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Cytokine and Chemokine Responses in Human Herpesvirus 8 Infection of Monocyte Derived Dendritic Cells and B Lymphocytes

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 (Unpublished)

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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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Knowlton, Emilee R.erk21@pitt.eduERK21
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRinaldo, Charlesrinaldo@pitt.eduRINALDO
Committee MemberJenkins, Frankfjenkins@pitt.eduFJENKINS
Committee MemberKalinski, Pawelpak5@pitt.eduPAK5
Committee MemberWang, Tianyitywang@pitt.eduTYWANG
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


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