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Microbiota-derived acetate protects against respiratory syncytial virus infection through a GPR43-type 1 interferon response.

ABSTRACT: Severe respiratory syncytial virus (RSV) infection is a major cause of morbidity and mortality in infants?<2 years-old. Here we describe that high-fiber diet protects mice from RSV infection. This effect was dependent on intestinal microbiota and production of acetate. Oral administration of acetate mediated interferon-? (IFN-?) response by increasing expression of interferon-stimulated genes in the lung. These effects were associated with reduction of viral load and pulmonary inflammation in RSV-infected mice. Type 1 IFN signaling via the IFN-1 receptor (IFNAR) was essential for acetate antiviral activity in pulmonary epithelial cell lines and for the acetate protective effect in RSV-infected mice. Activation of Gpr43 in pulmonary epithelial cells reduced virus-induced cytotoxicity and promoted antiviral effects through IFN-? response. The effect of acetate on RSV infection was abolished in Gpr43-/- mice. Our findings reveal antiviral effects of acetate involving IFN-? in lung epithelial cells and engagement of GPR43 and IFNAR.

SUBMITTER: Antunes KH

PROVIDER: S-EPMC6646332 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Microbiota-derived acetate protects against respiratory syncytial virus infection through a GPR43-type 1 interferon response.

Antunes Krist Helen KH Fachi José Luís JL de Paula Rosemeire R da Silva Emanuelle Fraga EF Pral Laís Passariello LP Dos Santos Adara Áurea AÁ Dias Greicy Brisa Malaquias GBM Vargas José Eduardo JE Puga Renato R Mayer Fabiana Quoos FQ Maito Fábio F Zárate-Bladés Carlos R CR Ajami Nadim J NJ Sant'Ana Marcella Ramos MR Candreva Thamiris T Rodrigues Hosana Gomes HG Schmiele Marcio M Silva Clerici Maria Teresa Pedrosa MTP Proença-Modena José Luiz JL Vieira Angélica Thomas AT Mackay Charles R CR Mansur Daniel D Caballero Mauricio T MT Marzec Jacqui J Li Jianying J Wang Xuting X Bell Douglas D Polack Fernando P FP Kleeberger Steven R SR Stein Renato T RT Vinolo Marco Aurélio Ramirez MAR de Souza Ana Paula Duarte APD

Nature communications 20190722 1

Severe respiratory syncytial virus (RSV) infection is a major cause of morbidity and mortality in infants <2 years-old. Here we describe that high-fiber diet protects mice from RSV infection. This effect was dependent on intestinal microbiota and production of acetate. Oral administration of acetate mediated interferon-β (IFN-β) response by increasing expression of interferon-stimulated genes in the lung. These effects were associated with reduction of viral load and pulmonary inflammation in RS ...[more]

PMID: 31332169

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Project description:BackgroundRespiratory syncytial virus (RSV) infects the lung epithelium where it stimulates the production of numerous host cytokines that are associated with disease burden and acute lung injury. Characterizing the host cytokine response to RSV infection, the regulation of host cytokines and the impact of neutralizing an RSV-inducible cytokine during infection were undertaken in this study.MethodsA549, primary human small airway epithelial (SAE) cells and wild-type, TIR-domain-containing adapter-inducing interferon-β (Trif) and mitochondrial antiviral-signaling protein (Mavs) knockout (KO) mice were infected with RSV and cytokine responses were investigated by ELISA, multiplex analysis and qPCR. Neutralizing anti-leukemia inhibitory factor (LIF) IgG or control IgG was administered to a group of wild-type animals prior to RSV infection.Results and discussionRSV-infected A549 and SAE cells release a network of cytokines, including newly identified RSV-inducible cytokines LIF, migration inhibitory factor (MIF), stem cell factor (SCF), CCL27, CXCL12 and stem cell growth factor beta (SCGF-β). These RSV-inducible cytokines were also observed in the airways of mice during an infection. To identify the regulation of RSV inducible cytokines, Mavs and Trif deficient animals were infected with RSV. In vivo induction of airway IL-1β, IL-4, IL-5, IL-6, IL-12(p40), IFN-γ, CCL2, CCL5, CCL3, CXCL1, IP-10/CXCL10, IL-22, MIG/CXCL9 and MIF were dependent on Mavs expression in mice. Loss of Trif expression in mice altered the RSV induction of IL-1β, IL-5, CXCL12, MIF, LIF, CXCL12 and IFN-γ. Silencing of retinoic acid-inducible gene-1 (RIG-I) expression in A549 cells had a greater impact on RSV-inducible cytokines than melanoma differentiation-associated protein 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2), and Trif expression. To evaluate the role of LIF in the airways during RSV infection, animals were treated with neutralizing anti-LIF IgG, which enhanced RSV pathology observed with increased airspace protein content, apoptosis and airway hyperresponsiveness compared to control IgG treatment.ConclusionsRSV infection in the epithelium induces a network of immune factors to counter infection, primarily in a RIG-I dependent manner. Expression of LIF protects the lung from lung injury and enhanced pathology during RSV infection.

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Microbiota-derived acetate protects against respiratory syncytial virus infection through a GPR43-type 1 interferon response.

Publications

Microbiota-derived acetate protects against respiratory syncytial virus infection through a GPR43-type 1 interferon response.

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