Interfering With Inflammatory Cytokine Production During Antibody-Enhanced Dengue Virus Infection
Public DepositedAdd to collection
You do not have access to any existing collections. You may create a new collection.
Downloadable Content
Download PDFCitation
MLA
Callaway, Justin. Interfering With Inflammatory Cytokine Production During Antibody-enhanced Dengue Virus Infection. Chapel Hill, NC: University of North Carolina at Chapel Hill Graduate School, 2014. https://doi.org/10.17615/w97g-h526APA
Callaway, J. (2014). Interfering With Inflammatory Cytokine Production During Antibody-Enhanced Dengue Virus Infection. Chapel Hill, NC: University of North Carolina at Chapel Hill Graduate School. https://doi.org/10.17615/w97g-h526Chicago
Callaway, Justin. 2014. Interfering With Inflammatory Cytokine Production During Antibody-Enhanced Dengue Virus Infection. Chapel Hill, NC: University of North Carolina at Chapel Hill Graduate School. https://doi.org/10.17615/w97g-h526- Last Modified
- March 19, 2019
- Creator
-
Callaway, Justin
- Affiliation: School of Medicine, Department of Microbiology and Immunology
- Abstract
- Dengue virus (DENV) is the most burdensome arbovirus in the world, infecting nearly 400 million people annually. Patients develop lifelong immunity to the original infecting serotype but only transient immunity to the remaining serotypes. Over time, the cross-reactive immune response weakens and can cause severe dengue disease upon infection with a heterologous serotype of DENV. This creates high serum viremia and aberrant production of cytokines, potentially progressing to life-threatening hypovolemic shock due to vascular leakage. One contributing mechanism is antibody-dependent enhancement (ADE) increasing entry of DENV into Fc-receptor-bearing cells, increasing production of cytokines and virus. One cytokine elevated in the profiles of many severe dengue patients is interleukin-1beta (IL-1beta). IL-1beta is uniquely regulated, requiring one stimulus to induce synthesis of precursor pro-IL-1beta and a second stimulus to activate assembly of the inflammasome. The inflammasome activates caspase-1, which cleaves pro-IL-1beta into its biologically-active form. We sought to identify the steps modulated by ADE to increase IL-1beta secretion. We found that ADE induces IL1B and pro-IL-1beta expression rapidly after inoculation, inducing secretion of mature IL-1beta by 4 hours post-inoculation (hpi). This required activation of a signaling axis consisting of spleen tyrosine kinase (Syk) and extracellular signal-regulated kinase 1/2 (ERK1/2). Interestingly, ADE did not detectably increase caspase-1 activation, but IL-1beta processing required caspase-1 activity. Importantly, activation of Syk by ADE also induced expression of TNF and IL6, suggesting that interfering with Syk may reduce expression of many ADE-induced cytokines. Additionally, we found that the cell-type used to propagate DENV in vitro impacted the induction of IL-1beta secretion by primary monocytes. Inoculation of monocytes with supernatants from DENV-infected Vero cells induced IL-1beta secretion independent of ADE. This was due to an inflammatory moiety produced by DENV-infected Vero cells. Purification of Vero-derived DENV eliminated this factor and made ADE required for IL-1beta secretion. Interestingly, DENV-infected mosquito cells did not produce a similar inflammatory component. ADE increased IL-1beta secretion when monocytes were inoculated with supernatant from DENV-infected mosquito cells without need to purify DENV. This study indicates that the source and purity of DENV preparations can significantly impact studies of the innate immune response to DENV.
- Date of publication
- December 2014
- Keyword
- Subject
- DOI
- Identifier
- Resource type
- Rights statement
- In Copyright
- Advisor
- De Silva, Aravinda Manu
- Heise, Mark
- Ting, Jenny P.-Y.
- Matsushima, Glenn
- Su, Lishan
- Degree
- Doctor of Philosophy
- Degree granting institution
- University of North Carolina at Chapel Hill Graduate School
- Graduation year
- 2014
- Language
- Publisher
- Place of publication
- Chapel Hill, NC
- Access right
- This item is restricted from public view for 1 year after publication.
- Date uploaded
- April 22, 2015
Relations
- Parents:
This work has no parents.
Items
Thumbnail | Title | Date Uploaded | Visibility | Actions |
---|---|---|---|---|
Callaway_unc_0153D_14922.pdf | 2019-04-15 | Public | Download |