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

Chang, Chih-Hung; Liao, Chun-Che; Liou, An-Ting; Chang, Ya‐Shu; Chang, Yao-Tang; Tzeng, Bing-Hsiean; Chen, Chien‐Chang; Shih, Chiaho

doi:10.1038/s41598-019-47455-3

Cited by 13 publications

(9 citation statements)

References 60 publications

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“…In contrast, in the previous intraperitoneally or intracerebrally inoculated animal models, no obviously positive CVA16 antigen or pathological change was found in the CNS, which demonstrated that CA16 had no signi cant neurotropism in these models [11,14]. Despite some evidence showing that CA16 infection is associated with damage to muscle tissues, we did not observe the apparent relationship between limb paralysis and the presence of infectious particles in the skeletal muscle from nasally infected mice, which is different from previous studies [38,39] and also suggested that infection sensitivity differs slightly between respiratory inoculation and the intraperitoneal-or intracerebral-inoculation route. Consistent with previous studies in orally infected immunode ciency AG129 mice [40], the small quantity of infectious viral RNA in the limbs suggests that limb paralysis might be a consequence of virus neuro-invasion rather than direct damage to limb muscle.…”

Section: Discussioncontrasting

confidence: 99%

A hSCARB2-transgenic mouse model for Coxsackievirus A16 pathogenesis

Chen

Yang

et al. 2020

Preprint

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Background: Coxsackievirus A16 (CA16) is one of the neurotropic pathogen that has been associated with severe neurological forms of hand, foot, and mouth disease (HFMD), but its pathogenesis is not yet clear. The limited species tropism of CA16 make the establishment of a suitable animal model that can recapitulate the neurological pathology observed in human HFMD more difficult. Because the human scavenger receptor class B, member 2 (hSCARB2) is a cellular receptor for CA16, we used transgenic mice bearing human SCARB2 and nasally infected them with CA16 to study the pathogenicity of the virus.Methods: Coxsackievirus A16 was administered by intranasal instillation to groups of hSCARB2 transgenic mice and clinical signs were observed. Sampled at different time-points to document and characterize the mode of viral dissemination, pathological change and immune response of CA16 infection. Results: Weight loss and virus replication in lung and brain were observed in hSCARB2 mice infected with CA16, indicating that these animals could model the neural infection process. Viral antigens were observed in the alveolar epithelia and brainstem cells. The typical histopathology was interstitial pneumonia with infiltration of significant lymphocytes into the alveolar interstitial in lung and diffuse punctate hemorrhages in the capillaries of the brainstem. In addition, we detected the expression levels of inflammatory cytokines and detected high levels of interleukin IL-1β, IL-6, IL-18, and IFN-γ in nasal mucosa, lungs and brain tissues. Conclusions: The hSCARB2-transgenic mice can be productively infected with CA16 via respiratory route and exhibited a clear tropism to lung and brain tissues, which can serve as a model to investigate the pathogenesis of CA16 associated respiratory and neurological disease.

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Section: Discussioncontrasting

confidence: 99%

A hSCARB2-transgenic mouse model for Coxsackievirus A16 pathogenesis

Chen

Yang

et al. 2020

Preprint

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“…Interestingly, VP1-280T is located near the binding site with the VP2-EF loop and human SCARB2 receptor for viral entry ( Zhou et al, 2019 ). Overall, our current results warrants further studies on the functional significance of these disease-associated mutations in animal models ( Liao et al, 2014 ; Shih et al, 2018 ; Chang et al, 2019 ; Liou et al, 2019 ), once infectious cDNA clones can be successfully isolated from these patients in the future. Furthermore, our findings here could facilitate earlier detection based on the risk score in predicting severe cases infected with EV-A71 in clinical medicine.…”

Section: Introductionmentioning

confidence: 64%

“…Viral strains of EV-A71 were isolated from throat swabs of patients by the Section of Clinical Virology and Molecular Diagnosis, Department of Laboratory Medicine, Changhua Christian Hospital, Taiwan. Virus preparation was as described previously ( Liao et al, 2014 ; Liou et al, 2016 , 2019 ; Chang et al, 2019 ).…”

Section: Methodsmentioning

confidence: 99%

“…In severe cases, it can lead to encephalitis, acute flaccid paralysis, tachycardia, cardiopulmonary failure, and death. Studies in various animal models demonstrated that EV-A71 can target multiple tissues, including the central nerve system ( Cox et al, 2017 ; Shih et al, 2018 ), and recently, the cardiopulmonary system ( Chang et al, 2019 ). Current treatment for EV-A71 remains supportive, and no antivirals are commercially available.…”

Section: Introductionmentioning

confidence: 99%

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Novel Naturally Occurring Mutations of Enterovirus 71 Associated With Disease Severity

et al. 2021

Self Cite

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Infection with the re-emerging enterovirus 71 (EV-A71) is associated with a wide range of disease severity, including herpangina, encephalitis, and cardiopulmonary failure. At present, there is no FDA-approved therapeutics for EV-A71. Early diagnosis for the high-risk children is the key to successful patient care. We examined viral genome sequences at the 5′ untranslated region (UTR) and the capsid protein VP1 from 36 mild and 27 severe cases. We identified five EV-A71 mutations associated with severe diseases, including (1) the 5′ UTR mutations C580U, A707G, C709U; (2) a VP1 alanine-to-threonine mutation at position 280 (280T), and (3) a VP1 glutamic acid-to-(non-glutamic acid) at position 145 [145(non-E)]. SCARB2 is a known entry receptor for EV-A71. Based on a recent cryoEM structure of the EV-A71-SCARB2 binding complex, VP1-280T is near the binding interface between the VP1-VP2 complex and its entry receptor SCARB2. A de novo created hydrogen bonding between the mutant VP1-280T and the VP2-139T, could help strengthen a web-like interaction structure of the VP1-VP2 complex. A stabilized loop turn of VP2, once in contact with SCARB2, can enhance interaction with the host SCARB2 receptor for viral entry. Our findings here could facilitate early detection of severe cases infected with EV-A71 in clinical medicine. In addition, it opens up the opportunity of functional studies via infectious cDNA cloning, site-directed mutagenesis, and animal models in the future.

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“…Our findings suggested EV71 infection could skew host TCRβ repertoire and also expand VP1-specific TCRβ CDR3 clones. Although these results may not adapt to other EV71 infection mouse models directly [61][62][63] and could not completely reflect natural situations in human beings due to the limited experimental mouse model and bioinformatic prediction, these findings could partly broaden our knowledge in EV71 pathogenesis and provide an insight in the anti-viral therapy development potentially via manipulating expanded TCRβ CDR3 clones in virus infection.…”

Section: Discussionmentioning

confidence: 87%

Enterovirus 71 Infection Shapes Host T Cell Receptor Repertoire and Presumably Expands VP1-Specific TCRβ CDR3 Cluster

Liao

Chen

et al. 2020

Pathogens

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Enterovirus 71 (EV71) has become an important public health problem in the Asia-Pacific region in the past decades. EV71 infection might cause neurological and psychiatric complications and even death. Although an EV71 vaccine has been currently approved, there is no effective therapy for treating EV71-infected patients. Virus infections have been reported to shape host T cell receptor (TCR) repertoire. Therefore, understanding of host TCR repertoire in EV71 infection could better the knowledge in viral pathogenesis and further benefit the anti-viral therapy development. In this study, we used a mouse-adapted EV71 (mEV71) model to observe changes of host TCR repertoire in an EV71-infected central nervous system. Neonate mice were infected with mEV71 and mouse brainstem TCRβ repertoires were explored. Here, we reported that mEV71 infection impacted host brainstem TCRβ repertoire, where mEV71 infection skewed TCRβ diversity, changed VJ combination usages, and further expanded specific TCRβ CDR3 clones. Using bioinformatics analysis and ligand-binding prediction, we speculated the expanded TCRβ CDR3 clone harboring CASSLGANSDYTF sequence was capable of binding cleaved EV71 VP1 peptides in concert with major histocompatibility complex (MHC) molecules. We observed that mEV71 infection shaped host TCRβ repertoire and presumably expanded VP1-specific TCRβ CDR3 in mEV71-infected mouse brainstem that integrated EV71 pathogenesis in central nervous system.

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

Cited by 13 publications

References 60 publications

A hSCARB2-transgenic mouse model for Coxsackievirus A16 pathogenesis

A hSCARB2-transgenic mouse model for Coxsackievirus A16 pathogenesis

Novel Naturally Occurring Mutations of Enterovirus 71 Associated With Disease Severity

Enterovirus 71 Infection Shapes Host T Cell Receptor Repertoire and Presumably Expands VP1-Specific TCRβ CDR3 Cluster

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