Laboratory of Clinical and Experimental Immunology - Pontifical Catholic University of Rio Grande do Sul, Porto Alegre; National Heart and Lung Institute and, Department of Infectious Disease, Imperial College London, London.
Centre for Molecular Bacteriology and Infection, Department of Infectious Disease, Imperial College London, London.
J Allergy Clin Immunol. 2023 Feb;151(2):447-457.e5. doi: 10.1016/j.jaci.2022.09.026. Epub 2022 Oct 7.
Microbiota are recognized to play a major role in regulation of immunity through release of immunomodulatory metabolites such as short-chain fatty acids (SCFAs). Rhinoviruses (RVs) induce upper respiratory tract illnesses and precipitate exacerbations of asthma and chronic obstructive pulmonary disease through poorly understood mechanisms. Local interactions between SCFAs and antiviral immune responses in the respiratory tract have not been previously investigated.
We sought to investigate whether pulmonary metabolite manipulation through lung-delivered administration of SCFAs can modulate antiviral immunity to RV infection.
We studied the effects of intranasal administration of the SCFAs acetate, butyrate, and propionate on basal expression of antiviral signatures, and of acetate in a mouse model of RV infection and in RV-infected lung epithelial cell lines. We additionally assessed the effects of acetate, butyrate, and propionate on RV infection in differentiated human primary bronchial epithelial cells.
Intranasal acetate administration induced basal upregulation of IFN-β, an effect not observed with other SCFAs. Butyrate induced RIG-I expression. Intranasal acetate treatment of mice increased interferon-stimulated gene and IFN-λ expression during RV infection and reduced lung virus loads at 8 hours postinfection. Acetate ameliorated virus-induced proinflammatory responses with attenuated pulmonary mucin and IL-6 expression observed at day 4 and 6 postinfection. This interferon-enhancing effect of acetate was confirmed in human bronchial and alveolar epithelial cell lines. In differentiated primary bronchial epithelial cells, butyrate treatment better modulated IFN-β and IFN-λ gene expression during RV infection.
SCFAs augment antiviral immunity and reduce virus load and proinflammatory responses during RV infection.
微生物群被认为通过释放免疫调节代谢物（如短链脂肪酸 [SCFAs]）在免疫调节中发挥主要作用。鼻病毒（RV）通过尚未充分了解的机制引起上呼吸道疾病，并使哮喘和慢性阻塞性肺疾病恶化。呼吸道中 SCFAs 与抗病毒免疫反应之间的局部相互作用尚未得到先前的研究。
我们旨在研究通过肺部递送 SCFAs 进行肺部代谢物操作是否可以调节 RV 感染的抗病毒免疫。
我们研究了鼻内给予 SCFAs 乙酸盐、丁酸盐和丙酸盐对基础抗病毒特征表达的影响，以及在 RV 感染的小鼠模型中和在 RV 感染的肺上皮细胞系中乙酸盐的作用。我们还评估了乙酸盐、丁酸盐和丙酸盐对分化的人原代支气管上皮细胞中 RV 感染的影响。
鼻内给予乙酸盐诱导 IFN-β 的基础上调，而其他 SCFAs 则没有观察到这种作用。丁酸盐诱导 RIG-I 表达。鼻内给予乙酸盐处理的小鼠在 RV 感染期间增加了干扰素刺激基因和 IFN-λ 的表达，并在感染后 8 小时降低了肺部病毒载量。乙酸盐减轻了病毒诱导的促炎反应，在感染后第 4 天和第 6 天观察到肺粘蛋白和 IL-6 表达减弱。在人类支气管和肺泡上皮细胞系中证实了乙酸盐的这种增强干扰素作用。在分化的原代支气管上皮细胞中，丁酸盐处理在 RV 感染期间更好地调节 IFN-β 和 IFN-λ 基因表达。
SCFAs 增强了抗病毒免疫，减少了 RV 感染期间的病毒载量和促炎反应。
