Allergen-Specific Treg Cells Upregulated by Lung-Stage S. japonicum Infection Alleviates Allergic Airway Inflammation.

Zhidan Li,Zhaojun Wang,Wei Zhang,Yanmin Wan,Feng Qian,Bin Xu,Qunfeng Wu,Chengsong Sun,Yuxiang Xie,Wei Hu,Jian Li,Wenbin Yang,Fang Luo,Bingkuan Zhu,Jiaxu Chen,Xiaoling Wang

doi:10.3389/fcell.2021.678377

Abstract

Schistosoma japonicum infection showed protective effects against allergic airway inflammation (AAI). However, controversial findings exist especially regarding the timing of the helminth infection and the underlying mechanisms. Most previous studies focused on understanding the preventive effect of S. japonicum infection on asthma (infection before allergen sensitization), whereas the protective effects of S. japonicum infection (allergen sensitization before infection) on asthma were rarely investigated. In this study, we investigated the protective effects of S. japonicum infection on AAI using a mouse model of OVA-induced asthma. To explore how the timing of S. japonicum infection influences its protective effect, the mice were percutaneously infected with cercaria of S. japonicum at either 1 day (infection at lung-stage during AAI) or 14 days before ovalbumin (OVA) challenge (infection at post–lung-stage during AAI). We found that lung-stage S. japonicum infection significantly ameliorated OVA-induced AAI, whereas post–lung-stage infection did not. Mechanistically, lung-stage S. japonicum infection significantly upregulated the frequency of regulatory T cells (Treg cells), especially OVA-specific Treg cells, in lung tissue, which negatively correlated with the level of OVA-specific immunoglobulin E (IgE). Depletion of Treg cells in vivo partially counteracted the protective effect of lung-stage S. japonicum infection on asthma. Furthermore, transcriptomic analysis of lung tissue showed that lung-stage S. japonicum infection during AAI shaped the microenvironment to favor Treg induction. In conclusion, our data showed that lung-stage S. japonicum infection could relieve OVA-induced asthma in a mouse model. The protective effect was mediated by the upregulated OVA-specific Treg cells, which suppressed IgE production. Our results may facilitate the discovery of a novel therapy for AAI.

Highlights

The prevalence of asthma has increased dramatically in the past three decades (Eder et al, 2006; Ali, 2011) and represents a great health burden, especially in developed countries (Barnes, 2004; Thomsen, 2015)
A mouse model of OVA-induced airway inflammation (AAI) was adopted to test the protective effect of S. japonicum infection on allergic asthma
We found that the ratio of OVA-specific interleukin 4 (IL-4)+ versus interferon γ (IFN-γ)+ CD4+ T cells significantly decreased after lung-stage S. japonicum infection (Supplementary Figure 2), suggesting that specific CD4+ T cell responses shifted from TH2 toward TH1 responses

Summary

Introduction

The prevalence of asthma has increased dramatically in the past three decades (Eder et al, 2006; Ali, 2011) and represents a great health burden, especially in developed countries (Barnes, 2004; Thomsen, 2015). A putative explanation to this phenomenon is that the overall reduction in common TH1-inducing (bacterial, viral, and parasitical) infections results in a decreased ability to counterbalance TH2polarized allergic diseases (Umetsu, 2012; Yang et al, 2016; Stiemsma and Turvey, 2017). Following this lead, a variety of experimental studies have shown that helminth infections can downregulate host immunity and immunopathology in allergy and other immune disorders (Sitcharungsi and Sirivichayakul, 2013; Maizels, 2016; Maizels and McSorley, 2016). These explorations hold great promise in identifying a new and more specific intervention measure for atopic asthma that does not result in certain side effects, such as increased susceptibility to infection and necrosis, which can be triggered by steroid hormone drugs such as dexamethasone (Kuprys-Lipinska and Kuna, 2014; Al-Ahmad et al, 2018; Falk, 2018)

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