Identification of Neutrophil-Related Factor LCN2 for Predicting Severity of Patients With Influenza A Virus and SARS-CoV-2 Infection

Abstract

BackgroundInfluenza and COVID-19 are respiratory infectious diseases that are characterized by high contagiousness and high mutation and pose a serious threat to global health. After Influenza A virus (IAV) and SARS-CoV-2 infection, severe cases may develop into acute lung injury. Immune factors act as an important role during infection and inflammation. However, the molecular immune mechanisms still remain unclear. We aimed to explore immune-related host factors and core biomarker for severe infection, to provide a new therapeutic target of host factor in patients.MethodsGene expression profiles were obtained from Gene Expression Omnibus and the Seurat R package was used for data process of single-cell transcriptome. Differentially expressed gene analysis and cell cluster were used to explore core host genes and source cells of genes. We performed Gene Ontology enrichment, Kyoto Encyclopedia of Genes and Genomes analysis, and gene set enrichment analysis to explore potential biological functions of genes. Gene set variation analysis was used to evaluate the important gene set variation score for different samples. We conduct Enzyme-linked immunosorbent assay (ELISA) to test plasma concentrations of Lipocalin 2 (LCN2).ResultsMultiple virus-related, cytokine-related, and chemokine-related pathways involved in process of IAV infection and inflammatory response mainly derive from macrophages and neutrophils. LCN2 mainly in neutrophils was significantly upregulated after either IAV or SARS-CoV-2 infection and positively correlated with disease severity. The plasma LCN2 of influenza patients were elevated significantly compared with healthy controls by ELISA and positively correlated with disease severity of influenza patients. Further bioinformatics analysis revealed that LCN2 involved in functions of neutrophils, including neutrophil degranulation, neutrophil activation involved in immune response, and neutrophil extracellular trap formation.ConclusionThe neutrophil-related LCN2 could be a promising biomarker for predicting severity of patients with IAV and SARS-CoV-2 infection and may as a new treatment target in severe patients.

A single-cell atlas of the peripheral immune response in patients with influenza A virus infection

“…The Neutrophils_LCN2 cluster was enriched in cytoplasmic translation, neutrophil activation, neutrophil degranulation involved in immune response, ATP metabolic process, and cellular response to interleukin-4. 15 Furthermore, the Neutrophils_LCN2 subset expressed genes related to lung inflammation (including LCN2 and DEFA3), suggesting that they play a role in recruiting neutrophils, inducing pro-inflammatory cytokine signaling, while also promoting anti-inflammatory actions. 16 Additionally, Neutrophils_CAB39L expressed CAB39L, which was mainly associated with substance and energy metabolism, while Neutrophils_ISG15 exhibited a transcriptional signature by expressing interferon-stimulated genes (ISGs), including ISG15, IFIT1, IFIT2, IFIT3, and RSAD2 ( Figures 5 C and S4 ).…”

Combination of transcriptional biomarkers and clinical parameters for early prediction of sepsis indued acute respiratory distress syndrome

“…Studies have revealed that LCN2 inhibition or silencing could exert protective effect on LPS-induced ARDS model via inhibition of ferroptosis-related inflammation and oxidative stress ( 23 ). Meanwhile, LCN2 was significantly elevated and positively correlated with disease severity in patients with influenza or COVID-19 ( 24 ). Interestingly, LCN2 expression is markedly upregulated in septic ALI mice compared with those without ALI, which is consistence with our findings ( 25 ).…”

Health disparities in COVID-19: immune and vascular changes are linked to disease severity and persist in a high-risk population in Riverside County, California

“…LCN2, or Lipocalin-2 (also known as neutrophil gelatinase-associated lipocalin or NGAL), is an acute-phase protein involved in immune response and inflammation [ 57 ]. Recent work has indicated that elevated LCN2 levels are correlated with the severity of COVID-19 infection and may serve as a potential biomarker for disease progression [ 58 ]. Our finding that higher MHCII expression by monocytes is associated with improved prognosis confirms results found in recent studies [ 59 , 60 ].…”