Unique role for chemokine(C-C motif) ligand-3 in neutrophil-mediated fatal immunopathology during enterovirus 71 infection
作者单位：State Key Laboratory of Pathogens and BiosecurityBeijing Institute of Microbiology and Epidemiology College of Animal ScienceJilin University Institute of ImmunologyPLAThird Military Medical University Department of Pathophysiology and High Altitude PathologyThird Military Medical University Liver Disease Center for Combined Traditional Chinese and Western Medicine TreatmentDitan Hospital Traditional Chinese MedicineInternal MedicineYou’an HospitalCapital Medical University Liver Failure Therapy and Research CenterBeijing 302 Hospital Department of Dermatologythe 105th Hospital of PLA Department of Microbiology and ImmunologyPennsylvania State University College of Medicine Systems Biology CenterDivision of Intramural ResearchNational HeartLung and Blood InstituteNational Institutes of Health
会议名称：《第十一届全国免疫学学术大会》
会议日期：2016年
学科分类：1007[医学-药学(可授医学、理学学位)] 100705[医学-微生物与生化药学] 1001[医学-基础医学(可授医学、理学学位)] 100103[医学-病原生物学] 10[医学]
关 键 词：Enterovirus 71 neutrophils CCL-3 PI3K miRNA
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 *** 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 infecti