Poly I:C Pre-Treatment Induced the Anti-Viral Interferon Response in Airway Epithelial Cells.

Type I and III interferons are among the most important antiviral mediators. Increased susceptibility to infections has been described as being associated with impaired interferon response in asthmatic patients. In this work, we focused on the modulation of interferon dysfunction after the rhinovirus infection of airway epithelial cells. Therefore, we tested polyinosinic:polycytidylic acid (poly I:C), a TLR3 agonist, as a possible preventive pre-treatment to improve this anti-viral response. In our human study on asthma, we found a deficiency in interferon levels in the nasal epithelial cells (NEC) from asthmatics at homeostatic level and after RV infection, which might contribute to frequent airway infection seen in asthmatic patients compared to healthy controls. Finally, pre-treatment with the immunomodulatory substance poly I:C before RV infection restored IFN responses in airway epithelial cells. Altogether, we consider poly I:C pre-treatment as a promising strategy for the induction of interferon response prior to viral infections. These results might help to improve current therapeutic strategies for allergic asthma exacerbations.

Vitamin D3 resolved human and experimental asthma via B lymphocyte-induced maturation protein 1 in T cells and innate lymphoid cells.

Background: Vitamin D3 (VitD3) is known to have immunomodulatory functions, and VitD3 deficiency is associated with more severe asthma. Objective: We aimed to assess the immunoregulatory effects of VitD3 food supplementation on asthma manifestation, with particular focus on T cells and type 2 innate lymphoid cells. Methods: Preschool children and adult asthmatic cohorts were analyzed in the context of VitD3 supplementation and serum levels. In a murine model of ovalbumin-induced asthma, effects of diet VitD3 sufficiency and deficiency on T cells and type 2 innate lymphoid cells immune mechanisms were investigated. Results: We found less severe and better-controlled asthma phenotypes along with reduced need for steroid medication in preschool children and asthmatic adults with VitD3 supplementation. VitD3 serum levels correlated with B lymphocyte-induced maturation protein 1 (Blimp-1) expression in blood peripheral mononuclear cells. VitD3-supplement-fed mice showed decreased asthmatic traits, with a decrease in IgE serum levels, reduced airway mucus, and increased IL-10 production by lung cells. Furthermore, we discovered an upregulation of effector T cells and Blimp-1+ lung tissue-resident memory T cells as well as induction of anti-inflammatory Blimp-1+ lung innate lymphoid cells producing IL-10. Conclusion: Supplementing VitD3 resulted in amelioration of clinical asthma manifestations in human studies as well as in experimental allergic asthma, indicating that VitD3 shifts proinflammatory immune responses to anti-inflammatory immune responses via upregulating Blimp-1 in lung innate lymphoid cells and tissue-resident memory cells.

Rhinovirus Suppresses TGF-ß-GARP Presentation by Peripheral NK Cells.

Asthma is a chronic airway disease whose exacerbations are often triggered by rhinovirus infection. TGF-ß1 induces rhinovirus replication in infected cells. Moreover, TGF-ß1 is a pleiotropic mediator that is produced by many immune cells in the latent, inactive form bound to the latency-associated peptide (LAP) and to the transmembrane protein glycoprotein A repetitions predominant (GARP). In this study we wanted to investigate the effect of rhinovirus infection on the TGF-ß secretion and the downstream signaling via TGF-ßRI/RII in peripheral blood mononuclear cells from control and asthmatic patients after rhinovirus infection ex vivo. Here, we found a significant upregulation of TGF-ßRII in untouched PBMCs of asthmatics as well as a suppression of TGF-ß release in the rhinovirus-infected PBMC condition. Moreover, consistent with an effect of TGF-ß on Tregs, PBMCs infected with RV induced Tregs, and TGF-ßRII directly correlated with RV1b mRNA. Finally, we found via flow cytometry that NK cells expressed less GARP surface-bound TGF-ß, while cytokine-producing NKbright cells were induced. In summary, we show that rhinovirus infection inhibits TGF-ß release in PBMCs, which results in the activation of both Treg and NK cells.

Regulation and Function of Interferon-Lambda (IFNλ) and Its Receptor in Asthma.

Asthma is a chronic respiratory disease affecting people of all ages, especially children, worldwide. Origins of asthma are suggested to be placed in early life with heterogeneous clinical presentation, severity and pathophysiology. Exacerbations of asthma disease can be triggered by many factors, including viral respiratory tract infections. Rhinovirus (RV) induced respiratory infections are the predominant cause of the common cold and also play a crucial role in asthma development and exacerbations. Rhinovirus mainly replicates in epithelial cells lining the upper and lower respiratory tract. Type III interferons, also known as interferon-lambda (IFNλ), are potent immune mediators of resolution of infectious diseases but they are known to be involved in autoimmune diseases as well. The protective role of type III IFNs in antiviral, antibacterial, antifungal and antiprotozoal functions is of major importance for our innate immune system. The IFNλ receptor (IFNλR) is expressed in selected types of cells like epithelial cells, thus orchestrating a specific immune response at the site of viruses and bacteria entry into the body. In asthma, IFNλ restricts the development of TH2 cells, which are induced in the airways of asthmatic patients. Several studies described type III IFNs as the predominant type of interferon increased after infection caused by respiratory viruses. It efficiently reduces viral replication, viral spread into the lungs and viral transmission from infected to naive individuals. Several reports showed that bronchial epithelial cells from asthmatic subjects have a deficient response of type III interferon after RV infection ex vivo. Toll like Receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) expressed on infectious agents, and induce the development of antiviral and antibacterial immunity. We recently discovered that activation of TLR7/8 resulted in enhanced IFNλ receptor mRNA expression in PBMCs of healthy and asthmatic children, opening new therapeutic frontiers for rhinovirus-induced asthma. This article reviews the recent advances of the literature on the regulated expression of type III Interferons and their receptor in association with rhinovirus infection in asthmatic subjects.