Severe COVID-19 Shares a Common Neutrophil Activation Signature with Other Acute Inflammatory States

• Published in: Cells (Basel, Switzerland) Switzerland), 2022-03, Vol.11 (5), p.847
• Main Authors: Schimke, Lena F, Marques, Alexandre H C, Baiocchi, Gabriela Crispim, de Souza Prado, Caroline Aliane, Fonseca, Dennyson Leandro M, Freire, Paula Paccielli, Rodrigues Plaça, Desirée, Salerno Filgueiras, Igor, Coelho Salgado, Ranieri, Jansen-Marques, Gabriel, Rocha Oliveira, Antonio Edson, Peron, Jean Pierre Schatzmann, Cabral-Miranda, Gustavo, Barbuto, José Alexandre Marzagão, Camara, Niels Olsen Saraiva, Calich, Vera Lúcia Garcia, Ochs, Hans D, Condino-Neto, Antonio, Overmyer, Katherine A, Coon, Joshua J, Balnis, Joseph, Jaitovich, Ariel, Schulte-Schrepping, Jonas, Ulas, Thomas, Schultze, Joachim L, Nakaya, Helder I, Jurisica, Igor, Cabral-Marques, Otávio
• Format: Article
• Language: English
• Subjects: acute inflammatory states; Artificial Intelligence; Cell activation; Chemokines; Child; Coronaviruses; COVID-19; COVID-19 - complications; COVID-19 - genetics; Cytokines; Datasets; Histiocytosis; Humans; Immune response; Inflammation; Influenza; integrative analysis of omics data; Leukocytes (neutrophilic); Lymphocytes; Lymphocytosis; Lymphohistiocytosis, Hemophagocytic - complications; Mucocutaneous lymph node syndrome; Multisystem inflammatory syndrome in children; Neutrophil Activation; Patients; Plasma proteins; Pneumonia; SARS-CoV-2; Systemic Inflammatory Response Syndrome; systems biology; transcriptome profile; Transcriptomes
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells11050847

Severe COVID-19 patients present a clinical and laboratory overlap with other hyperinflammatory conditions such as hemophagocytic lymphohistiocytosis (HLH). However, the underlying mechanisms of these conditions remain to be explored. Here, we investigated the transcriptome of 1596 individuals, including patients with COVID-19 in comparison to healthy controls, other acute inflammatory states (HLH, multisystem inflammatory syndrome in children [MIS-C], Kawasaki disease [KD]), and different respiratory infections (seasonal coronavirus, influenza, bacterial pneumonia). We observed that COVID-19 and HLH share immunological pathways (cytokine/chemokine signaling and neutrophil-mediated immune responses), including gene signatures that stratify COVID-19 patients admitted to the intensive care unit (ICU) and COVID-19_nonICU patients. Of note, among the common differentially expressed genes (DEG), there is a cluster of neutrophil-associated genes that reflects a generalized hyperinflammatory state since it is also dysregulated in patients with KD and bacterial pneumonia. These genes are dysregulated at the protein level across several COVID-19 studies and form an interconnected network with differentially expressed plasma proteins that point to neutrophil hyperactivation in COVID-19 patients admitted to the intensive care unit. scRNAseq analysis indicated that these genes are specifically upregulated across different leukocyte populations, including lymphocyte subsets and immature neutrophils. Artificial intelligence modeling confirmed the strong association of these genes with COVID-19 severity. Thus, our work indicates putative therapeutic pathways for intervention.