Exploring the neutrophil proteome in influenza and COVID-19: results from the INNOVATE study

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Introduction: Studies exploring the neutrophil proteome in COVID-19 showed a key role for neutrophils in viral infection, with changes during acute infection linked to disease severity and outcomes. Data on neutrophil proteome is lacking in other viral infections. Understanding neutrophil proteomic and functional changes in influenza is of importance to further understanding of the disease. Methods: INNOVATE was an observational cohort study enrolling hospitalized patients with PCR virus positive test for influenza, SARS-CoV-2 or other viruses, and participants without infection. Blood sampling was performed 9:00–11:00AM, peripheral blood neutrophils were isolated with EasySep kit and processed for mass spectrometry. Results: 91 hospitalized patients were enrolled (December 2022 to March 2023): 20 patients with confirmed influenza, 27 patients with SARS-CoV-2 and 9 with RSV, 35 patients with no respiratory infection (controls). Neutrophil proteomics revealed 202 significantly altered proteins in influenza compared to controls (171 upregulated and 31 downregulated; FDR-adjusted p-value <0.05). Proteins increased in abundance in influenza included components of the MCM complex, SMARCB1, and IL1R2, linked to DNA-replication and ER-stress pathways. Proteins significantly lower in influenza included MPO, and glycogenolysis regulators PYGL and PYGB. In contrast, the overwhelming signal in SARS-CoV-2 and RSV vs. control neutrophils was IFN-related, indicating molecular differences between viral infections. Conclusions: Proteomics revealed circulating neutrophils are altered during influenza infection, including unique increases in ER stress pathways not observed in other viruses investigated.

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