influenza G, Kawaoka Y (2007) Orthomyxoviuses. In:

influenza A virus (IAV) infections cause ailment in birds and a number of mammalian species including human population worldwide and have inordinate impact on human health and prosperity. They are the major causative agents of acute viral infections of the respiratory tract which may cause severity from asymptomatic infection to primary viral pneumonia and death. This virus genome consists of 8 fragments of negative-sense single-stranded RNA which encodes for 11 major proteins (1). In the 20th century, three novel strains of influenza virus arose that caused the 1918, 1957, and 1968 pandemics which lead to high mortality rates (2). The main antigenic elements of influenza A viruses are the hem-agglutinin (H) and neuraminidase (N) trans-membrane glycoproteins. On the basis of the antigenicity of these glycoproteins, influenza A viruses are further divided into 16 H (H1 to H16) and 9 N (N1 to N9) subtypes. Currently, H1N1 and H3N2 subtypes are the main isolates circulating in the human population (3, 4). In human, influenza A virus infection promotes the massive release of inflammatory cytokines and chemokines which lead to pulmonary edema, pneumonia, alveolar hemorrhage (5).

MicroRNAs are small non-coding RNAs (~22 nt), which modulate cellular gene expression by interrupting the mRNA translation. Recent findings report that several host cellular microRNAs (cell-associated or cell-free) are involved in influenza A virus infection and disease progression in humans. For example, miR- 323, miR-491, and miR-654 bind to the PBI gene and inhibit the replication of the H1N1 influenza A virus (6). While miR-155 gets up-regulate during IAV infection and promotes type I interferon (IFN) signaling which results in activation of host antiviral innate immune response in macrophages (7). Since miRNAs are associated in several cellular processes from developmental biology to disease pathology, they are supposed to be potent modulators of a range of biological processes.

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Circulating miRNAs have been reported to exhibit typical expression patterns in context to a number of different pathological conditions, including cardiovascular, cerebrovascular, systemic inflammatory diseases, cancer, infectious diseases and metabolic disorders such as type 2diabetes and obesity (8, 9). Thus, this modulation in the expression level of different circulating miRNAs due to influenza virus infection can be quantified or detected in circulation by different techniques which proposed them as potential biomarkers for various diseases.










1.      Wright PF, Neumann G, Kawaoka Y (2007) Orthomyxoviuses. In: Knipe DM, Howley PM, Griffin DE, Lamb RA, Martin MA, editors. Philadelphia: Fields Virology, Wolters Kluwer; Lippincott Williams & Wilkins. pp. 1727–1740

2.      Morens, D. M., Subbarao, K., and Taubenberger, J. K. (2012) Engineering H5N1 avian influenza viruses to study human adaptation. Nature 486., 335-340

3.      Stohr K. 2005. Avian influenza and pandemics-research needs and opportunities. N. Engl. J. Med.352:405–407 

4.      Tumpey TM, et al. 2005. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science 310:77–80 

5.      Teijaro, J. R., Walsh, K. B., Cahalan, S., Fremgen, D. M., Roberts, E., Scott, F., Martinborough, E., Peach, R., Oldstone, M. B., and Rosen, H. (2011) Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection. Cell 146., 980-991

6.      Song, L., Liu, H., Gao, S., Jiang, W., and Huang, W. (2010) Cellular microRNAs inhibit replication of the H1N1 influenza A virus in infected cells. J Virol 84., 8849-8860

7.      Zhang, H., Zhao, Z., Pang, X., Yang, J., Yu, H., Zhang, Y., Zhou, H., and Zhao, J. (2017) Genistein Protects Against OxLDL-Induced Inflammation Through MicroRNA-155/SOCS1-Mediated Repression of NF-kB Signaling Pathway in HUVECs. Inflammation Aug;40(4)., 1450-1459

8.       Tan KS, Armugam A, Sepramaniam S, Lim KY, Setyowati KD et al. (2009) Expression profile of MicroRNAs in young stroke patients. PLOS ONE. 4: e7689.10.1371/journal.pone.0007689

Contu R, Latronico MV, Condorelli G, (2010). Circulating microRNAs as potential biomarkers of coronary artery disease: a promise to be fulfilled? Circ Res. 2010;107:573–574.



































. Significant resources are linked to influenza epidemics due to excess hospitalizations and lost productivity in workplaces, as well as the need for the production of yearly updated vaccines to cover the currently circulating influenza virus strains1. Otherwise healthy subjects will recover within 1–2 weeks without treatment, but the infection may also lead to severe morbidity and mortality, especially in elderly and immune compromised individuals2. New strains of influenza virus with pandemic potential will continue to emerge due to mutation, genetic reassortment, and a complex animal reservoir.

MicroRNAs (miRNAs) are a class of short (~22 nt), endogenous regulatory RNAs that have been identified in a wide range of organisms, including animals, plants, viruses, and fungi3. They modulate gene expression by interfering with mRNA translation most commonly by destabilising mRNA thereby facilitating degradation. The origin of cell-free circulating miRNAs is still unclear; they may be breakdown products originating from lysed cells, or they may be actively secreted from cells to act in a paracrine manner, or perhaps a combination of the two14. Regulation of cell-associated and cell-free miRNAs in circulation in response to IAV infection may thus have different causes and functions. In PBMCs of critically ill patients with H1N1 infection, expression of hsa-miR-29a, -31, and -148a were all determined individually to have diagnostic potential12
















Influenza A viruses cause frequent outbreaks of acute respiratory tract infections and represent a significant public health threat(Lapinsky, 2010). The recent pandemic outbreak caused by the swineorigin influenza A/H1N1 virus in 2009 (Smith et al., 2009) affected most countries, and its severe manifestations caused over 18,000 con- firmed deaths worldwide (Writing Committee of the WHOCoCAoPI et al., 2010) but estimates of deaths go as high as 270,000 (Dawood et al., 2012). Several studies have revealed that pandemic (pdm) A/ H1N1 virus strain infects and efficiently replicates in epithelial cells and macrophages of the lower respiratory tract leading to cell activation and the production of inflammatory mediators that contribute to an acute inflammatory microenvironment in the lung (Itoh et al., 2009). Even though immune mediators such as cytokines, chemokines and growth factors are critical to controlling influenza A virus infection, their overproduction in an uncontrolled inflammatory response can lead to devastating lung damage (Zuniga et al., 2011; Monsalvo et al., 2011; Bermejo-Martin et al., 2010). Humans infected by pdm A/H1N1 strain often-present high serum levels of pro-inflammatory cytokines and chemokines, which are believed to contribute to the disease pathogenesis and the development of acute respiratory distress syndrome (ARDS) (Zuniga et al., 2011; Monsalvo et al., 2011; Bermejo-Martin et al., 2010; Bautista et al., 2013). Experimental and cross-sectional studies have demonstrated that exaggerated production of inflammatory/angiogenic and metabolic mediators is associated with a higher risk to develop ARDS in pdm A/H1N1 infected patients (Bautista et al., 2013; Ubags et al., 2014). However, the mechanisms related with the immunopathogenesis of severe pneumonia by pdm A/H1N1 virus are not fully comprehended. Understanding the factors determining these poor outcomes is therefore of great importance, particularly in the context of the appearance of newly more pathogenic or oseltamivir resistant strains. In this context, miRNAs regulate the expression of other genes by different mechanisms and influence most of the cellular processes including antiviral inflammatory responses (Perera and Ray, 2007). Circulating miRNA concentrations differ according to physiological and pathological states such as obesity, type 2 diabetes, systemic inflammatory diseases, cancer and infectious diseases (Contu et al., 2010; Zampetaki et al., 2010; Houzet et al., 2008; Pan et al., 2012), suggesting that miRNAs may be useful biomarkers for diagnosis and clinical progression of various diseases. We studied the expression profile of miRNAs in peripheral blood from critically ill patients with pdm A/H1N1 virus infection as well as in pdm A/H1N1 patients with mild disease, asymptomatic household contacts and healthy donor controls to determine its role as a biomarker related to severe disease and to possibly understand its role on dysregulated inflammatory responses.







. The entire viral genome consists of 8 segments of negative-sense single-stranded RNA and encodes for 11 major proteins 1. Although the life cycle of the influenza virus has been well described, the exact pathophysiology in particular, the role of microRNA in the host response to viral infection has not been well characterized. There are only a limited number of therapeutic approaches which target either the neuraminidase or the M2 ion channel. Vaccines are also limited by the seasonal antigenic drift which limits the efficacy of inactivated and live attenuated vaccines targeting specific influenza virus strains from each of the major circulating serotypes – H1N1 and H3N2 2.

Recent studies suggest that host cellular microRNAs (miRNAs) are involved in the regulation of influenza A H1N1 replication in vitro 3-5. miRNAs are small non-coding RNAs of approximately 22 nucleotides in length. They bind to target regions within the genome (mRNA and DNA) with perfect or partial complementarity and thus regulate the expression levels of the target gene.

Circulating miRNAs have been shown to exhibit distinctive expression patterns in relation to a number of different pathological conditions, including cerebrovascular, cardiovascular and metabolic disorders and thus have been proposed as potential biomarkers 6-8. This role is enhanced by their remarkable stability under harsh conditions such as exposure to extreme pH, boiling and multiple freeze-thaw cycles 9. The presence of stable circulating miRNAs also suggests a potential role as paracrine agents where a miRNA secreted by a particular organ/cell could be released into circulation to mediate its effect on a different target site. For example, miR-150 synthesized by blood and monocytic cells were packaged into microvesicles and transported to endothelial cells, effectively reducing its target gene (MYB) expression 10. and these profiles have the potential to aid in diagnosis and treatment.










Influenza virus (IV) causes a potentially serious infection with symptoms including headache, fever, pneumonia, and even death. The ease with which this pathogen can spread can cause widespread epidemics (38). The main antigenic determinants of influenza A viruses are the hemagglutinin (H) and neuraminidase (N) transmembrane glycoproteins. Based on the antigenicity of these glycoproteins, influenza A viruses are further subdivided into 16 H (H1 to H16) and 9 N (N1 to N9) subtypes. H1N1 and H3N2 subtypes are the main isolates currently circulating in the human population (38, 42). In recent years, H5N1 and H1N1 have also caused hundreds of deaths and billions of dollars in economic losses (21).

Cyclooxygenase-2 (COX2) expression is present in airway epithelial cells after influenza virus infection (27). COX2 catalyzes the first step in the biosynthesis of prostaglandins from arachidonic acid and is important in host responses to infection (7, 10, 33). The ability of COX2 products to modulate inflammation and immune responses is well documented (1, 4, 6, 22, 24, 29). COX2 is a main cause of inflammation during influenza virus infection and cooperates with other proinflammatory cytokines and interleukins (ILs), such as inducible nitric oxide, interferon (IFN), and IL-32. Furthermore, COX2 is the primary mediator of the body’s protection from influenza virus infection (20). However, the acute and sometimes extensive inflammation in the respiratory system is also a common cause of death by influenza infection.

In mammalian cells, DNA methylation is performed by three members of the DNA methyltransferase (DNMT) family: DNMT1, DNMT3a, and DNMT3b. DNA methylation involves the formation of a covalent bond between a methyl group and a dinucleotide CpG (8). The majority of CpG dinucleotides in the genome, dispersed across retrotransposons or throughout coding regions and introns of genes, are methylated in normal cells. However, approximately 15% of CpGs are clustered in CpG islands in the promoter regions of genes and are normally unmethylated (8). Recent studies showed that tumorigenesis is coupled with aberrant methylation in the promoter of tumor suppressor genes and changes in expression of DNMT family members (9, 13). Additionally, some investigators have reported that the members of the DNMT family can be regulated by certain viral proteins such as the hepatitis B virus (HBV) X protein, which directly affects the expression of COX2, a gene critical to proinflammatory processes (17, 32, 48). The results of these studies indicate that similar aberrant epigenetic processes induced by certain viral proteins may occur in other viral infections and may constitute a potential new pathway leading to the expression of inflammation genes. However, the mechanism by which viral proteins can lead to epigenetic changes requires more investigation.

MicroRNAs (miRNAs) are small noncoding RNAs that naturally exist in mammalian cells and play a role similar to small interfering RNAs (siRNAs). Mature miRNAs are 19- to 25-nucleotide-long molecules cleaved from 70- to 100-nucleotide hairpin pre-miRNA precursor molecules. In animals, single-stranded miRNAs bind, through partial sequence homology, to the 3? untranslated region (3?-UTR) of target mRNAs and block translation or, less frequently, induce mRNA degradation (3). The miRNA29 (miR29) family, which includes miR29a, miR29b, and miR29c, is involved in apoptosis, tumorigenesis, and chronic lymphocyte leukemia (12, 46). miRNAs of the miR29 family were identified bound to the 3?-UTR of DNMT3a and DNMT3b, indicating that they may have a role in regulating DNA methylation levels by regulating the expression of DNMT3a and 3b in lung cancer (11). However, little is known about the role of miR29 during viral infection.

The gene encoding lambda-1 IFN (IFN-?1), also known as IL-29, is located on human chromosome 19. IFN-?1, IL-28A (IFN-?2), and IL-28B (IFN-?3) were identified as type III IFNs in 2003 (16, 36). Type I and type III IFNs have similar biological functions, and their expression is induced in a number of viral infections including type IV (15, 44). Additionally, the antiviral activity of type 1 and type III INF on IV has also been reported (44). These studies indicate that IFN-?1 may be an important member of the antiviral network to protect cells from IV infection.

As DNMT3a and DNMT3b have been reported to play a role during HBV infection, similar regulation may also occur in other viral infections. In this study, our aim was to discover how epigenetic modifications affect the expression of proinflammatory genes in response to influenza A virus infection. Our results demonstrate that cooperation between miR29-mediated epigenetic modifications and activation of the protein kinase A (PKA) signaling pathway mediate the upregulation of COX2 and consequent IFN-?1 production. This study describes a previously unrecognized proinflammatory mechanism that occurs during influenza A virus infection.



















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