Freire Paula P, Marques Alexandre Hc, Baiocchi Gabriela C, Schimke Lena F, Fonseca Dennyson Lm, Salgado Ranieri C, Filgueiras Igor S, Napoleao Sarah Ms, Plaça Desirée R, Akashi Karen T, Hirata Thiago Dominguez Crespo, El Khawanky Nadia, Giil Lasse M, Cabral-Miranda Gustavo, Carvalho Robson F, Ferreira Luis Carlos S, Condino-Neto Antonio, Nakaya Helder I, Jurisica Igor, Ochs Hans D, Camara Niels Olsen Saraiva, Calich Vera Lúcia G, Cabral-Marques Otavio
Department of Immunology, Institute of Biomedical Sciences, and.
Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
JCI Insight. 2021 May 24;6(10):147535. doi: 10.1172/jci.insight.147535.
The fact that the COVID-19 fatality rate varies by sex and age is poorly understood. Notably, the outcome of SARS-CoV-2 infections mostly depends on the control of cytokine storm and the increasingly recognized pathological role of uncontrolled neutrophil activation. Here, we used an integrative approach with publicly available RNA-Seq data sets of nasopharyngeal swabs and peripheral blood leukocytes from patients with SARS-CoV-2, according to sex and age. Female and young patients infected by SARS-CoV-2 exhibited a larger number of differentially expressed genes (DEGs) compared with male and elderly patients, indicating a stronger immune modulation. Among them, we found an association between upregulated cytokine/chemokine- and downregulated neutrophil-related DEGs. This was correlated with a closer relationship between female and young subjects, while the relationship between male and elderly patients was closer still. The association between these cytokine/chemokines and neutrophil DEGs is marked by a strongly correlated interferome network. Here, female patients exhibited reduced transcriptional levels of key proinflammatory/neutrophil-related genes, such as CXCL8 receptors (CXCR1 and CXCR2), IL-1β, S100A9, ITGAM, and DBNL, compared with male patients. These genes are well known to be protective against inflammatory damage. Therefore, our work suggests specific immune-regulatory pathways associated with sex and age of patients infected with SARS-CoV-2 and provides a possible association between inverse modulation of cytokine/chemokine and neutrophil transcriptional signatures.
新冠病毒疾病（COVID-19）的死亡率因性别和年龄而异，这一事实目前仍鲜为人知。值得注意的是，严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染的结果主要取决于细胞因子风暴的控制以及未受控制的中性粒细胞活化日益被认识到的病理作用。在此，我们采用综合方法，依据性别和年龄，分析了来自SARS-CoV-2患者的鼻咽拭子和外周血白细胞的公开RNA测序数据集。与男性和老年患者相比，感染SARS-CoV-2的女性和年轻患者表现出更多的差异表达基因（DEG），表明其免疫调节更强。其中，我们发现细胞因子/趋化因子上调与中性粒细胞相关DEG下调之间存在关联。这与女性和年轻受试者之间的关系更为密切相关，而男性和老年患者之间的关系则更为紧密。这些细胞因子/趋化因子与中性粒细胞DEG之间的关联以高度相关的干扰基因组网络为特征。在此，与男性患者相比，女性患者关键促炎/中性粒细胞相关基因的转录水平降低，如CXC趋化因子配体8（CXCL8）受体（CXCR1和CXCR2）、白细胞介素-1β（IL-1β）、钙结合蛋白A9（S100A9）、整合素αM（ITGAM）和双调蛋白（DBNL）。众所周知，这些基因具有抗炎症损伤的保护作用。因此，我们的研究揭示了与感染SARS-CoV-2患者的性别和年龄相关的特定免疫调节途径，并提供了细胞因子/趋化因子与中性粒细胞转录特征反向调节之间的可能关联。
