Unique role for chemokine(C-C motif) ligand-3 in neutrophil-mediated fatal immunopathology during enterovirus 71 infection
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- 英文论文题名：Unique role for chemokine(C-C motif) ligand-3 in neutrophil-mediated fatal immunopathology during enterovirus 71 infection
- 论文作者：Zhao Zhongpeng ; Li Min ; Zhang Yi ; Tian Yi ; Yang Xia ; Wang Yuguang ; Li Xiuhui ; Yang Penghui ; Xing Li ; Gao Weiwu ; Tang Jun ; Duan Yueqiang ; Yang Wenxian ; Song Jiansun ; Zhao Keji ; Wu Yuzhang ; Ni Bing ; Wang Xiliang
- 英文论文作者：Zhao Zhongpeng ; Li Min ; Zhang Yi ; Tian Yi ; Yang Xia ; Wang Yuguang ; Li Xiuhui ; Yang Penghui ; Xing Li ; Gao Weiwu ; Tang Jun ; Duan Yueqiang ; Yang Wenxian ; Song Jiansun ; Zhao Keji ; Wu Yuzhang ; Ni Bing ; Wang Xiliang ; State Key Laboratory of Pathogens and Biosecurity ; Beijing Institute of Microbiology and Epidemiology ; College of Animal Science ; Jilin University ; Institute of Immunology ; PLA ; Third Military Medical University ; Department of Pathophysiology and High Altitude Pathology ; Third Military Medical University ; Liver Disease Center for Combined Traditional Chinese and Western Medicine Treatment ; Ditan Hospital ; Traditional Chinese Medicine ; Internal Medicine ; You’an Hospital ; Capital Medical University ; Liver Failure Therapy and Research Center ; Beijing 302 Hospital ; Department of Dermatology ; the 105th Hospital of PLA ; Department of Microbiology and Immunology ; Pennsylvania State University College of Medicine ; Systems Biology Center ; Division of Intramural Research ; National Heart ; Lung and Blood Institute ; National Institutes of Health
- 年：2016
- 作者机构：State Key Laboratory of Pathogens and Biosecurity,Beijing Institute of Microbiology and Epidemiology;College of Animal Science,Jilin University;Institute of Immunology,PLA,Third Military Medical University;Department of Pathophysiology and High Altitude Pathology,Third Military Medical University;Liver Disease Center for Combined Traditional Chinese and Western Medicine Treatment,Ditan Hospital;Traditional Chinese Medicine,Internal Medicine,You’an Hospital,Capital Medical University;Liver Failure Therapy and Research Center,Beijing 302 Hospital;Department of Dermatology,the 105th Hospital of PLA;Department of Microbiology and Immunology,Pennsylvania State University College of Medicine;Systems Biology Center,Division of Intramural Research,National Heart,Lung and Blood Institute,National Institutes of Health;
- 英文论文关键词：Enterovirus 71 ; neutrophils ; CCL-3 ; PI3K ; miRNA
- 会议召开时间：2016-11-04
- 会议录名称：第十一届全国免疫学学术大会摘要汇编
- 英文会议录名称：Abstracts of 2016 CSI Congress on Immunology
- 语种：英文
- 分类号：R373.2
- 学会代码：IGMD
- 会议名称：第十一届全国免疫学学术大会
- 会议地点：中国安徽合肥
- 主办单位：中国免疫学会
- 学会名称：中国免疫学会
- 页数：1
- 文件大小：341k
- 原文格式：D
- 会议级别：全国
摘要
Enterovirus 71 infections are common and frequently asymptomatic or benign but can manifest the critical symptom of severe inflammation of the central nervous system with subsequent pulmonary edema and cardiorespiratory distress. A hallmark of EV71 infection is marked elevation of neutrophil level, yet the exact contribution of neutrophils to severe/fatal immunopathology remains unclear.In this study of human EV71 infection cases and an EV71 infection mouse model, we demonstrate functional contribution of the host innate immune system to the life-threatening state of this infectious disease. Specifically, humans and mice with active EV71 infection showed significantly increased neutrophils in central nervous system(cerebral spinal fluid of humans and brain of mice). Depletion of neutrophils from the EV71-infected mice, both by antibody inhibition and gene knockout, led to a marked enhancement of survival; in contrast, depletion of macrophages had no affect on survival, even though elevated macrophage count in brain accompanied the EV71 infection. Chemokine [C-Cmotif] ligand(CCL)-3 and CCL-2 were up-regulated in both patients and mice with active EV71 infection, but only CCL-3 contributed to the accumulation and activation of neutrophils in the disease focus and to the survival rate of the mice. The mechanism underlying the immunopathogenic role of CCL-3 in mice may be mediated by CCR1/3 in humans and CCR5 in mice, according to the accompanying selective elevations observed. Molecular studies showed that the CCL-3 expression was regulated at the transcriptional level at least partly through the PI3 K and NF-k B pathway. Deep sequencing of neutrophils from both human and mouse CNS tissues identified 5 miRNAs with EV71 infection-related differential expression that target CCL-3 and may regulate it at the post-transcriptional level. The results validated the pivotal roles and underlying mechanisms of CCL-3 in the neutrophil-mediated severe immunopathology of EV71 infection, providing potential diagnostic and therapeutic strategies for EV71 infection by targeting the CCL3 axis.
Enterovirus 71 infections are common and frequently asymptomatic or benign but can manifest the critical symptom of severe inflammation of the central nervous system with subsequent pulmonary edema and cardiorespiratory distress. A hallmark of EV71 infection is marked elevation of neutrophil level, yet the exact contribution of neutrophils to severe/fatal immunopathology remains unclear.In this study of human EV71 infection cases and an EV71 infection mouse model, we demonstrate functional contribution of the host innate immune system to the life-threatening state of this infectious disease. Specifically, humans and mice with active EV71 infection showed significantly increased neutrophils in central nervous system(cerebral spinal fluid of humans and brain of mice). Depletion of neutrophils from the EV71-infected mice, both by antibody inhibition and gene knockout, led to a marked enhancement of survival; in contrast, depletion of macrophages had no affect on survival, even though elevated macrophage count in brain accompanied the EV71 infection. Chemokine [C-Cmotif] ligand(CCL)-3 and CCL-2 were up-regulated in both patients and mice with active EV71 infection, but only CCL-3 contributed to the accumulation and activation of neutrophils in the disease focus and to the survival rate of the mice. The mechanism underlying the immunopathogenic role of CCL-3 in mice may be mediated by CCR1/3 in humans and CCR5 in mice, according to the accompanying selective elevations observed. Molecular studies showed that the CCL-3 expression was regulated at the transcriptional level at least partly through the PI3 K and NF-k B pathway. Deep sequencing of neutrophils from both human and mouse CNS tissues identified 5 miRNAs with EV71 infection-related differential expression that target CCL-3 and may regulate it at the post-transcriptional level. The results validated the pivotal roles and underlying mechanisms of CCL-3 in the neutrophil-mediated severe immunopathology of EV71 infection, providing potential diagnostic and therapeutic strategies for EV71 infection by targeting the CCL3 axis.
Enterovirus 71 infections are common and frequently asymptomatic or benign but can manifest the critical symptom of severe inflammation of the central nervous system with subsequent pulmonary edema and cardiorespiratory distress. A hallmark of EV71 infection is marked elevation of neutrophil level, yet the exact contribution of neutrophils to severe/fatal immunopathology remains unclear.In this study of human EV71 infection cases and an EV71 infection mouse model, we demonstrate functional contribution of the host innate immune system to the life-threatening state of this infectious disease. Specifically, humans and mice with active EV71 infection showed significantly increased neutrophils in central nervous system(cerebral spinal fluid of humans and brain of mice). Depletion of neutrophils from the EV71-infected mice, both by antibody inhibition and gene knockout, led to a marked enhancement of survival; in contrast, depletion of macrophages had no affect on survival, even though elevated macrophage count in brain accompanied the EV71 infection. Chemokine [C-Cmotif] ligand(CCL)-3 and CCL-2 were up-regulated in both patients and mice with active EV71 infection, but only CCL-3 contributed to the accumulation and activation of neutrophils in the disease focus and to the survival rate of the mice. The mechanism underlying the immunopathogenic role of CCL-3 in mice may be mediated by CCR1/3 in humans and CCR5 in mice, according to the accompanying selective elevations observed. Molecular studies showed that the CCL-3 expression was regulated at the transcriptional level at least partly through the PI3 K and NF-k B pathway. Deep sequencing of neutrophils from both human and mouse CNS tissues identified 5 miRNAs with EV71 infection-related differential expression that target CCL-3 and may regulate it at the post-transcriptional level. The results validated the pivotal roles and underlying mechanisms of CCL-3 in the neutrophil-mediated severe immunopathology of EV71 infection, providing potential diagnostic and therapeutic strategies for EV71 infection by targeting the CCL3 axis.
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