EV71-infected CD14<sup>+</sup>cells modulate the immune activity of T lymphocytes in rhesus monkeys

Wang, Jingjing; Pu, Jing; Huang, Hongtai; Zhang, Ying; Liu, Longding; Yang, Erxia; Zhou, Xiaofang; Ma, Na; Zhao, Hang; Wang, Lichun; Xie, Zhen; Tang, Donghong; Li, Qihan

doi:10.1038/emi.2013.44

Cited by 15 publications

(15 citation statements)

References 45 publications

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“…Production of such inflammatory cytokines are mediated by monocytes, macrophages, as well as T and B lymphocytes 46 . Furthermore, these immune cells were the subsets shown to be the most susceptible to EV-A71 in this study and elsewhere [47][48][49] .…”

Section: Discussionsupporting

confidence: 57%

TREM-1 activation is a potential key regulator in driving severe pathogenesis of enterovirus A71 infection

Amrun

Tan

Rickett

et al. 2020

Sci Rep

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Hand, foot and mouth disease (HFMD), caused by enterovirus A71 (EV-A71), presents mild to severe disease, and sometimes fatal neurological and respiratory manifestations. However, reasons for the severe pathogenesis remain undefined. To investigate this, infection and viral kinetics of EV-A71 isolates from clinical disease (mild, moderate and severe) from Sarawak, Malaysia, were characterised in human rhabdomyosarcoma (RD), neuroblastoma (SH-SY5Y) and peripheral blood mononuclear cells (PBMCs). High resolution transcriptomics was used to decipher EV-A71-host interactions in PBMCs. Ingenuity analyses revealed similar pathways triggered by all EV-A71 isolates, although the extent of activation varied. Importantly, several pathways were found to be specific to the severe isolate, including triggering receptor expressed on myeloid cells 1 (TREM-1) signalling. Depletion of TREM-1 in EV-A71-infected PBMCs with peptide LP17 resulted in decreased levels of pro-inflammatory genes for the moderate and severe isolates. Mechanistically, this is the first report describing the transcriptome profiles during EV-A71 infections in primary human cells, and the potential involvement of TREM-1 in the severe disease pathogenesis, thus providing new insights for future treatment targets. Hand, foot and mouth disease (HFMD) is a febrile illness that predominantly affects infants and young children, and is characterised by rash and blisters on the hands, mouth, feet and bottoms 1-3. Outbreaks of HFMD are caused by human enterovirus group A members (HE-A), mainly coxsackieviruses A16, A6 and A10, and enterovirus A71 (EV-A71) 1,4,5. While often benign and self-limiting 2 , the disease can cause cardiopulmonary and neurological complications such as myocarditis, brainstem encephalitis, aseptic meningitis, and neurogenic pulmonary oedema, which can be fatal 6,7. The severe manifestations of HFMD are often associated with cases of EV-A71 infections, rather than coxsackievirus A16 8. EV-A71 belongs to the Enterovirus A species, Enterovirus genus, from the Picornaviridae family 9,10. The virus has a positive-sense RNA genome of 7.4 kb and encodes for four structural (VP1-4) and seven non-structural (2A-C and 3A-D) proteins 9. First isolated in California, USA, in 1969 11 , the virus is transmitted via the oral-foecal route, saliva and respiratory secretions 12. Based on the sequence analysis of VP1 gene, the virus can be broadly categorised into six genogroups: A, B, C, D, E and F 7,10,13. Whereas genogroup A contains the Californian prototype virus BrCr, genogroups B and C consist of various strains, and are further categorised into sub-genogroups B0-B5 and C1-C5 10. B and C genogroups are globally distributed, whereas D, and E and F are limited to India and Africa respectively 7,10. After the almost total eradication of poliovirus, EV-A71 is now noted as one of the most prevalent neurotropic enteroviruses, and is especially endemic in the Asia-Pacific region 14-17. Currently, the

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Section: Discussionsupporting

confidence: 57%

TREM-1 activation is a potential key regulator in driving severe pathogenesis of enterovirus A71 infection

Amrun

Tan

Rickett

et al. 2020

Sci Rep

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“…We observed aggregated virus in the cells of the blood-brain barrier structure during the early phase of infection (day 3 p.i. ), which was different than the peak viral loads observed in the peripheral nerves and CNS of rhesus monkeys on days 7 and 10, respectively (Wang et al, 2013). In this case, we speculated that EV71 circulated to the blood-brain barrier structure and encountered astrocytes when it sojourned in immune cells, such as DCs.…”

Section: Discussionmentioning

confidence: 56%

“…The experiments also suggested that viral infection in these cells was dependent on phagocytosis and the presence of complement in at least the in vitro culture system, which suggests that the virus (which is an exogenous pathogen facing astrocyte immune cells in the CNS) exhibits a preference for astrocytes compared with neurons, a finding that facilitated the elucidation of the pathogenesis of EV71 infection in the CNS. Our previous data and the results reported by others indicated that EV71 is capable of transferring to target organs in the body by sojourning in immune cells, such as CD14 + or dendritic cells, and most likely spreads to the CNS through peripheral nerves via retrograde axonal transport (Wang et al, 2013). We observed aggregated virus in the cells of the blood-brain barrier structure during the early phase of infection (day 3 p.i.…”

Section: Discussionmentioning

confidence: 62%

The Preferential Infection of Astrocytes by Enterovirus 71 Plays a Key Role in the Viral Neurogenic Pathogenesis

Feng

Guo

Fan

et al. 2016

Front. Cell. Infect. Microbiol.

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The pathological manifestations of fatal cases of human hand, foot, and mouth disease (HFMD) caused by enterovirus 71 (EV71) are characterized by inflammatory damage to the central nervous system (CNS). Here, the dynamic distribution of EV71 in the CNS and the subsequent pathological characteristics within different regions of neonatal rhesus macaque brain tissue were studied using a chimeric EV71 expressing green fluorescence protein. The results were compared with brain tissue obtained from the autopsies of deceased EV71-infected HFMD patients. These observations suggested that the virus was prevalent in areas around the blood vessels and nerve nuclei in the brain stem and showed a preference for astrocytes in the CNS. Interestingly, infected astrocytes within the in vivo and in vitro human and macaque systems exhibited increased expression of excitatory neurotransmitters and cytokines that also stimulated the neuronal secretion of the excitatory neurotransmitters noradrenalin and adrenalin, and this process most likely plays a role in the pathophysiological events that occur during EV71 infection.

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“…Furthermore, there was a significant increase in the number of CD14 ϩ cells in the brain. It has been demonstrated that EV-A71 has the ability to replicate in CD14 ϩ cells, and the infected CD14 ϩ cells are capable of stimulating the proliferation of T cells and further stimulating the release of functional cytokines in rhesus monkeys (49). The functional role of CD14 ϩ cells in our humanized mouse model warrants further investigation.…”

Section: Discussionmentioning

confidence: 88%

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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EV71-infected CD14⁺cells modulate the immune activity of T lymphocytes in rhesus monkeys

Cited by 15 publications

References 45 publications

TREM-1 activation is a potential key regulator in driving severe pathogenesis of enterovirus A71 infection

TREM-1 activation is a potential key regulator in driving severe pathogenesis of enterovirus A71 infection

The Preferential Infection of Astrocytes by Enterovirus 71 Plays a Key Role in the Viral Neurogenic Pathogenesis

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

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EV71-infected CD14+cells modulate the immune activity of T lymphocytes in rhesus monkeys

Cited by 15 publications

References 45 publications

TREM-1 activation is a potential key regulator in driving severe pathogenesis of enterovirus A71 infection

TREM-1 activation is a potential key regulator in driving severe pathogenesis of enterovirus A71 infection

The Preferential Infection of Astrocytes by Enterovirus 71 Plays a Key Role in the Viral Neurogenic Pathogenesis

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

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EV71-infected CD14⁺cells modulate the immune activity of T lymphocytes in rhesus monkeys