Jang Jessica C, Chen Gang, Wang Spencer H, Barnes Mark A, Chung Josiah I, Camberis Mali, Le Gros Graham, Cooper Philip J, Steel Cathy, Nutman Thomas B, Lazar Mitchell A, Nair Meera G
Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California, United States of America.
Malaghan Institute of Medical Research, Wellington, New Zealand.
PLoS Pathog. 2015 Jan 8;11(1):e1004579. doi: 10.1371/journal.ppat.1004579. eCollection 2015 Jan.
Parasitic helminth infections can be associated with lifelong morbidity such as immune-mediated organ failure. A better understanding of the host immune response to helminths could provide new avenues to promote parasite clearance and/or alleviate infection-associated morbidity. Murine resistin-like molecules (RELM) exhibit pleiotropic functions following helminth infection including modulating the host immune response; however, the relevance of human RELM proteins in helminth infection is unknown. To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene (hRetnTg+). Following infection with the helminth Nippostrongylus brasiliensis (Nb), hResistin expression was significantly upregulated in infected tissue. Compared to control hRetnTg- mice, hRetnTg+ mice suffered from exacerbated Nb-induced inflammation characterized by weight loss and increased infiltration of inflammatory monocytes in the lung, along with elevated Nb egg burdens and delayed parasite expulsion. Genome-wide transcriptional profiling of the infected tissue revealed that hResistin promoted expression of proinflammatory cytokines and genes downstream of toll-like receptor signaling. Moreover, hResistin preferentially bound lung monocytes, and exogenous treatment of mice with recombinant hResistin promoted monocyte recruitment and proinflammatory cytokine expression. In human studies, increased serum resistin was associated with higher parasite load in individuals infected with soil-transmitted helminths or filarial nematode Wuchereria bancrofti, and was positively correlated with proinflammatory cytokines. Together, these studies identify human resistin as a detrimental factor induced by multiple helminth infections, where it promotes proinflammatory cytokines and impedes parasite clearance. Targeting the resistin/proinflammatory cytokine immune axis may provide new diagnostic or treatment strategies for helminth infection and associated immune-mediated pathology.
寄生性蠕虫感染可能与诸如免疫介导的器官衰竭等终身性发病相关。更好地了解宿主对蠕虫的免疫反应可为促进寄生虫清除和/或减轻感染相关发病提供新途径。小鼠抵抗素样分子（RELM）在蠕虫感染后表现出多效性功能，包括调节宿主免疫反应；然而，人类RELM蛋白在蠕虫感染中的相关性尚不清楚。为了研究人类抵抗素（hResistin）的功能，我们利用了表达人类抵抗素基因的转基因小鼠（hRetnTg+）。在用巴西日圆线虫（Nb）感染后，hResistin在感染组织中的表达显著上调。与对照hRetnTg-小鼠相比，hRetnTg+小鼠遭受Nb诱导的炎症加剧，其特征为体重减轻、肺部炎性单核细胞浸润增加，同时Nb虫卵负荷升高且寄生虫排出延迟。感染组织的全基因组转录谱分析显示，hResistin促进促炎细胞因子和Toll样受体信号下游基因的表达。此外，hResistin优先结合肺单核细胞，用重组hResistin对小鼠进行外源处理可促进单核细胞募集和促炎细胞因子表达。在人体研究中，感染土源性蠕虫或丝虫班氏吴策线虫的个体血清抵抗素升高与寄生虫负荷较高相关，且与促炎细胞因子呈正相关。总之，这些研究确定人类抵抗素是多种蠕虫感染诱导的有害因子，它促进促炎细胞因子并阻碍寄生虫清除。靶向抵抗素/促炎细胞因子免疫轴可能为蠕虫感染和相关免疫介导的病理提供新的诊断或治疗策略。
