Sustained High Levels of Interleukin-6 Contribute to the Pathogenesis of Enterovirus 71 in a Neonate Mouse Model

Abstract

Enterovirus 71 (EV71) is the major causative agent of hand, foot, and mouth disease (HFMD) in young children and has been consistently associated with the most severe complications of the disease, including central nervous system inflammation and pulmonary edema. Increasing frequency and amplitude of EV71 outbreaks have raised awareness and concerns worldwide. Previous reports proposed that overwhelming virus replication combined with the induction of massive proinflammatory cytokines is responsible for the pathogenicity of EV71. Specifically, elevated interleukin-6 (IL-6) levels were observed consistently in patients and strongly correlated with disease severity. In this study, we show in the neonate mouse model that sustained high levels of IL-6 produced upon EV71 infection lead to severe tissue damage and eventually death of the animals. Administration of anti-IL-6 neutralizing antibodies after the onset of the clinical symptoms successfully improved the survival rates and clinical scores of the infected hosts. Compared to untreated infected controls, anti-IL-6-treated mice displayed reduced tissue damage, absence of splenic atrophy, and increased immune cell activation. In addition, markedly elevated systemic levels of IL-10 were measured in the protected animals. Furthermore, there was no significant difference in virus titers between anti-IL-6-treated mice and untreated mice, indicating that the anti-IL-6 antibody-mediated protection is independent of the virus load. Our findings thus demonstrate that IL-6 plays a major role in EV71-induced immunopathogenesis. As there is still neither vaccine nor treatment available against EV71, anti-IL-6 antibody treatment represents a potential therapeutic approach to providing protection from the most severe complications of the disease.

IL-36–Induced Toxicity in Neonatal Mice Involves TNF-α Production by Liver Myeloid Cells

“…At the NN stage, in transition between fetal and AD life, the liver is still highly enriched with fetal hematopoietic cells, including precursor myeloid cells, capable of producing inflammatory mediators in response to circulating danger signals. The similar observation of lethal responses to LPS in 1-wk-old, but not in 2-wk-old, mice (34) suggests that the critical role of liver immune cells identified in our study may explain the reported exaggerated inflammatory responses to TLR agonists or pathogens (35,36). Furthermore, although the role of regulatory lymphocytes was not investigated in our study, their potential protective effect against toxicity in AD cannot be excluded.…”

“…Previous reports have shown that NN mice can manifest excessive and deleterious inflammatory responses (33)(34)(35)(36). Enterovirus 71 infection of NN mice results in excessive, IL-6-mediated responses leading to massive tissue damage and eventually death (35). NN mice also raised higher, uncontrolled, and toxic TNF-a-mediated responses to murine hepatitis virus-A59 or to the injection of soluble LPS or polyinosinic-polycytidylic acid (36).…”

“…Yet, this immunoregulation may be overwhelmed, as shown in this article in the response to TT/Alum/IL-36b. Previous reports have shown that NN mice can manifest excessive and deleterious inflammatory responses (33)(34)(35)(36). Enterovirus 71 infection of NN mice results in excessive, IL-6-mediated responses leading to massive tissue damage and eventually death (35).…”

Early expression of local cytokines during systemic Candida albicans infection in a murine intravenous challenge model

“…Van Snick 1990 demonstrated that limited IL-6 production was found in conventional mice with healing infection of the yeast and indicates that IL-6 production must be strictly regulated to avoid immunopathological consequences from its deregulation (37). In the neonatal mouse model infected with enterovirus 71, sustained high levels of IL-6 production lead to severe tissue damage and eventually death of the animals (38). In another study by Tanaka et al (39), overexpression of IL-6 promotes myocardial injury by interrupting the cytokine network and viral clearance and indicated that IL-6 is one factor that accelerates tissue damage in the viral myocarditis.…”

Association of IP-10 gene polymorphism with susceptibility to Enterovirus 71 infection

“…Although understanding of EV71 infection has recently improved, EV71 pathogenesis has yet to be fully elucidated (1). The outcome of a virus infection is the result of a complex interaction of the virus, environmental factors and host genetics.…”