Alveolar Macrophages Are Key Players in the Modulation of the Respiratory Antiviral Immunity Induced by Orally Administered Lacticaseibacillus rhamnosus CRL1505.

Valeria Garcia-Castillo,Fernanda Raya Tonetti,Julio Villena,Md Aminul Islam,Hideki Takahashi,Mikado Tomokiyo,Haruki Kitazawa

doi:10.3389/fimmu.2020.568636

Abstract

The oral administration of Lacticaseibacillus rhamnosus CRL1505 differentially modulates the respiratory innate antiviral immune response triggered by Toll-like receptor 3 (TLR3) activation in infant mice, improving the resistance to Respiratory Syncytial Virus (RSV) infection. In this work, by using macrophages depletion experiments and a detailed study of their production of cytokines and antiviral factors we clearly demonstrated the key role of this immune cell population in the improvement of both viral elimination and the protection against lung tissue damage induced by the CRL1505 strain. Orally administered L. rhamnosus CRL1505 activated alveolar macrophages and enhanced their ability to produce type I interferons (IFNs) and IFN-γ in response to RSV infection. Moreover, an increased expression of IFNAR1, Mx2, OAS1, OAS2, RNAseL, and IFITM3 was observed in alveolar macrophages after the oral treatment with L. rhamnosus CRL1505, which was consistent with the enhanced RSV clearance. The depletion of alveolar macrophages by the time of L. rhamnosus CRL1505 administration abolished the ability of infant mice to produce increased levels of IL-10 in response to RSV infection. However, no improvement in IL-10 production was observed when primary cultures of alveolar macrophages obtained from CRL1505-treated mice were analyzed. Of note, alveolar macrophages from the CRL1505 group had an increased production of IL-6 and IL-27 suggesting that these cells may play an important role in limiting inflammation and protecting lung function during RSV infection, by increasing the maturation and activation of Treg cells and their subsequent production of IL-10. In addition, we provided evidence of the important role of CD4+ cells and IFN-γ in the activation of alveolar macrophages highlighting a putative pathway through which the intestinal and respiratory mucosa are communicated under the influence of L. rhamnosus CRL1505.

Highlights

The effect of the intestinal microbiota on the immune responses in the respiratory tract and its impact on the outcome of viral infections has been explored during the last decade [1,2,3]
We found that L. rhamnosus CRL1505 differentially regulated the respiratory innate antiviral immune response triggered by the activation of Toll-like receptor 3 (TLR3), improving the resistance to Respiratory Syncytial Virus (RSV) infection
These results indicated that containing liposomes (CLP) treatment is useful for evaluating the role of alveolar macrophages in the immunomodulatory effect of the CRL1505 strain in our experimental models, since these immune cells are decreased at the time of lactobacilli administration, while their number return to normality when the poly(I:C) or RSV challenges occur

Summary

Introduction

The effect of the intestinal microbiota on the immune responses in the respiratory tract and its impact on the outcome of viral infections has been explored during the last decade [1,2,3] Those studies demonstrated that the signals provided by the intestinal microbiota act at multiple levels in the respiratory mucosa stimulating an antiviral state in non-immune cells and innate immune cells that would allow an efficient control of viral replication early during the infection. The immunological changes induced in the respiratory tract by the dietary treatment significantly increased the resistance of mice to the challenge with Respiratory Syncytial Virus (RSV)

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