Differential Expression of Serum Exosome microRNAs and Cytokines in Influenza A and B Patients Collected in the 2016 and 2017 Influenza Seasons.

Sreekumar Othumpangat,Michael L Kashon,Samira Mubareka,Carmen N Burrell,John D Noti,Donald H Beezhold,William G Lindsley

doi:10.3390/pathogens10020149

Abstract

MicroRNAs (miRNAs) have remarkable stability and are key regulators of mRNA transcripts for several essential proteins required for the survival of cells and replication of the virus. Exosomes are thought to play an essential role in intercellular communications by transporting proteins and miRNAs, making them ideal in the search for biomarkers. Evidence suggests that miRNAs are involved in the regulation of influenza virus replication in many cell types. During the 2016 and 2017 influenza season, we collected blood samples from 54 patients infected with influenza and from 30 healthy volunteers to identify the potential role of circulating serum miRNAs and cytokines in influenza infection. Data comparing the exosomal miRNAs in patients with influenza B to healthy volunteers showed 76 miRNAs that were differentially expressed (p < 0.05). In contrast, 26 miRNAs were differentially expressed between patients with influenza A (p < 0.05) and the controls. Of these miRNAs, 11 were commonly expressed in both the influenza A and B patients. Interferon (IFN)-inducing protein 10 (IP-10), which is involved in IFN synthesis during influenza infection, showed the highest level of expression in both influenza A and B patients. Influenza A patients showed increased expression of IFNα, GM-CSF, interleukin (IL)-13, IL-17A, IL-1β, IL-6 and TNFα, while influenza B induced increased levels of EGF, G-CSF, IL-1α, MIP-1α, and TNF-β. In addition, hsa-miR-326, hsa-miR-15b-5p, hsa-miR-885, hsa-miR-122-5p, hsa-miR-133a-3p, and hsa-miR-150-5p showed high correlations to IL-6, IL-15, IL-17A, IL-1β, and monocyte chemoattractant protein-1 (MCP-1) with both strains of influenza. Next-generation sequencing studies of H1N1-infected human lung small airway epithelial cells also showed similar pattern of expression of miR-375-5p, miR-143-3p, 199a-3p, and miR-199a-5p compared to influenza A patients. In summary, this study provides insights into the miRNA profiling in both influenza A and B virus in circulation and a novel approach to identify the early infections through a combination of cytokines and miRNA expression.

Highlights

Influenza viruses belong to the Orthomyxoviridae family of human respiratory pathogens
The demographic data clearly indicates no significant difference in symptoms was reported for influenza A and B patients
Among the patients recruited for our study, 19 participants in the healthy control group had received an influenza vaccination, whereas only four patients had been vaccinated in the influenza A-positive group and seven patients had been vaccinated in the influenza B-positive group when they were enrolled

Summary

Introduction

Influenza viruses belong to the Orthomyxoviridae family of human respiratory pathogens. Influenza D viruses primarily infect cattle and are not human pathogens. Our laboratory [4,5,6] and others [7,8] have shown that the early stage of influenza virus infection significantly alters the miRNA profile in human lung epithelial cells. The levels of let-7f, hsa-miR-20b, and hsa-miR-30e-3p were altered in the plasma of patients with small-cell lung cancer [19]. The exosomal hsa-miR-145 and hsa-miR-200c have been found to be altered in ovarian cancer [20]. These studies along with several other studies demonstrate the importance of exosomal miRNAs as biomarkers of disease

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