Pathologic and immunologic characteristics of coxsackievirus A16 infection in rhesus macaques

Wang, Jingjing; Zhang, Ying; Zhang, Xiaolong; Hu, Yuanliang; Dong, Chuan; Yang, Erxia; Che, Yanchun; Pu, Jing; Xi, Wang; Liu, Longding; Liao, Yun; Feng, Min; Liang, Yan; Zhao, Tiantian; Jiang, Li; He, Zhanlong; Lu, Shuaiyao; Wang, Lichun; Li, Yanyan; Fan, Shengtao; Guo, Lei; Li, Qihan

doi:10.1016/j.virol.2016.10.031

Cited by 25 publications

(23 citation statements)

References 39 publications

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“…For immunohistochemical detection of the VP1 antigen of EV-D68, slides of paraffin-embedded sections were detected by anti-EV-D68 monoclonal antibodies (GeneTex, Inc., Irvine, CA, USA) and horseradish peroxidase (HRP)-conjugated anti-rabbit IgG antibodies (Cell Signaling Techonology, Shanghai, CST-US subsidiary in China). Peroxidase activity was detected with an Enhanced HRP-DAB Chromogenic Substrate Kit (TianGen Biotech, Co., Ltd., Beijing, China) [19,20].…”

Section: Histopathological and Immunohistochemical (Ihc) Stainingmentioning

confidence: 99%

“…The cell nuclei were strained by DAPI (Beyotime Biotech, Co., Ltd., Shanghai, China). The primary antibody was detected using 5 µg/mL of Fluorescein Avidin DCS (Vector Laboratories, Inc., Burlingame, CA, USA) and 2 µg/mL Texas-Red-conjugated goat anti-rabbit IgG antibodies (Molecular Probes, Carlsbad, CA, USA) [20,21]. The stained slides were analyzed under a Leica TCS SP8Laser Confocal microscope (Leica Microsystems, Wetzlar, Germany).…”

Section: Laser Confocal Microscopy Analysis Of the Infected Ferret Lumentioning

confidence: 99%

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Nasal Infection of Enterovirus D68 Leading to Lower Respiratory Tract Pathogenesis in Ferrets (Mustela putorius furo)

Zheng

Sun

Guo

et al. 2017

Viruses

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Data from EV-D68-infected patients demonstrate that pathological changes in the lower respiratory tract are principally characterized by severe respiratory illness in children and acute flaccid myelitis. However, lack of a suitable animal model for EV-D68 infection has limited the study on the pathogenesis of this critical pathogen, and the development of a vaccine. Ferrets have been widely used to evaluate respiratory virus infections. In the current study, we used EV-D68-infected ferrets as a potential animal to identify impersonal indices, involving clinical features and histopathological changes in the upper and lower respiratory tract (URT and LRT). The research results demonstrate that the EV-D68 virus leads to minimal clinical symptoms in ferrets. According to the viral load detection in the feces, nasal, and respiratory tracts, the infection and shedding of EV-D68 in the ferret model was confirmed, and these results were supported by the EV-D68 VP1 immunofluorescence confocal imaging with α2,6-linked sialic acid (SA) in lung tissues. Furthermore, we detected the inflammatory cytokine/chemokine expression level, which implied high expression levels of interleukin (IL)-1a, IL-8, IL-5, IL-12, IL-13, and IL-17a in the lungs. These data indicate that systemic observation of responses following infection with EV-D68 in ferrets could be used as a model for EV-D68 infection and pathogenesis.

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Section: Histopathological and Immunohistochemical (Ihc) Stainingmentioning

confidence: 99%

Section: Laser Confocal Microscopy Analysis Of the Infected Ferret Lumentioning

confidence: 99%

Nasal Infection of Enterovirus D68 Leading to Lower Respiratory Tract Pathogenesis in Ferrets (Mustela putorius furo)

Zheng

Sun

Guo

et al. 2017

Viruses

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“…Thus there is an urgent need for a multivalent vaccine against multiple enteroviruses that would help to control enterovirus-related HFMD epidemics. In our previous study, we found that there were significant anti-CA16 neutralizing antibodies in the healthy junior rhesus macaque immunized with the experimentally inactivated CA16 vaccine, but these neutralizing antibodies failed to protect against CA16 infection[12]. Hence, it is our hope that further investigations of the molecular mechanisms of EV71 and CA16 will provide a new strategy for the development of a broad-spectrum HFMD vaccine.…”

Section: Introductionmentioning

confidence: 99%

Different microRNA profiles reveal the diverse outcomes induced by EV71 and CA16 infection in human umbilical vein endothelial cells using high-throughput sequencing

Zheng

et al. 2017

PLoS ONE

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Enterovirus 71 (EV71) and Coxsackievirus A16 (CA16) remain the predominant pathogens in hand, foot, and mouth disease (HFMD), but the factors underlying the pathogenesis of EV71 and CA16 infections have not been elucidated. Recently, the functions of microRNAs (miRNAs) in pathogen-host interactions have been highlighted. In the present study, we performed comprehensive miRNA profiling in EV71- and CA16-infected human umbilical vein endothelial cells (HUVECs) at multiple time points using high-throughput sequencing. The results showed that 135 known miRNAs exhibited remarkable differences in expression. Of these, 30 differentially expressed miRNAs presented opposite trends in EV71- and CA16-infected samples. Subsequently, we mainly focused on the 30 key differentially expressed miRNAs through further screening to predict targets. Gene ontology (GO) and pathway analysis of the predicted targets showed the enrichment of 14 biological processes, 9 molecular functions, 8 cellular components, and 85 pathways. The regulatory networks of these miRNAs with predicted targets, GOs, pathways, and co-expression genes were determined, suggesting that miRNAs display intricate regulatory mechanisms during the infection phase. Consequently, we specifically analyzed the hierarchical GO categories of the predicted targets involved in biological adhesion. The results indicated that the distinct changes induced by EV71 and CA16 infection may be partly linked to the function of the blood-brain barrier. Taken together, this is the first report describing miRNA expression profiles in HUVECs with EV71 and CA16 infections using high-throughput sequencing. Our data provide useful insights that may help to elucidate the different host-pathogen interactions following EV71 and CA16 infection and offer novel therapeutic targets for these infections.

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“…A total of 20 transgenic mice (weight: 17.00-20.00 g, 4 weeks old) were randomly divided into the control and CA16 groups. Based our earlier work on nasally infected CA16 tree shrew [17] and rhesus macaques model [18], fteen mice were infected with 10 4.5 50% cell culture infectious doses (CCID50) of CA16 via the nostrils dropwise. The CA16 virus strain (sub-genotype B) was isolated from a throat swab from an HFMD patient obtained in Guangxi in 2010 (GenBank: JN590244.1) and grown in Vero cells (ATCC, Manassas, VA, USA), which were maintained in Dulbecco's Modi ed Eagle Medium (DMEM, HyClone, Logan, UT, USA) supplemented with 10% fetal bovine serum (FBS, Gibco, Grand Island, NY, USA).…”

Section: Mouse Study Designmentioning

confidence: 99%

“…Hamsters could develop neurological disease by inoculating of the mouse-adapted strains, but it should be noted that mouse-adapted strains are unable to represent all the typical characters of clinical viruses. As for the respiratory infection animal models, our group has developed large animal models including tree shrew [17] and rhesus macaques [18] to study the pathological mechanisms of neurological lesions, but their use are limited for ethical and economical reasons. Therefore, we would like to further investigate the suitability of small animals to study CA16 infections via respiratory route based on our previous work.…”

Section: Introductionmentioning

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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Pathologic and immunologic characteristics of coxsackievirus A16 infection in rhesus macaques

Cited by 25 publications

References 39 publications

Nasal Infection of Enterovirus D68 Leading to Lower Respiratory Tract Pathogenesis in Ferrets (Mustela putorius furo)

Nasal Infection of Enterovirus D68 Leading to Lower Respiratory Tract Pathogenesis in Ferrets (Mustela putorius furo)

Different microRNA profiles reveal the diverse outcomes induced by EV71 and CA16 infection in human umbilical vein endothelial cells using high-throughput sequencing

A hSCARB2-transgenic mouse model for Coxsackievirus A16 pathogenesis

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