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Enterovirus 71 targets the cardiopulmonary system in a robust oral infection mouse model.

ABSTRACT: Severe infection with the re-emerging enterovirus 71 (EV71 or EV-A71) can cause cardiopulmonary failure. However, in patients' heart and lung, viral protein has not been detected. In mouse models, heart disease has not been reported. EV71-infected brainstem is generally believed to be responsible for the cardiopulmonary collapse. One major limitation in EV71 research is the lack of an efficient oral infection system using non-mouse-adapted clinical isolates. In a robust oral infection NOD/SCID mouse model, we detected EV71 protein at multiple organs, including heart and lung, in 100% of moribund mice with limb paralysis. Infiltrating leukocytes were always detected in heart and muscle, and VP1-positive M2 macrophages were abundant in the lung. Functional dissection on the pathogenesis mechanism revealed severe apoptosis, inflammatory cytokines, and abnormal electrocardiogram (EKG) in orally infected hearts. Therefore, cardiopulmonary disease could be one plausible cause of death in this mouse model. Inoculation of EV71 through an oral route resulted in viral infection in the intestine, viremia, and EV71 appeared to spread to peripheral tissues via blood circulation. Infectious virus was no longer detected in the blood on day 5 post-infection by the plaque formation assay. We demonstrated that both EV71 clinical isolate and cloned virus can target the cardiopulmonary system via a natural infection-like oral route.

SUBMITTER: Chang CS

PROVIDER: S-EPMC6668393 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Enterovirus 71 targets the cardiopulmonary system in a robust oral infection mouse model.

Chang Chih-Shin CS Liao Chun-Che CC Liou An-Ting AT Chang Ya-Shu YS Chang Ya-Ting YT Tzeng Bing-Hsiean BH Chen Chien-Chang CC Shih Chiaho C

Scientific reports 20190731 1

Severe infection with the re-emerging enterovirus 71 (EV71 or EV-A71) can cause cardiopulmonary failure. However, in patients' heart and lung, viral protein has not been detected. In mouse models, heart disease has not been reported. EV71-infected brainstem is generally believed to be responsible for the cardiopulmonary collapse. One major limitation in EV71 research is the lack of an efficient oral infection system using non-mouse-adapted clinical isolates. In a robust oral infection NOD/SCID m ...[more]

PMID: 31366973

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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.

Dataset Information

Enterovirus 71 targets the cardiopulmonary system in a robust oral infection mouse model.

Publications

Enterovirus 71 targets the cardiopulmonary system in a robust oral infection mouse model.

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