Immunocompetent and Immunodeficient Mouse Models for Enterovirus 71 Pathogenesis and Therapy

Shih, Chiaho; Liao, Chun-Che; Chang, Ya‐Shu; Wu, Szu-Yao; Chang, Chih-Hung; Liou, An-Ting

doi:10.3390/v10120674

Cited by 34 publications

(27 citation statements)

References 107 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2F), suggesting that EV71 could spread from intestine to liver and kidney through the blood circulation. (5) It is very common to observe muscle infection with EV71 in mouse models 1 . However, myositis in humans has not been reported.…”

Section: Discussionmentioning

confidence: 99%

“…Epidemics of enterovirus 71 (EV71 or EV-A71) occurred frequently worldwide 1–4 . In a recent outbreak in Shanghai, China, near 1000 deaths of children were reported 5 .…”

Section: Introductionmentioning

confidence: 99%

“…Sudden death and cardiopulmonary collapse are most common in fatal cases of EV71 infection. It is generally believed that mortality is due to neurogenic pulmonary edema and cardiac decompensation from CNS infection, inflammation, and the consequent sympathetic hyperactivity 1–3,13 (Fig. 1A, middle).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Chang¹,

Liao²,

Liou³

et al. 2019

Sci Rep

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Epidemics of enterovirus 71 (EV71 or EV-A71) occurred frequently worldwide 1–4 . In a recent outbreak in Shanghai, China, near 1000 deaths of children were reported 5 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Chang¹,

Liao²,

Liou³

et al. 2019

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

“…We compared the amino acid sequence of the EV71-js1 with the sequences of three reported mouse-virulent EV71 strains 540v/vNM/05, MP4 and Isehara/Japan/ 99 that are capable of infecting neonatal mice or adult hSCARB2-transgenic mice [24]. The 540v/ vNM/05 strain was modified by mutating the Q145 of VP1 to E145 according to a mouse-adapted strain MP-26M [25].…”

Section: Sequence Analysis Of Ev71-js1mentioning

confidence: 99%

An infectious clone of enterovirus 71(EV71) that is capable of infecting neonatal immune competent mice without adaptive mutations

Zhang

Song

Zou

et al. 2020

Emerging Microbes & Infections

View full text Add to dashboard Cite

Enterovirus 71 (EV71) is a major pathogen that causes hand, foot and mouth disease (HFMD), which is a life threatening disease in certain children. The pathogenesis of EV71-caused HFMD is poorly defined due to the lack of simple and robust animal models with severe phenotypes that recapitulate symptoms observed in humans. Here, we generated the infectious clone of a clinical isolate from a severe HFMD patient. Virus rescued from the cDNA clone was infectious in cell lines. When administrated intraperitoneally to neonatal ICR, BALB/c and C57 immune competent mice at a dosage of1.4 × 10 4 pfu per mouse, the virus caused weight loss, paralysis and death in the infected mice after 4-5 days of infection. In the infected mice, detectable viral replication was detected in various tissues such as heart, liver, brain, lung, kidney, small intestine, leg skeletal muscle and medulla oblongata. The histology of the infected mice included massive myolysis, glomerular atrophy, villous blunting in small intestine, widened alveolar septum, diminished alveolar spaces and lymphocytes infiltration into the lung. By using the UV-inactivated virus as a control, we elucidated that the virus first amplified in the leg skeletal muscle tissue and the muscle tissue served as a primary viral replication site. In summary, we generated a stable EV71 infectious clone that is capable of infecting neonatal immune competent mice without adaptive mutations and provide a simple, valuable animal model for the studies of EV71pathogenesis and therapy.

show abstract

Immunocompetent and Immunodeficient Mouse Models for Enterovirus 71 Pathogenesis and Therapy

Cited by 34 publications

References 107 publications

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

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

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

An infectious clone of enterovirus 71(EV71) that is capable of infecting neonatal immune competent mice without adaptive mutations

Contact Info

Product

Resources

About