CD4 T-Cell-Independent Antibody Response Reduces Enterovirus 71 Lethality in Mice by Decreasing Tissue Viral Loads

Wang, Li-Chiu; Kao, Chia Min; Ling, Pin; Su, Ih Jen; Chang, Tung Miao; Chen, Shun Hua

doi:10.1155/2012/580696

Cited by 12 publications

(19 citation statements)

References 31 publications

(36 reference statements)

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“…However, we found that deficiency of B cells, but not CD4 T cells, abolished the protective effect of Flt3 ligand, suggesting that innate B cells, but not T helper cells, might contribute to Flt3 ligand-mediated protection in our model. These results are consistent with our previous report demonstrating that CD4 T cell-deficient mice can produce neutralizing antibodies to protect mice from EV-A71 infection possibly through innate B cells 31 . Our additional results showing the failure of Flt3 ligand to increase the production of T helper 2 cytokines (IL-4 and IL-5) in EV-A71-infected mice (Supplementary Fig.…”

Section: Discussionsupporting

confidence: 93%

Flt3 ligand treatment reduces enterovirus A71 lethality in mice with enhanced B cell responses

Lin¹,

Wang²,

Lee³

et al. 2018

Sci Rep

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Enterovirus A71 (EV-A71) infection can induce encephalitis, which causes death or long-term neurological sequelae, especially in young children. Using a murine infection model, we searched for anti-EV-A71 agents, because effective therapies are not available to control fatal infection. In EV-A71-infected mice, treatment with the hematopoietic growth factor, Fms-like tyrosine-kinase 3 ligand (Flt3 ligand) before infection reduced the lethality and tissue viral loads. Flt3 ligand failed to enhance the production of type I interferons. Instead, Flt3 ligand boosted the numbers of dendritic cells and, particularly lymphocytes in infected organs with an expansion of spleen B cells, and resulted in an increased titer of virus-specific antibody with neutralizing activity in the serum. The protective effect of Flt3 ligand was abolished in B cell-deficient mice. Our findings revealed that Flt3 ligand administration promotes resistance to EV-A71 infection with enhanced B cell response in a mechanism rarely reported before.

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Section: Discussionsupporting

confidence: 93%

Flt3 ligand treatment reduces enterovirus A71 lethality in mice with enhanced B cell responses

Lin¹,

Wang²,

Lee³

et al. 2018

Sci Rep

Self Cite

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“…Although cellular immune response has been confirmed an important role in the disease of HFMD, some of the immune mediators identified here are also important for an effective B cell-mediated humoral response, including neutralizing antibody production [18], [19]. We examined EV71 VP-1–specific IgG and IgM antibody levels in patient plasma.…”

Section: Resultsmentioning

confidence: 95%

Comparative Study of the Cytokine/Chemokine Response in Children with Differing Disease Severity in Enterovirus 71-Induced Hand, Foot, and Mouth Disease

et al. 2013

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BackgroundEnterovirus 71 (EV71) infection can lead to a rapidly progressing, life-threatening, and severe neurological disease in young children, including the development of human hand, foot, and mouth disease (HFMD). This study aims to further characterize the specific immunological features in EV71–mediated HFMD patients presenting with differing degrees of disease severity.MethodologyComprehensive cytokine and chemokine expression were broadly evaluated by cytokine antibody array in EV71–infected patients hospitalized for HFMD compared to Coxsackievirus A16-infected patients and age-matched healthy controls. More detailed analysis using Luminex-based cytokine bead array was performed in EV71–infected patients stratified into diverse clinic outcomes. Additionally, immune cell frequencies in peripheral blood and EV71–specific antibodies in plasma were also examined.Principal FindingsExpression of several cytokines and chemokines were significantly increased in plasma from EV71–infected patients compared to healthy controls, which further indicated that: (1) GM-CSF, MIP-1β, IL-2, IL-33, and IL-23 secretion was elevated in patients who rapidly developed disease and presented with uncomplicated neurological damage; (2) G-CSF and MCP-1 were distinguishably secreted in EV71 infected very severe patients presenting with acute respiratory failure; (3) IP-10, MCP-1, IL-6, IL-8, and G-CSF levels were much higher in cerebrospinal fluid than in plasma from patients with neurological damage; (4) FACS analysis revealed that the frequency of CD19+HLADR+ mature B cells dynamically changed over time during the course of hospitalization and was accompanied by dramatically increased EV71–specific antibodies. Our data provide a panoramic view of specific immune mediator and cellular immune responses of HFMD and may provide useful immunological profiles for monitoring the progress of EV71–induced fatal neurological symptoms with acute respiratory failure.

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“…Tonsils are an important site outside the CNS for viral replication in HFMD [17] , thus viral genomic load in throat swabs theoretically correlates with viral burden. In animal models, EV-A71 viral load is lower in surviving animals [ 18 , 19 ]. Therefore, we hypothesised that increasing viral load measured in throat swabs would correlate with the clinical severity of HFMD.…”

Section: Discussionmentioning

confidence: 99%

Enterovirus genomic load and disease severity among children hospitalised with hand, foot and mouth disease

et al. 2020

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Background: Examining associations between viral genomic loads of enteroviruses and clinical severity is important for promoting and improving development of antiviral drugs related to hand, foot and mouth disease (HFMD). Methods: Throat swabs were collected from HFMD cases at acute phase of illness using a standardized technique in a prospective study. The viral genomic load was categorized into low, medium, and high groups using parameters of real-time reverse transcription-polymerase chain reaction. The clinical severities were assessed with four indicators, respectively. Findings: We analysed 1109 HFMD cases, including 538 children with CV-A6, 231 with CV-A16, 156 with EV-A71, 78 with CV-A10, 59 with CV-A4, and 47 with CV-A2. EV-A71 genomic load categories were associated with risks of diagnoses of CNS complications (p = 0.016), requiring systemic corticosteroids or IVIG (p = 0.011), intensive care unit admission (p = 0.002) and length of hospital stay over 5 days (p = 0.048). In the multivariate analyses, point estimates of adjusted odds ratio (OR) tended to increase with viral genomic loads for all four severe outcomes and ORs of highest viral genomic load were all significantly larger than one for EV-A71. Interpretation: HFMD clinical severities positively associate with viral genomic loads of EV-A71 in throat swabs. Specific antiviral drugs should be developed to reduce enterovirus load and to alleviate the clinical severities for HFMD cases.

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CD4 T-Cell-Independent Antibody Response Reduces Enterovirus 71 Lethality in Mice by Decreasing Tissue Viral Loads

Cited by 12 publications

References 31 publications

Flt3 ligand treatment reduces enterovirus A71 lethality in mice with enhanced B cell responses

Flt3 ligand treatment reduces enterovirus A71 lethality in mice with enhanced B cell responses

Comparative Study of the Cytokine/Chemokine Response in Children with Differing Disease Severity in Enterovirus 71-Induced Hand, Foot, and Mouth Disease

Enterovirus genomic load and disease severity among children hospitalised with hand, foot and mouth disease

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