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Association between single nucleotide polymorphisms in TLR4, TLR2, TLR9, VDR, NOS2 and CCL5 genes with acute viral bronchiolitis.

ABSTRACT: BACKGROUND:Acute viral bronchiolitis is the leading cause of hospitalization among infants during the first year of life. Most infants hospitalized for bronchiolitis do not present risk factors and are otherwise healthy. Our objective was to determine the genetic features associated with the risk and a severe course of bronchiolitis. METHODS:We prospectively evaluated 181 infants with severe bronchiolitis admitted at three hospitals over a 2-year period, who required oxygen therapy. The control group consisted of 536 healthy adults. Patients were evaluated for the presence of comorbidities (premature birth, chronic respiratory disease, and congenital heart disease), underwent nasopharyngeal aspirate testing for virus detection by multiplex-PCR, and SNPs identification in immune response genes. Patient outcomes were assessed. RESULTS:We observed association between SNP rs2107538*CCL5 and bronchiolitis caused by respiratory syncytial virus(RSV) and RSV-subtype-A, and between rs1060826*NOS2 and bronchiolitis caused by rhinovirus. SNPs rs4986790*TLR4, rs1898830*TLR2, and rs2228570*VDR were associated with progression to death. SNP rs7656411*TLR2 was associated with length of oxygen use; SNPs rs352162*TLR9, rs187084*TLR9, and rs2280788*CCL5 were associated with requirement for intensive care unit admission; while SNPs rs1927911*TLR4, rs352162*TLR9, and rs2107538*CCL5 were associated with the need for mechanical ventilation. CONCLUSIONS:Our findings provide some evidence that SNPs in CCL5 and NOS2 are associated with presence of bronchiolitis and SNPs in TLR4, TLR2, TLR9, VDR and CCL5 are associated with severity of bronchiolitis.

SUBMITTER: Alvarez AE

PROVIDER: S-EPMC7127094 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Association between single nucleotide polymorphisms in TLR4, TLR2, TLR9, VDR, NOS2 and CCL5 genes with acute viral bronchiolitis.

Alvarez Alfonso Eduardo AE Marson Fernando Augusto Lima FAL Bertuzzo Carmen Sílvia CS Bastos Juliana Cristina Santiago JCS Baracat Emilio Carlos Elias ECE Brandão Marcelo Barciela MB Tresoldi Antônia Teresinha AT das Neves Romaneli Mariana Tresoldi MT Almeida Celize Cruz Bresciani CCB de Oliveira Therezinha T Schlodtmann Patricia Godano PG Corrêa Ester E de Miranda Maria Luisa Ferreira MLF Dos Reis Marcelo Conrado MC De Pieri José Vicente JV Arns Clarice Weis CW Ribeiro José Dirceu JD

Gene 20171215

<h4>Background</h4>Acute viral bronchiolitis is the leading cause of hospitalization among infants during the first year of life. Most infants hospitalized for bronchiolitis do not present risk factors and are otherwise healthy. Our objective was to determine the genetic features associated with the risk and a severe course of bronchiolitis.<h4>Methods</h4>We prospectively evaluated 181 infants with severe bronchiolitis admitted at three hospitals over a 2-year period, who required oxygen therap ...[more]

PMID: 29253610

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Project description:BackgroundInterleukin-17 (IL-17) acts as a key regulator in central nervous system (CNS) inflammation. ?? T cells are an important innate source of IL-17. Both IL-17+ ?? T cells and microglia, the major resident immune cells of the brain, are involved in various CNS disorders such as multiple sclerosis and stroke. Also, activation of Toll-like receptor (TLR) signaling pathways contributes to CNS damage. However, the mechanisms underlying the regulation and interaction of these cellular and molecular components remain unclear.ObjectiveIn this study, we investigated the crosstalk between ?? T cells and microglia activated by TLRs in the context of neuronal damage. To this end, co-cultures of IL-17+ ?? T cells, neurons, and microglia were analyzed by immunocytochemistry, flow cytometry, ELISA and multiplex immunoassays.ResultsWe report here that IL-17+ ?? T cells but not naïve ?? T cells induce a dose- and time-dependent decrease of neuronal viability in vitro. While direct stimulation of ?? T cells with various TLR ligands did not result in up-regulation of CD69, CD25, or in IL-17 secretion, supernatants of microglia stimulated by ligands specific for TLR2, TLR4, TLR7, or TLR9 induced activation of ?? T cells through IL-1? and IL-23, as indicated by up-regulation of CD69 and CD25 and by secretion of vast amounts of IL-17. This effect was dependent on the TLR adaptor myeloid differentiation primary response gene 88 (MyD88) expressed by both ?? T cells and microglia, but did not require the expression of TLRs by ?? T cells. Similarly to cytokine-primed IL-17+ ?? T cells, IL-17+ ?? T cells induced by supernatants derived from TLR-activated microglia also caused neurotoxicity in vitro. While these neurotoxic effects required stimulation of TLR2, TLR4, or TLR9 in microglia, neuronal injury mediated by bone marrow-derived macrophages did not require TLR signaling. Neurotoxicity mediated by IL-17+ ?? T cells required a direct cell-cell contact between T cells and neurons.ConclusionTaken together, these results point to a crucial role for microglia activated through TLRs in polarization of ?? T cells towards neurotoxic IL-17+ ?? T cells.

Dataset Information

Association between single nucleotide polymorphisms in TLR4, TLR2, TLR9, VDR, NOS2 and CCL5 genes with acute viral bronchiolitis.

Publications

Association between single nucleotide polymorphisms in TLR4, TLR2, TLR9, VDR, NOS2 and CCL5 genes with acute viral bronchiolitis.

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