Knowlton, Emilee R.
(2013)
Cytokine and Chemokine Responses in Human Herpesvirus 8 Infection of Monocyte Derived Dendritic Cells and B Lymphocytes.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Human herpesvirus-8 induces a wide range of inflammatory immune mediators known to contribute to its associated cancer, Kaposi’s Sarcoma (KS). Soluble immune mediators, such as cytokines, chemokines and growth factors produced during HHV-8 infection have been associated with tumor-cell proliferation, angiogenesis and vascular permeability. We sought to determine immune mediator production by two antigen presenting cells (APC) that are susceptible to HHV-8 infection, i.e., monocyte derived Dendritic cells (MDDC) and B lymphocytes.
Dendritic cells abundantly express the HHV-8 receptor, type II C-type lectin, DC-specific ICAM-3 grabbing nonintegrin (DC-SIGN) resulting in viral entry, whereas only a small percentage of activated B cells express DC-SIGN in vitro. Despite this, HHV-8 infection of MDDC results in an abortive replicative cycle, whereas full-lytic cycle replication occurs in the B cells. I hypothesized that immune mediators produced by HHV-8 infected APC are unique between cell types and that HHV-8 infects a subset of B cells and initiates cytokine and chemokine production that contributes to HHV-8 replication, viral dissemination and initiation of KS and HHV-8 lymphomas.
I used a cytometric bead array to determine cytokine and chemokine production in B cells and MDDC, as well as qRT-PCR, TCID50 assay and flow cytometry to determine HHV-8 replication in B cells. I identified significant differences in the quality and quantity of cytokine and chemokine profiles of HHV-8 infected APC. MDDC produced significant levels of MCP-1, MIP-1α, MIP-1β, RANTES, IP-10 and IL-10, while B cells produced significant levels of MIP-1α, MIP-1β, IL-6, TNF-α and IL-8. HHV-8 lytic replication in B cells resulted in polyfunctional immune mediator activity that may contribute to viral replication and proliferation of target cell populations in HHV-8 related cancers. The importance of this work was demonstrated by the detection of B cell-produced cytokines and chemokines in HHV-8/HIV co-infected individuals who developed KS. This is the first extensive, multiparameter, longitudinal study of HHV-8 infection of B cells and immune mediators in development of KS. This study provides novel targets for vaccine development and treatment options for KS, which could have great implications on Public Health.
Share
| Citation/Export: |
|
| Social Networking: |
|
Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Knowlton, Emilee R. | erk21@pitt.edu | ERK21 | |
|
| ETD Committee: |
|
| Date: |
29 January 2013 |
| Date Type: |
Publication |
| Defense Date: |
4 December 2012 |
| Approval Date: |
29 January 2013 |
| Submission Date: |
19 November 2012 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
156 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Infectious Diseases and Microbiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
HHV-8, KSHV, B lymphocytes, Cytokines, Kaposi's Sarcoma, Dendritic Cells |
| Date Deposited: |
29 Jan 2013 22:22 |
| Last Modified: |
01 Jan 2018 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/16473 |
Metrics
Monthly Views for the past 3 years
Plum Analytics
Actions (login required)
 |
View Item |
![[img]](https://d-scholarship.pitt.edu/style/images/fileicons/application_vnd.ms-excel.png)
![[feed]](/images/feed-icon-32x32.png){kind=icon}