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 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-β response. The effect of acetate on RSV infection was abolished in Gpr43 − / − mice. Our findings reveal antiviral effects of acetate involving IFN-β in lung epithelial cells and engagement of GPR43 and IFNAR.

Respiratory Syncytial Virus (RSV) is the major cause of acute bronchiolitis in infants under 2 years old. Necroptosis has been implicated in the outcomes of respiratory virus infections. Here we report that RSV infection triggers necroptosis in primary mouse macrophages and human monocytes in a RIPK1-, RIPK3-, and MLKL-dependent manner. Moreover, necroptosis pathways are harmful to RSV clearance from alveolar macrophages. Additionally, Ripk3-/- mice were protected from RSV-induced weight loss and presented reduced viral loads in the lungs.Alveolar macrophage depletion also protected mice from weight loss and decreased lung RSV virus load. Importantly, alveolar macrophage depletion abolished the upregulation of Ripk3 and Mlkl gene expression induced by RSV infection in the lung tissue.Autocrine TNF mediated RSV-triggered macrophage necroptosis and necroptosis pathways were also involved in TNF secretion even when macrophages were committed to cell death, which can worsen lung injury during RSV infection. In line, Tnfr1-/- mice had a marked decrease in Ripk3 and Mlkl gene expression and a sharp reduction in the numbers of necrotic alveolar macrophages in the lungs. Finally, we provide evidence that elevated nasal levels of TNF are associated with disease severity in infants with RSV bronchiolitis.We propose that targeting TNF and/or the necroptotic machinery may be valuable as therapeutic approaches to reduce the respiratory morbidity caused by RSV infection in young children.

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Respiratory syncytial virus (RSV) is a seasonal pathogen responsible for the highest percentage of viral bronchiolitis in pediatric patients. There are currently no vaccine available and therapeutic methods to mitigate the severity of RSV bronchiolitis are limited. OM-85, an oral standardized bacterial lysate isolated from human respiratory strains and widely used to prevent recurrent infections and/or exacerbations in populations at risk, has been shown to be effective and safe in children and adults. Here, we demonstrate that airway administration of OM-85 in Balb/c mice prior to infection prevents RSV-induced disease, resulting in inhibition of viral replication associated with less perivascular and peribronchial inflammation in the lungs. These protective effects are dose and time-dependent with complete protection using 1mg dose of OM-85 only four times intranasally. Mechanistic insights using this topical route in the airways revealed increased alveolar macrophages, a selective set of tolerogenic DCs, Treg and Th1 expansion in the lung, even in the absence of infection, contributing to a better Th1/Th2 balance and preventing ILC2 recruitment in the airways and associated inflammatory sequelae. OM-85 preventive treatment also improved antiviral response by increasing IFNβ and its responsive genes in the lung. In vitro, OM-85 protects against RSV infection in a type I interferon pathway. Our animal model data suggest that intranasal use of OM-85 should be considered as a potential prophylactic product to prevent RSV bronchiolitis once human studies confirm these findings.

In transplantation, donor dendritic cells (do-DCs) initiate the alloimmune response either by direct interaction with host T cells or by transferring intact donor MHC to host DCs. However, how do-DCs can be targeted for improving allograft survival is still unclear. Here we show CD103+ DCs are the major do-DC subset involved in the acute rejection of murine skin transplants. In the absence of CD103+ do-DCs, less donor MHC-II is carried to host lymph nodes, fewer allogenic T cells are primed and allograft survival is prolonged. Incubation of skin grafts with the anti-inflammatory mycobacterial protein DnaK reduces donor MHC-II on CD103+DCs and prolongs graft survival. This effect is mediated through IL-10-induced March1, which ubiquitinates and decreases MHC-II levels. Importantly, in vitro pre-treatment of human DCs with DnaK reduces their ability to prime alloreactive T cells. Our findings demonstrate a novel therapeutic approach to dampen alloimmunity by targeting donor MHC-II on CD103+DCs.

Summary Respiratory syncytial virus (RSV)-specific CD81 T cell responses do not protect against reinfection. Activation of mammalian target of rapamycin (mTOR) impairs memory CD8 1 T cell differentiation. Our hypothesis was that RSV inhibits the formation of CD8 1 T cells memory responses through mTOR activation. To explore this, human and mouse T cells were used. RSV induced mTOR phosphorylation at Ser2448 in CD8 T cells. mTOR activation by RSV was completely inhibited using rapamycin. RSV-infected children presented higher mTOR gene expression on nasal washes comparing to children infected with metapneumovirus and rhinovirus. In addition, RSV-infected infants presented a higher frequency of CD8 1 pmTORser2448 1 T cells in nasal washes compared to RSV-negative infants.Rapamycin treatment increased the frequency of mouse CD8 RSV-M 282-90 pentamer-positive T cells and the frequency of RSV-specific memory T cells precursors. These data demonstrate that RSV is activating mTOR directly in CD8 T cells, indicating a role for mTOR during the course of RSV infection.

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The esophagus and mouth tumors are very frequent malignancies worldwide. Lipopolysaccharides (LPS) are capable of regulating gene expression of pro-inflammatory cytokines by binding to toll-like receptor 4 (TLR4). Recent studies show that LPS can increase the migration ability of human esophageal cancer cell line HKESC-2 by increasing its adhesion properties. However, the effect of LPS has not been tested on viability of human esophageal and oral cancer cells. This study aimed to determine the action of LPS on the cell proliferation and viability in