infection. Moreover, under basal conditions, A/J neutrophils overexpressed primary granule protein genes for myeloperoxidase and multiple serine proteases. During infection, myeloperoxidase and elastase protein were released in the bronchoalveolar spaces at higher concentrations compared to C57BL/6 mice. In contrast, genes from other granule types were not differentially expressed between these 2 strains. We found that depletion of neutrophils led to mitigation of lung injury in infected A/J mice while having no effect in the C57BL/6 mice, demonstrating that an altered neutrophil phenotype and recruitment profile is a major driver of lung immunopathology in susceptible mice. These results suggest that host susceptibility to pulmonary coronaviral infections may be governed in part by underlying differences in neutrophil phenotypes, which can vary between mice strains, through mechanisms involving primary granule proteins as mediators of neutrophil-driven lung injury.
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影响因子：
12.3
作者：
Aschenbrenner AC;Mouktaroudi M;Krämer B;Oestreich M;Antonakos N;Nuesch-Germano M;Gkizeli K;Bonaguro L;Reusch N;Baßler K;Saridaki M;Knoll R;Pecht T;Kapellos TS;Doulou S;Kröger C;Herbert M;Holsten L;Horne A;Gemünd ID;Rovina N;Agrawal S;Dahm K;van Uelft M;Drews A;Lenkeit L;Bruse N;Gerretsen J;Gierlich J;Becker M;Händler K;Kraut M;Theis H;Mengiste S;De Domenico E;Schulte-Schrepping J;Seep L;Raabe J;Hoffmeister C;ToVinh M;Keitel V;Rieke G;Talevi V;Skowasch D;Aziz NA;Pickkers P;van de Veerdonk FL;Netea MG;Schultze JL;Kox M;Breteler MMB;Nattermann J;Koutsoukou A;Giamarellos-Bourboulis EJ;Ulas T;German COVID-19 Omics Initiative (DeCOI)
通讯作者：
German COVID-19 Omics Initiative (DeCOI)
影响因子：
5.4
作者：
Khanolkar, Aaruni;Hartwig, Stacey M.;Harty, John T.
通讯作者：
Harty, John T.
影响因子：
5.5
作者：
Cheemarla, Nagarjuna R.;Del Rocio Banos-Lara, Ma;Guerrero-Plata, Antonieta
通讯作者：
Guerrero-Plata, Antonieta
影响因子：
4.4
作者：
Luan, Yi;Yuan, Qianying;Wang, Qijun;Compton, Susan;Wu, Dianqing;Tang, Wenwen
通讯作者：
Tang, Wenwen
影响因子：
64.5
作者：
Brandes M;Klauschen F;Kuchen S;Germain RN
通讯作者：
Germain RN