The relationship between cytokine and neutrophil gene network distinguishes SARS-CoV-2–infected patients by sex and age
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
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
View: Text | PDF
Research Article COVID-19 Inflammation

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

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

×

Figure 7

Transcriptional differences in cytokine-mediated signaling pathway and neutrophil-mediated immunity distinguish females and males.

Options: View larger image (or click on image) Download as PowerPoint
Transcriptional differences in cytokine-mediated signaling pathway and n...
(A and B) Violin plots present differentially expressed genes (DEGs; adjusted P < 0.05 and log2FC fold change [log2FC] >1) of cytokine-mediated signaling pathway (CMSP) (A) and neutrophil-mediated immunity (NMI) (B) of SARS-CoV-2–positive (SC2) females versus SC2 males from the GSE152075 data set. (C) DEGs of swabs from female versus male positive SC2 patients from the GSE156063 data set associated with CMSP and NMI. (D) Unsupervised hierarchical clustering heatmap of CMSP and NMI genes (normalized gene expression in log2 CPM). Red tracks denote CMSP genes, and blue tracks represent NMI genes. (E) Multivariate regression of gene expression of CD14, CXCR1, CXCR2, IL-1β, NBEAL2, and S100A9 according to viral load and sex. Results indicate that the variation observed for expression values of these 6 genes dependent mainly on sex-specific differences. SC2, SARS-CoV-2 group; Neg. SC2, negative SARS-CoV-2 group; CPM, counts per million.