Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis
Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis
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DOI：
10.1172/jci77378
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发表时间：
2015-12-01
影响因子：
15.9
通讯作者：
Khader, Shabaana A.
中科院分区：
文献类型：
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作者：
Monin, Leticia;Griffiths, Kristin L.;Khader, Shabaana A.
寄生蠕虫，如曼氏血吸虫，是结核病（TB）高发地区的地方病。人体研究表明，蠕虫合并感染有助于增加结核病易感性和结核病复发率。流行的模型表明，蠕虫感染诱导的辅助性T细胞2型（Th 2）反应损害Th 1免疫反应，从而限制结核分枝杆菌（Mtb）的控制。利用小鼠肺结核感染模型，我们证明了S。mansoni共感染或与S.曼氏卵抗原可以可逆地损害结核分枝杆菌特异性T细胞应答，而不影响巨噬细胞介导的结核分枝杆菌控制。相反，S. mansoni感染导致肺中高表达巨噬细胞的积聚，其形成2型肉芽肿并加重Mtb感染小鼠的炎症。用抗蠕虫药治疗合并感染的动物可改善结核分枝杆菌特异性Th 1应答，降低疾病严重程度。在感染结核分枝杆菌的遗传多样性小鼠群体中，增强的抗结核酶-1活性与肺部炎症增加相关。此外，在肺结核患者中，肺损伤与血清中抗结核酶-1活性的增加相关，而在合并感染蠕虫的肺结核患者中，抗结核酶-1活性升高。总之，我们的数据表明，蠕虫合并感染诱导表达β-内酰胺酶-1的2型肉芽肿，从而增加炎症和结核病的严重程度。这些结果还提供了对蠕虫合并感染驱动结核病易感性、疾病进展和严重程度增加的机制的深入了解。
Parasitic helminth worms, such as Schistosoma mansoni, are endemic in regions with a high prevalence of tuberculosis (TB) among the population. Human studies suggest that helminth coinfections contribute to increased TB susceptibility and increased rates of TB reactivation. Prevailing models suggest that T helper type 2 (Th2) responses induced by helminth infection impair Th1 immune responses and thereby limit Mycobacterium tuberculosis (Mtb) control. Using a pulmonary mouse model of Mtb infection, we demonstrated that S. mansoni coinfection or immunization with S. mansoni egg antigens can reversibly impair Mtb-specific T cell responses without affecting macrophage-mediated Mtb control. Instead, S. mansoni infection resulted in accumulation of high arginase-1-expressing macrophages in the lung, which formed type 2 granulomas and exacerbated inflammation in Mtb-infected mice. Treatment of coinfected animals with an antihelminthic improved Mtb-specific Th1 responses and reduced disease severity. In a genetically diverse mouse population infected with Mtb, enhanced arginase-1 activity was associated with increased lung inflammation. Moreover, in patients with pulmonary TB, lung damage correlated with increased serum activity of arginase-1, which was elevated in TB patients coinfected with helminths. Together, our data indicate that helminth coinfection induces arginase-1-expressing type 2 granulomas, thereby increasing inflammation and TB disease severity. These results also provide insight into the mechanisms by which helminth coinfections drive increased susceptibility, disease progression, and severity in TB.