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
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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

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Figure 2

Strength of the association between the upregulated cytokine genes and downregulated neutrophil genes.

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Strength of the association between the upregulated cytokine genes and d...
(A) Total number of DEGs associated with cytokine-mediated signaling pathways (CMSP, red bars) and neutrophil-mediated immunity (NMI, blue bars) when comparing SC2-positive patients with viral load-, sex-, and age-matched negative SC2 samples. (B) Network representation of matrix of Pearson correlations between genes, including also the estimated canonical variables. Gray edges connect pairs of genes with a Pearson correlation of ≥0.7, and those with a correlation of <0.7 were omitted. (C) Heliographic representation of the canonical-correlation analysis between CMSP and NMI genes, showing correlation of genes with their corresponding canonical variates, Cy-CV1 and Cy-CV2 and Ne-CV1 and Ne-CV2, respectively. CMSP and NMI genes with a correlation of ≥0.7 are colored in red and blue, respectively, while those with a correlation of <0.7 are gray in both groups. SC2, SARS-CoV-2 group; Neg. SC2, negative SARS-CoV-2 group; Cy-CV1, canonical variable 1 associated with CMSP genes; Cy-CV2, canonical variable 2 associated with CMSP genes; Ne-CV1, canonical variable 1 associated with NMI genes; Ne-CV2, canonical variable 2 associated with NMI genes.