肥大细胞促进结核病的病理变化和易感性

Ananya Gupta, Vibha Taneja, Javier Rangel-Moreno, Abhimanyu Abhimanyu, Mushtaq Ahmed, Nilofer Naqvi, Kuldeep Singh Chauhan, Daniela Trejo-Ponce de Leon, Gustavo Ramírez-Martínez, Luis Jiménez-Alvarez, Cesar Luna-Rivero, Joaquin Zuniga, Deepak Kaushal, Shabaana Khader
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摘要

结核病(TB)是由结核分枝杆菌(Mtb)引起的,全球约有四分之一的人口感染了这种疾病。虽然大多数感染者没有症状,但潜伏肺结核感染(LTBI)可发展为肺结核(PTB)。我们最近报告称,与猕猴中的LTBI相比,患有肺结核的猕猴肺中肥大细胞(MCs)的积累增加了。肥大细胞在体外通过脱颗粒和诱导促炎细胞因子对Mtb暴露做出反应。在本研究中,我们发现在人类和猕猴的肉芽肿中,MCs主要产生糜蛋白酶。通过 scRNA 序列分析,我们发现在 LTBI 和猕猴健康肺部中发现的 MCs 富含参与肿瘤坏死因子α、胆固醇和转化生长因子 beta 信号转导的基因。与此相反,在 PTB 中发现的 MCs 簇表达了与干扰素γ、氧化磷酸化和 MYC 信号转导相关的转录特征。此外,在小鼠模型中缺乏 MC 会改善对 Mtb 感染的控制,同时减少肺髓细胞的积累,并减轻慢性阶段的炎症。因此,这些研究结果为MCs在Mtb感染过程中的病理作用提供了新的证据,并可能成为宿主指导结核病治疗的新靶点。
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Mast cells promote pathology and susceptibility in tuberculosis
Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis (Mtb), infects approximately one-fourth of the world’s population. While most infected individuals are asymptomatic, latent TB infection (LTBI) can progress to cause pulmonary TB (PTB). We recently reported an increased accumulation of mast cells (MCs) in lungs of macaques with PTB, compared with LTBI in macaques. MCs respond in vitro to Mtb exposure via degranulation and by inducing proinflammatory cytokines. In the current study, we show the dominant production of chymase by MCs in granulomas of humans and macaques with PTB. Using scRNA seq analysis, we show that MCs found in LTBI and healthy lungs in macaques are enriched in genes involved in tumor necrosis factor alpha, cholesterol and transforming growth factor beta signaling. In contrast, MCs clusters found in PTB express transcriptional signatures associated with interferon gamma, oxidative phosphorylation, and MYC signaling. Additionally, MC deficiency in the mouse model showed improved control of Mtb infection that coincided with reduced accumulation of lung myeloid cells and diminished inflammation at chronic stages. Thus, these collective results provide novel evidence for the pathological contribution of MCs during Mtb infection and may represent a novel target for host directive therapy for TB.
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