Acute Chemokine Response in the Blood and Cerebrospinal Fluid of Children with Enterovirus 71–Associated Brainstem Encephalitis

Wang, Shih Min; Lei, Huan Yao; Yu, Chun Keung; Wang, Jen Ren; Su, Ih Jen; Liu, Ching Chuan

doi:10.1086/591462

Cited by 113 publications

(100 citation statements)

References 27 publications

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“…Elevated levels of several cytokines and chemokines have been reported for children with brainstem encephalitis and pulmonary edema (14,33,34). Likewise, the levels of proinflammatory cytokines implicated in EV71 infection, namely, IL-1␤, IL-10, MIP-2, TNF-␣, and IFN-␥, were found to be significantly elevated in infected AG129 mice.…”

Section: Discussionmentioning

confidence: 87%

See 1 more Smart Citation

A Non-Mouse-Adapted Enterovirus 71 (EV71) Strain Exhibits Neurotropism, Causing Neurological Manifestations in a Novel Mouse Model of EV71 Infection

Khong

Yan

Yeo

et al. 2012

J Virol

140

174

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Enterovirus 71 (EV71) is a neurotropic pathogen that has been consistently associated with the severe neurological forms of hand, foot, and mouth disease. The lack of a relevant animal model has hampered our understanding of EV71 pathogenesis, in particular the route and mode of viral dissemination. It has also hindered the development of effective prophylactic and therapeutic approaches, making EV71 one of the most pressing public health concerns in Southeast Asia. Here we report a novel mouse model of EV71 infection. We demonstrate that 2-week-old and younger immunodeficient AG129 mice, which lack type I and II interferon receptors, are susceptible to infection with a non-mouse-adapted EV71 strain via both the intraperitoneal (i.p.) and oral routes of inoculation. The infected mice displayed progressive limb paralysis prior to death. The dissemination of the virus was dependent on the route of inoculation but eventually resulted in virus accumulation in the central nervous systems of both animal groups, indicating a clear neurotropism of the virus. Histopathological examination revealed massive damage in the limb muscles, brainstem, and anterior horn areas. However, the minute amount of infectious viral particles in the limbs from orally infected animals argues against a direct viral cytopathic effect in this tissue and suggests that limb paralysis is a consequence of EV71 neuroinvasion. Together, our observations support that young AG129 mice display polio-like neuropathogenesis upon infection with a non-mouse-adapted EV71 strain, making this mouse model relevant for EV71 pathogenesis studies and an attractive platform for EV71 vaccine and drug testing.

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Section: Discussionmentioning

confidence: 87%

“…Several studies of humans and mice have suggested the possibility of EV71-induced immunopathogenesis (8,34). Elevated levels of several cytokines and chemokines have been reported for children with brainstem encephalitis and pulmonary edema (14,33,34).…”

Section: Discussionmentioning

confidence: 99%

A Non-Mouse-Adapted Enterovirus 71 (EV71) Strain Exhibits Neurotropism, Causing Neurological Manifestations in a Novel Mouse Model of EV71 Infection

Khong

Yan

Yeo

et al. 2012

J Virol

140

174

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show abstract

“…2B). In addition, the secretion of proinflammatory cytokines following EV71 infection has been suggested to contribute to EV71 pathogenesis (3,32,37,38). We then quantified proinflammatory cytokine (TNF-␣, IL-10, MCP-1, IL-6, IFN-␥, and IL-12) levels in Flt3L-DCs from WT and TLR9KO mice infected with EV71.…”

Section: Ev71 Infection Induces Nf-b Activation Through Tlr9mentioning

confidence: 99%

“…Several studies have addressed the elevated levels of cytokines and chemokines in children with brainstem encephalitis and pulmonary edema (3,6,37). To determine whether neurological manifestations are associated with increased cytokine and chemokine levels in brain tissue, the cytokine and chemokine levels were quantified from RNA transcripts collected from infected mice at 3, 7, and 11 days p.i.…”

Section: Ev71 Infection Induces Nf-b Activation Through Tlr9mentioning

confidence: 99%

Toll-Like Receptor 9-Mediated Protection of Enterovirus 71 Infection in Mice Is Due to the Release of Danger-Associated Molecular Patterns

Hsiao

Chou

et al. 2014

J Virol

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Enterovirus 71 (EV71), a positive-stranded RNA virus, is the major cause of hand, foot, and mouth disease (HFMD) with severe neurological symptoms. Antiviral type I interferon (alpha/beta interferon [IFN-␣/␤]) responses initiated from innate receptor signaling are inhibited by EV71-encoded proteases. It is less well understood whether EV71-induced apoptosis provides a signal to activate type I interferon responses as a host defensive mechanism. In this report, we found that EV71 alone cannot activate Toll-like receptor 9 (TLR9) signaling, but supernatant from EV71-infected cells is capable of activating TLR9. We hypothesized that TLR9-activating signaling from plasmacytoid dendritic cells (pDCs) may contribute to host defense mechanisms. To test our hypothesis, Flt3 ligand-cultured DCs (Flt3L-DCs) from both wild-type (WT) and TLR9 knockout (TLR9KO) mice were infected with EV71. More viral particles were produced in TLR9KO mice than by WT mice. In contrast, alpha interferon (IFN-␣), monocyte chemotactic protein 1 (MCP-1), tumor necrosis factor-alpha (TNF-␣), IFN-␥, interleukin 6 (IL-6), and IL-10 levels were increased in Flt3L-DCs from WT mice infected with EV71 compared with TLR9KO mice. Seven-day-old TLR9KO mice infected with a non-mouse-adapted EV71 strain developed neurological lesion-related symptoms, including hind-limb paralysis, slowness, ataxia, and lethargy, but WT mice did not present with these symptoms. Lung, brain, small intestine, forelimb, and hind-limb tissues collected from TLR9KO mice exhibited significantly higher viral loads than equivalent tissues collected from WT mice. Histopathologic damage was observed in brain, small intestine, forelimb, and hind-limb tissues collected from TLR9KO mice infected with EV71. Our findings demonstrate that TLR9 is an important host defense molecule during EV71 infection. IMPORTANCEThe host innate immune system is equipped with pattern recognition receptors (PRRs), which are useful for defending the host against invading pathogens. During enterovirus 71 (EV71) infection, the innate immune system is activated by pathogen-associated molecular patterns (PAMPs), which include viral RNA or DNA, and these PAMPs are recognized by PRRs. Toll-like receptor 3 (TLR3) and TLR7/8 recognize viral nucleic acids, and TLR9 senses unmethylated CpG DNA or pathogen-derived DNA. These PRRs stimulate the production of type I interferons (IFNs) to counteract viral infection, and they are the major source of antiviral alpha interferon (IFN-␣) production in pDCs, which can produce 200-to 1,000-fold more IFN-␣ than any other immune cell type. In addition to PAMPs, danger-associated molecular patterns (DAMPs) are known to be potent activators of innate immune signaling, including TLR9. We found that EV71 induces cellular apoptosis, resulting in tissue damage; the endogenous DNA from dead cells may activate the innate immune system through TLR9. Therefore, our study provides new insights into EV71-induced apoptosis, which stimulates TLR9 in EV71-associated infections.

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“…7,[24][25][26] In our previous study, we found that EV71 infection significantly increased the release of IL-8, IP-10, and CCL5 at 12-hour or 24-hour point of infection in human primary MDMs. 8 While Wang and others 27 explored the acute chemokine response in the blood and cerebrospinal fluid of children with EV71-associated BE and suggested that IL-8, IP-10, MCP-1, and possibly MIG, but not CCL5, were synthesized in the brain in response to encephalitis. CCL5, a chemokine produced by stimulated airway epithelial cells that attracts eosinophils, basophils, monocytes, and memory T lymphocytes, is implicated in a variety of diseases characterized by pulmonary arterial hypertension, lung eosinophilia, and inflammation.…”

Section: Resultsmentioning

confidence: 99%

Association of Chemotactic Chemokine Ligand 5 Polymorphisms with the Risk of Developing Severe Enterovirus 71 Infection

Pang

Bai

et al. 2015

The American Society of Tropical Medicine and Hygiene

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Abstract. Respiratory damage is a main manifestation of severe Enterovirus 71 (EV71) infection. Polymorphisms of -403G/A (rs2107538), -28C/G (rs2280788), and In1.1T/C (rs2280789) in chemotactic chemokine ligand 5 (CCL5) have linked with many respiratory diseases. In this study, we explored the possible correlation of CCL5 polymorphisms with severe EV71 infection. Blood samples were obtained from 87 children hospitalized for EV71 infection. Fifty-seven healthy children were enrolled as asymptomatic controls. Genotype and allele frequencies were analyzed by logistic regression analysis. There were statistically significant differences in polymorphisms of CCL5 -403G/A and In1.1T/C for dominant model (P = 0.016; P = 0.027) and additive model (P = 0.010; P = 0.019) between patients with severe EV71 infection and asymptomatic controls. With ordinal logistic regression model analysis, statistically significant differences were found between polymorphisms of CCL5 (-403G/A) (P = 0.034) with the severity of EV71 infection after adjusting for age. The frequency of A-C-C haplotype was significantly higher in EV71 infection patients than controls (P = 0.032). These results suggest that CCL5 -403G/A and In1.1T/C polymorphisms may contribute to severe EV71 infection and individuals with haplotype of A-C-C may exhibit higher risk of developing severe EV71 infection. These findings may provide insights into pathogenic and protective mechanisms of severe EV71 infection.

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Acute Chemokine Response in the Blood and Cerebrospinal Fluid of Children with Enterovirus 71–Associated Brainstem Encephalitis

Cited by 113 publications

References 27 publications

A Non-Mouse-Adapted Enterovirus 71 (EV71) Strain Exhibits Neurotropism, Causing Neurological Manifestations in a Novel Mouse Model of EV71 Infection

A Non-Mouse-Adapted Enterovirus 71 (EV71) Strain Exhibits Neurotropism, Causing Neurological Manifestations in a Novel Mouse Model of EV71 Infection

Toll-Like Receptor 9-Mediated Protection of Enterovirus 71 Infection in Mice Is Due to the Release of Danger-Associated Molecular Patterns

Association of Chemotactic Chemokine Ligand 5 Polymorphisms with the Risk of Developing Severe Enterovirus 71 Infection

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