Altered Cellular but Not Humoral Reactions in Children with Complicated Enterovirus 71 Infections in Taiwan

Yang, Kuender D.; Yang, Ming; Li, Chung Chen; Lin, Shu; Chong, Meng Chu; Wang, Chih Lu; Chen, Rong‐Fu; Lin, Tzou Yien

doi:10.1086/319255

Cited by 88 publications

(86 citation statements)

References 46 publications

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“…The blood samples were separated into plasma and blood cells by centrifugation at 1500 ϫ g for 15 min. The plasma was harvested for cytokine determination after heat inactivation at 56°C for 15 min, and the blood cells were separated into RBC and white blood cells by dextran (T500, 4.5%) sedimentation (9). The white blood cells were subjected to inactivation of all known potential infectious agents and fixation of leukocytes by 1% formaldehyde.…”

Section: Preparation Of Plasma and Leukocytes Under A Safety Proceduresmentioning

confidence: 99%

Altered p38 Mitogen-Activated Protein Kinase Expression in Different Leukocytes with Increment of Immunosuppressive Mediators in Patients with Severe Acute Respiratory Syndrome

Lee¹,

Chen²,

Liu³

et al. 2004

The Journal of Immunology

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Severe acute respiratory syndrome (SARS) has spread to a global pandemic, especially in Asia. The transmission route of SARS has been clarified, but the immunopathogenesis of SARS is unclear. In an age-matched case-control design, we studied immune parameters in 15 SARS patients who were previously healthy. Plasma was harvested for detection of virus load, cytokines, and nitrite/nitrate levels, and blood leukocytes were subjected to flow cytometric analysis of intracellular mitogen-activated protein kinases (MAPKs) in different leukocytes. Patients with SARS had significantly higher IL-8 levels (p = 0.016) in early stage, and higher IL-2 levels (p = 0.039) in late stage than normal controls. Blood TNF-α, IL-6, and IL-10, and nitrite/nitrate levels were not significantly elevated. In contrast, TGF-β and PGE2 levels were significantly elevated in SARS patients. Five of the 15 SARS patients had detectable coronaviruses in blood, but patients with detectable and undetectable viremia had no different profiles of immune mediators. Flow cytometric analysis of MAPKs activation by phospho-p38 and phospho-p44/42 (extracellular signal-regulated kinase) expression showed that augmented p38 activation (p = 0.044) of CD14 monocytes associated with suppressed p38 activation (p = 0.033) of CD8 lymphocytes was found in SARS patients. These results suggest that regulation of TGF-β and PGE2 production and MAPKs activation in different leukocytes may be considered while developing therapeutics for the SARS treatment.

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Section: Preparation Of Plasma and Leukocytes Under A Safety Proceduresmentioning

confidence: 99%

Altered p38 Mitogen-Activated Protein Kinase Expression in Different Leukocytes with Increment of Immunosuppressive Mediators in Patients with Severe Acute Respiratory Syndrome

Lee¹,

Chen²,

Liu³

et al. 2004

The Journal of Immunology

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“…Alteration of the cellular immunity of the host has also been suggested to be related to the severity of the disease (30).…”

mentioning

confidence: 99%

A Mouse-Adapted Enterovirus 71 Strain Causes Neurological Disease in Mice after Oral Infection

Wang

Chou²,

Lei³

et al. 2004

J Virol

237

241

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A mouse-adapted enterovirus 71 (EV71) strain with increased virulence in mice, MP4, was generated after four serial passages of the parental EV71 strain 4643 in mice. Strain MP4 exhibited a larger plaque size, grew more rapidly, and was more cytotoxic in vitro than strain 4643. Although strains 4643 and MP4 both induced apoptosis of SK-N-SH human neuroblastoma cells, MP4 was more virulent than 4643 in 1-day-old mice (50% lethal doses, 10 2 and 10 4 PFU/mouse, respectively). Strain MP4 (5 ؋ 10 6 PFU/mouse), but not 4643, could orally infect 7-day-old mice, resulting in rear-limb paralysis followed by death 5 to 9 days after inoculation with the virus. Histopathologically, neuronal loss and apoptosis were evident in the spinal cords as well as the brain stems of the infected mice. The limb muscles displayed massive necrosis. There was early and transient virus replication in the intestines, whereas the spinal cord, brain, and muscle became the sites of viral replication during the late phase of the infection. Virus transmission occurred among infected and noninfected cagemates, as demonstrated by the occurrence of seroconversion and the presence of viable viruses in the stool samples of the latter. Protection against EV71 challenge was demonstrated following administration of hyperimmune serum 1 day after inoculation with the virus. Nucleotide sequence analysis of the genome of EV71 strain MP4 revealed four nucleotide changes on the 5 untranslated region, three on the VP2 region, and eight on the 2C region, resulting in one and four amino acid substitutions in the VP2 and 2C proteins, respectively.Enterovirus 71 (EV71), a neurotropic virus with undefined pathogenesis, has caused significant morbidity and mortality worldwide and especially in the Asia-Pacific region since it was first described in 1969 in the United States (1, 2). EV71 infections are generally mild, such as hand-foot-and-mouth disease (HFMD) and herpangina, but occasionally lead to severe diseases such as aseptic meningitis, poliomyelitis-like paralysis, and possibly fatal encephalitis in neonates. The outbreak of EV71 in Taiwan in 1998 killed 78 children, and since then EV71 infection has become endemic in Taiwan (8, 16). Brain stem encephalitis associated with pulmonary edema and cardiac insufficiency were the primary manifestations in patients with neurologic involvement (10, 16, 28). The predominant pathological findings were in the thalamus, pons, midbrain, medulla oblongata, and spinal cord, with intense neutrophil and mononuclear cell infiltrates. There was severe congestion with focal hemorrhage and edema in the lungs (21). Although EV71 was recovered from the mycocardium, there was only mild degeneration of the mycocardium. Neurogenic shock as a result of brain stem encephalitis has been proposed as the cause of pulmonary and cardiac complications (13,16). It has also been postulated that overwhelming virus replication combined with damage in tissues with the induction of toxic inflammatory cytokines is one possible pathogenesis (14,15,27)...

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“…12,13 In humans, an extensive peripheral and central nervous system inflammatory response, with abnormal IL-10, IL-13 and interferon-c (IFN-c) cytokine production as well as lymphocyte depletion, appears to be responsible for the pathogenesis of EV71-associated pulmonary oedema. [14][15][16] However, to date the mechanism of the cellular immune response to EV71 has not been elucidated in detail.…”

Section: M M U N O L O G Y O R I G I N a L A R T I C L Ementioning

confidence: 99%

“…Blood samples were obtained on days 1-7 after onset, discharge from the hospital (day [7][8][9][10][11][12][13][14] and the fully recovered stage (defined as 1 month after illness onset), respectively. All samples were collected specifically for this study and were coded to protect confidentiality.…”

Section: Recruitment and Sample Collectionmentioning

confidence: 99%

Dominant CD4‐dependent RNA‐dependent RNA polymerase‐specific T‐cell responses in children acutely infected with human enterovirus 71 and healthy adult controls

Dang

Gao

et al. 2014

Immunology

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SummaryHuman enterovirus 71 (EV71) is one of the major causes of hand, foot and mouth disease (HFMD), which leads to significant mortality in infected children. A prophylactic vaccine is urgently needed. However, little is known about the protective T-cell immunity in individuals infected with the EV71 virus. In this study, we performed a comprehensive ex vivo interferon-c ELISPOT analysis in 31 children infected with EV71 as well as in 40 healthy adult controls of the CD4 + and CD8 + T-cell responses to overlapping peptides spanning the VP1 structural protein and RNAdependent RNA polymerase (RdRp) non-structural protein. EV71-specific CD4 T-cell responses were detected in most of the acute patients and were mostly CD4-dependent RdRp-specific responses. CD8-dependent VP1 and RdRp-specific responses were also detected in a small proportion of recently infected children. There was no significant association between the strength of the T-cell responses and disease severity observed during the acute EV71 infection phase. Interestingly, an RdRp-specific, but no VP1-specific, CD4-dependent T-cell response was detected in 30% of the adult controls, and no T-cell responses were detected in healthy children. In addition, 24 individual peptides containing potential T-cell epitope regions were identified. The data suggest that CD4-dependent RdRp-specific T-cell responses may play an important role in protective immunity, and the epitopes identified in this study should provide valuable information for future therapeutic and prophylactic vaccine design as well as basic research.

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Altered Cellular but Not Humoral Reactions in Children with Complicated Enterovirus 71 Infections in Taiwan

Cited by 88 publications

References 46 publications

Altered p38 Mitogen-Activated Protein Kinase Expression in Different Leukocytes with Increment of Immunosuppressive Mediators in Patients with Severe Acute Respiratory Syndrome

Altered p38 Mitogen-Activated Protein Kinase Expression in Different Leukocytes with Increment of Immunosuppressive Mediators in Patients with Severe Acute Respiratory Syndrome

A Mouse-Adapted Enterovirus 71 Strain Causes Neurological Disease in Mice after Oral Infection

Dominant CD4‐dependent RNA‐dependent RNA polymerase‐specific T‐cell responses in children acutely infected with human enterovirus 71 and healthy adult controls

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