Association of Enterovirus 71 encephalitis with the interleukin-8 gene region in Chinese children

Li, Jian; Lin, Aiwei; Yu, Chengwen; Zhang, Zhaofang; Xu, Daoyan; Hu, Wei; Liu, Liyan; Wang, Shaoning; Nie, Xiuzhen; Sun, Wenyan; Gai, Zhongtao; Chen, Zongbo

doi:10.3109/00365548.2015.1007473

Cited by 6 publications

(3 citation statements)

References 12 publications

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“…In the EV-A71-infected humanized mice, there was only a subtle increase in the IFN-␥ level, which might account for the absence of pulmonary edema in the humanized mice, although high viral loads and infiltrating lymphocytes were present in the brain and the lung. Recent findings suggested that patients with EV-A71 encephalitis have significantly higher frequencies of IL-8 -251TT genotype and IL-8 -251T alleles than patients with EV-A71-related HFMD without encephalitis, and patients with ANS dysregulation have higher plasma levels of IL-8 than patients with pulmonary edema (32,54). To the best of our knowledge, this is the first report showing that a level of human IL-8 was detected in the EV-A71-infected humanized mouse model.…”

Section: Discussionmentioning

confidence: 99%

Enterovirus A71 Infection Activates Human Immune Responses and Induces Pathological Changes in Humanized Mice

Liu

Her

et al. 2019

J Virol

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Since the discovery of enterovirus A71 (EV-A71) half a century ago, it has been recognized as the cause of large-scale outbreaks of hand-foot-and-mouth disease worldwide, particularly in the Asia-Pacific region, causing great concern for public health and economic burdens. Detailed mechanisms on the modulation of immune responses after EV-A71 infection have not been fully known, and the lack of appropriate models hinders the development of promising vaccines and drugs. In the present study, NOD-scid IL2Rγ−/− (NSG) mice with a human immune system (humanized mice) at the age of 4 weeks were found to be susceptible to a human isolate of EV-A71 infection. After infection, humanized mice displayed limb weakness, which is similar to the clinical features found in some of the EV-A71-infected patients. Histopathological examination indicated the presence of vacuolation, gliosis, or meningomyelitis in brain stem and spinal cord, which were accompanied by high viral loads detected in these organs. The numbers of activated human CD4+ and CD8+ T cells were upregulated after EV-A71 infection, and EV-A71-specific human T cell responses were found. Furthermore, the secretion of several proinflammatory cytokines, such as human gamma interferon (IFN-γ), interleukin-8 (IL-8), and IL-17A, was elevated in the EV-A71-infected humanized mice. Taken together, our results suggested that the humanized mouse model permits insights into the human immune responses and the pathogenesis of EV-A71 infection, which may provide a platform for the evaluation of anti-EV-A71 drug candidates in the future. IMPORTANCE Despite causing self-limited hand-food-and-mouth disease in younger children, EV-A71 is consistently associated with severe forms of neurological complications and pulmonary edema. Nevertheless, only limited vaccines and drugs have been developed over the years, which is possibly due to a lack of models that can more accurately recapitulate human specificity, since human is the only natural host for wild-type EV-A71 infection. Our humanized mouse model not only mimics histological symptoms in patients but also allows us to investigate the function of the human immune system during infection. It was found that human T cell responses were activated, accompanied by an increase in the production of proinflammatory cytokines in EV-A71-infected humanized mice, which might contribute to the exacerbation of disease pathogenesis. Collectively, this model allows us to delineate the modulation of human immune responses during EV-A71 infection and may provide a platform to evaluate anti-EV-A71 drug candidates in the future.

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Section: Discussionmentioning

confidence: 99%

Enterovirus A71 Infection Activates Human Immune Responses and Induces Pathological Changes in Humanized Mice

Liu

Her

et al. 2019

J Virol

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“…A recent report [38] showed that IL-8 exhibited high AUC values (0.95) through the ROC curve assay and the serum levels of IL-8 in EV71 critical infection (including frequent convulsions, coma, brain hernia, and pulmonary rales) were highest compared with mild cases and severe cases. Both Li et al [52] and Xu et al [37] considered that the frequency of IL-8-251 T alleles among 8 Mediators of Inflammation the severe cases (such as encephalitis and respiratory failure) was significantly higher than that of mild cases. In summary, the studies indicated a strong correlation between IL-8 and EV71-infected HFMD severity.…”

Section: Chemokinesmentioning

confidence: 99%

Predicting Severe Enterovirus 71-Infected Hand, Foot, and Mouth Disease: Cytokines and Chemokines

Zhang

Huang

et al. 2020

Mediators of Inflammation

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Enterovirus 71 (EV71) is one of the most common intestinal virus that causes hand, foot, and mouth disease (HFMD) in infants and young children (mostly ≤5 years of age). Generally, children with EV71-infected HFMD have mild symptoms that resolve spontaneously within 7-14 days without complications. However, some EV71-infected HFMD cases lead to severe complications such as aseptic meningitis, encephalitis, acute flaccid paralysis, pulmonary edema, cardiorespiratory complication, circulatory disorders, poliomyelitis-like paralysis, myocarditis, meningoencephalitis, neonatal sepsis, and even death. The mechanism of EV71 pathogenesis has been studied extensively, and the regulation of host immune responses is suspected to aggravate EV71induced severe complications. Recently, several cytokines or chemokines such as TNF-α, IFN-γ, IL-1β, IL-18, IL-33, IL-37, IL-4, IL-13, IL-6, IL-12, IL-23, IL-27, IL-35, IL-10, IL-22, IL-17F, IL-8, IP-10, MCP-1, G-CSF, and HMGB1 have been reported to be associated with severe EV71 infection by numerous research teams, including our own. This review is aimed at summarizing the pathophysiology of the cytokines and chemokines with severe EV71 infection.

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“…Increasing evidence suggests that inflammatory cytokines may play a central role in HFMD derived from EV-A71 infection 16 – 18 . It has also been postulated that dysregulation of inflammatory responses and cellular immunity are possibly responsible for this pathogenesis 19 – 22 .…”

Section: Discussionmentioning

confidence: 99%

Susceptibility and cytokine responses of human neuronal cells to multiple circulating EV-A71 genotypes in India

Mohanty

Varose

Saxena

2021

Sci Rep

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Enterovirus-A71 (EV-A71) associated Hand, foot and mouth disease (HFMD) is a highly contagious viral infection affecting children in Asia–Pacific region and has become a major threat to public health. Although several EV-A71 genotypes (C, D, and G) were isolated in India in recent years, no recognizable outbreak of EV-A71 caused HFMD, Acute Flaccid paralysis (AFP) or encephalitis have been reported so far. It is essential to study the pathogenicity or cell tropism of these Indian isolates in order to understand their tendency to cause disease. We investigated the susceptibility and cytokine responses of indigenous EV-A71 genotypes (D and G) isolated from cases of AFP and genotype C viruses isolated from cases of HFMD and encephalitis, in human cells in-vitro. Although all three EV-A71 genotypes could infect and replicate in human muscle and neuronal cells, the genotype D virus showed a delayed response in human neuronal cells. Quantification of cytokine secretion in response to these isolates followed by confirmation with gene expression assays in human neuronal cells revealed significantly higher secretion of pro-inflammatory cytokines TNF-α IL-8, IL-6, IP-10 (p < 0.001) in G genotype infected cells as compared to pathogenic C genotypes whereas the genotype D virus could not induce any of the inflammatory cytokines. These findings will help to better understand the host response to indigenous EV-A71 genotypes for management of future EV-A71 outbreaks in India, if any.

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Association of Enterovirus 71 encephalitis with the interleukin-8 gene region in Chinese children

Cited by 6 publications

References 12 publications

Enterovirus A71 Infection Activates Human Immune Responses and Induces Pathological Changes in Humanized Mice

Enterovirus A71 Infection Activates Human Immune Responses and Induces Pathological Changes in Humanized Mice

Predicting Severe Enterovirus 71-Infected Hand, Foot, and Mouth Disease: Cytokines and Chemokines

Susceptibility and cytokine responses of human neuronal cells to multiple circulating EV-A71 genotypes in India

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