The relationship between cytokine and neutrophil gene network distinguishes SARS-CoV-2–infected patients by sex and age

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Abstract

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.

Authors

Paula P. Freire, Alexandre H.C. Marques, Gabriela C. Baiocchi, Lena F. Schimke, Dennyson L.M. Fonseca, Ranieri C. Salgado, Igor S. Filgueiras, Sarah M.S. Napoleao, Desirée R. Plaça, Karen T. Akashi, Thiago Dominguez Crespo Hirata, Nadia El Khawanky, Lasse M. Giil, Gustavo Cabral-Miranda, Robson F. Carvalho, Luis Carlos S. Ferreira, Antonio Condino-Neto, Helder I. Nakaya, Igor Jurisica, Hans D. Ochs, Niels Olsen Saraiva Camara, Vera Lúcia G. Calich, Otavio Cabral-Marques