title: A new treatment for neurogenic inflammation caused by EV71 with CR2-targeted complement inhibitor.
abstract: BACKGROUND
  Enterovirus 71 (EV71), one of the most important neurotropic EVs, has caused death and long-term neurological sequelae in hundreds of thousands of young children in the Asia-Pacific region in the past decade. The neurological diseases are attributed to infection by EV71 inducing an extensive peripheral and central nervous system (CNS) inflammatory response with abnormal cytokine production and lymphocyte depletion induced by EV71 infection. In the absence of specific antiviral agents or vaccines, an effective immunosuppressive strategy would be valuable to alleviate the severity of the local inflammation induced by EV71 infection.
  
  
  OBJECTIVE
  The complement system plays a pivotal role in the inflammatory response. Inappropriate or excessive activation of the complement system results in a severe inflammatory reaction or numerous pathological injuries. Previous studies have revealed that EV71 infection can induce complement activation and an inflammatory response of the CNS. CR2-targeted complement inhibition has been proved to be a potential therapeutic strategy for many diseases, such as influenza virus-induced lung tissue injury, postischemic cerebral injury and spinal cord injury. In this paper, a mouse model is proposed to test whether a recombinant fusion protein consisting of CR2 and a region of Crry (CR2-Crry) is able to specifically inhibit the local complement activation induced by EV71 infection, and to observe whether this treatment strategy can alleviate or even cure the neurogenic inflammation.
  
  
  METHODS
  CR2-Crry is expressed in CHO cells, and its biological activity is determined by complement inhibition assays. 7-day-old ICR mice are inoculated intracranially with EV71 to duplicate the neurological symptoms. The mice are then divided into two groups, in one of which the mice are treated with CR2-Crry targeted complement inhibitor, and in the other with phosphate-buffered saline. A group of mice deficient in complement C3, the breakdown products of which bind to CR2, are also infected with EV71 virus. The potential bioavailability and efficacy of the targeted complement inhibitor are evaluated by histology, immunofluorescence staining and radiolabeling.
  
  
  CONCLUSIONS
  CR2-Crry-mediated targeting complement inhibition will alleviate the local inflammation and provide an effective treatment for the severe neurological diseases associated with EV71 infection.
authors.affiliation: Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing, China. hongbinsong@263.net
authors.forename: Shaofu
authors.initials: S
authors.lastname: Qiu
authors.forename: Nan
authors.initials: N
authors.lastname: Liu
authors.forename: Leili
authors.initials: L
authors.lastname: Jia
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Wenli
authors.initials: W
authors.lastname: Su
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Lixue
authors.initials: L
authors.lastname: Song
authors.forename: Chaojie
authors.initials: C
authors.lastname: Yang
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Chuanfu
authors.initials: C
authors.lastname: Zhang
authors.forename: Zhongqiang
authors.initials: Z
authors.lastname: Wang
authors.forename: Fei
authors.initials: F
authors.lastname: Qiao
authors.forename: Stephen
authors.initials: S
authors.lastname: Tomlinson
authors.forename: Carl
authors.initials: C
authors.lastname: Atkinson
authors.forename: Yansong
authors.initials: Y
authors.lastname: Sun
authors.forename: Liuyu
authors.initials: L
authors.lastname: Huang
authors.forename: Hongbin
authors.initials: H
authors.lastname: Song
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhenjun
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D001688:Biological Products / Q000008:administration & dosage; D004195:Disease Models, Animal; D029821:Enterovirus A, Human / Q000472:pathogenicity*; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D051379:Mice; D008813:Mice, Inbred ICR; D020078:Neurogenic Inflammation / Q000188:drug therapy*; D011951:Receptors, Complement / Q000008:administration & dosage / Q000235:genetics; D017463:Receptors, Complement 3b; D017464:Receptors, Complement 3d / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D001688:Biological Products; C081470:Cr1l protein, mouse; D007166:Immunosuppressive Agents; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D017464:Receptors, Complement 3d; D011993:Recombinant Fusion Proteins