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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.

SUBMITTER: Khong WX

PROVIDER: S-EPMC3067852 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Sustained high levels of interleukin-6 contribute to the pathogenesis of enterovirus 71 in a neonate mouse model.

Khong Wei Xin WX Foo Damian G W DG Trasti Scott L SL Tan Eng Lee EL Alonso Sylvie S

Journal of virology 20110112 7

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 respons ...[more]

PMID: 21228224

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Project description:Enterovirus 71 (EV71) can cause a severe hand-foot-mouth disease in children. However, the precise mechanism of EV71-associated disease, particularly the neuropathogenesis and pulmonary disorder, is still not fully understood because no suitable animal models are available. The human scavenger receptor class B, member 2 (hSCARB2), is a cellular receptor for EV71. Here, we generated a novel knock-in (KI) mouse model using the CRISPR/Cas9 system to insert the hSCARB2 gene into the mouse Rosa26 locus to study the pathogenesis of EV71. The hSCARB2 KI mice infected with clinical isolates of EV71 showed neurological symptoms, such as ataxia, paralysis, and death. Viral replication was detected in mainly astrocytes and a limited number of neurons and microglia, accompanied by gliosis. Vascular leakage and alveoli filled with erythrocytes were detected, suggesting that edema and hemorrhage, which are observed in human patients, also occurred in EV71-infected KI mice. In addition, proinflammatory cytokines and chemokines were significantly increased in the serum of infected KI mice. These pathological features of the KI mice after infection resembled those of EV71 encephalomyelitis in humans. Therefore, our KI mouse model is suitable to study the pathogenesis of EV71 and is of great significance for development of antiviral drugs and vaccines to treat or prevent EV71 infection.IMPORTANCE Enterovirus 71 (EV71) is associated with severe hand-foot-mouth disease. Recently, outbreaks of EV71 infection with high mortality have been reported in the Asia-Pacific region, posing a great challenge for global public health. To date, the precise mechanism of EV71-induced disease, particularly the neuropathogenesis and respiratory disorders, is still not fully understood because no suitable animal models are available. Human scavenger receptor class B, member 2 (hSCARB2), has been identified as a cellular receptor for EV71. Here, we introduce a novel CRISPR/Cas9-mediated hSCARB2 knock-in (KI) mouse model for the study of EV71 pathogenesis, which is of great significance for the development of antiviral drugs and vaccines.

Project description:BackgroundWe previously reported that Enterovirus 71 (EV71) infection activates autophagy, which promotes viral replication both in vitro and in vivo. In the present study we further investigated whether EV71 infection of neuronal SK-N-SH cells induces an autophagic flux. Furthermore, the effects of autophagy on EV71-related pathogenesis and viral load were evaluated after intracranial inoculation of mouse-adapted EV71 (MP4 strain) into 6-day-old ICR suckling mice.ResultsWe demonstrated that in EV71-infected SK-N-SH cells, EV71 structural protein VP1 and nonstructural protein 2C co-localized with LC3 and mannose-6-phosphate receptor (MPR, endosome marker) proteins by immunofluorescence staining, indicating amphisome formation. Together with amphisome formation, EV71 induced an autophagic flux, which could be blocked by NH₄Cl (inhibitor of acidification) and vinblastine (inhibitor of fusion), as demonstrated by Western blotting. Suckling mice intracranially inoculated with EV71 showed EV71 VP1 protein expression (representing EV71 infection) in the cerebellum, medulla, and pons by immunohistochemical staining. Accompanied with these infected brain tissues, increased expression of LC3-II protein as well as formation of LC3 aggregates, autophagosomes and amphisomes were detected. Amphisome formation, which was confirmed by colocalization of EV71-VP1 protein or LC3 puncta and the endosome marker protein MPR. Thus, EV71-infected suckling mice (similar to EV71-infected SK-N-SH cells) also show an autophagic flux. The physiopathological parameters of EV71-MP4 infected mice, including body weight loss, disease symptoms, and mortality were increased compared to those of the uninfected mice. We further blocked EV71-induced autophagy with the inhibitor 3-methyladenine (3-MA), which attenuated the disease symptoms and decreased the viral load in the brain tissues of the infected mice.ConclusionsIn this study, we reveal that EV71 infection of suckling mice induces an amphisome formation accompanied with the autophagic flux in the brain tissues. Autophagy induced by EV71 promotes viral replication and EV71-related pathogenesis.

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Sustained high levels of interleukin-6 contribute to the pathogenesis of enterovirus 71 in a neonate mouse model.

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Sustained high levels of interleukin-6 contribute to the pathogenesis of enterovirus 71 in a neonate mouse model.

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