Pharyngeal Microflora Disruption by Antibiotics Promotes Airway Hyperresponsiveness after Respiratory Syncytial Virus Infection

Ke Ni,Yu Deng,Enmei Liu,Zhou Fu,Na Zang,Yan Luo,Qiuling Xia,Zhengxiu Luo,Simin Li,Lijia Wang,Xiaohong Xie,Stephania Ann Cormier

doi:10.1371/journal.pone.0041104

Abstract

BackgroundRegulatory T cells (Treg cells), which are essential for regulation of immune response to respiratory syncytial virus (RSV) infection, are promoted by pharyngeal commensal pneumococcus. The effects of pharyngeal microflora disruption by antibiotics on airway responsiveness and relative immune responses after RSV infection have not been clarified.MethodsFemale BALB/c mice (aged 3 weeks) were infected with RSV and then treated with either oral antibiotics or oral double distilled water (ddH2O) from 1 d post infection (pi). Changes in pharyngeal microflora were analyzed after antibiotic treatment for 7 d and 14 d. At 8 d pi and 15 d pi, the inflammatory cells in bronchoalveolar lavage fluid (BALF) were investigated in combination with tests of pulmonary histopathology, airway hyperresponsiveness (AHR), pulmonary and splenic Treg cells responses. Pulmonary Foxp3 mRNA expression, IL-10 and TGF-β1 in BALF and lung homogenate were investigated at 15 d pi. Ovalbumin (OVA) challenge was used to induce AHR after RSV infection.ResultsThe predominant pharyngeal commensal, Streptococcus, was cleared by antibiotic treatment for 7 d. Same change also existed after antibiotic treatment for 14 d. After RSV infection, AHR was promoted by antibiotic treatment at 15 d pi. Synchronous decreases of pulmonary Treg cells, Foxp3 mRNA and TGF-β1 were detected. Similar results were observed under OVA challenge.ConclusionsAfter RSV infection, antibiotic treatment cleared pharyngeal commensal bacteria such as Streptococcus, which consequently, might induce AHR and decrease pulmonary Treg cells.

Highlights

Respiratory syncytial virus (RSV) is one of the most common pathogens responsible for lower respiratory tract infection in infants and young children
Our study shows for the first time that after respiratory syncytial virus (RSV) infection in early life, pharyngeal microflora disruption by antibiotic therapy can promote airway hyperresponsiveness (AHR) and reduce pulmonary Treg cells synchronously
Treatment protocols were conducted as follows: (1) oral cefoperazone treatment ad libitum after RSV infection: contained the RSV+7d-Antibiotics group and the RSV+14d-Antibiotics group; (2) oral cefoperazone treatment ad libitum after mock infection: contained the 7d-Antibiotics group and the 14dAntibiotics group; (3) oral ddH2O treatment ad libitum after RSV infection: contained RSV groups tested at 8 d pi and 15 d pi; (4) oral ddH2O treatment ad libitum after mock infection: contained mock groups tested at 8 d pi and 15 d pi

Summary

Introduction

Respiratory syncytial virus (RSV) is one of the most common pathogens responsible for lower respiratory tract infection in infants and young children. The exact factor that links RSV infection and recurrent wheezing is not clear. Antibiotic use, resulting in alteration of bacterial colonization in airway in neonates, is related to later recurrent wheezing [2,3]. Antibiotic treatment is used frequently in patients with RSV infection [4]. It is speculated that abuse of antibiotic treatment is the link between RSV infection and recurrent wheezing. Regulatory T cells (Treg cells), which are essential for regulation of immune response to respiratory syncytial virus (RSV) infection, are promoted by pharyngeal commensal pneumococcus. The effects of pharyngeal microflora disruption by antibiotics on airway responsiveness and relative immune responses after RSV infection have not been clarified

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Results

Conclusion