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Towards understanding plasmablast development in dengue virus infection

Dobbs, Andrea (2014) Towards understanding plasmablast development in dengue virus infection. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Dengue is a re-emerging global public health threat that over one-third of the world’s current population stands at risk of developing. Persistent upticks in climate warming, population growth and global transportation have the potential to spread the four dengue virus (DENV) serotypes to new geographical areas, thereby increasing the number of at-risk individuals. Annually 50 to 100 million dengue cases develop worldwide; approximately five hundred thousand of these cases degenerate into severe disease. In some instances, regions lacking the means to provide supportive therapy have experienced 40 percent case-fatality rates. The economic and global impacts of dengue remains unchallenged due to inadequate control measures and the absence of licensed vaccines. A more thorough understanding of DENV pathogenesis would open the door to designing the effective vaccine and antiviral drug candidates essential to the global health community’s efforts to control dengue. This thesis focuses on understanding a recently observed characteristic of DENV pathogenesis: four to seven days after disease onset, peripheral plasmablasts undergo a massive expansion. Relative to other heavily studied cell types, very little is known about the role plasmablasts play in the overall model of DENV pathogenesis. At the start of this project, it was unknown if this robust plasmablast response to DENV originated from the DENV specific memory B-cell subset or if it was driven by naïve B-cells. To facilitate investigation of the events relating to DENV-induced B-cell activation, peripheral blood mononuclear cells (PBMCs) were collected from healthy individuals with previous DENV exposures. Using an in vitro model, I showed that DENV was able to drive differentiation of DENV specific memory B-cells into DENV specific IgG secreting plasmablasts. After observing that DENV could drive a plasmablast response, I also demonstrated that monocytes, the primary target cells, played an important role in this plasmablast development. This work leads to the important conclusion that DENV is able to drive the differentiation of DENV specific memory B-cells into IgG secreting plasmablasts with the help of monocytes. However, it is unlikely that the secondary response mounted by this memory subset will be sufficient to produce the high percentage of plasmablasts seen in acute patients. These research findings are important in the ongoing effort to identify the early events essential for driving the robust plasmablast response observed during DENV infections


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Dobbs, Andreaakd32@pitt.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorBarratt-Boyes, Simon Msmbb@pitt.eduSMBB
Committee MemberKelly, Stefano Colestefcole@pitt.eduSTEFCOLE
Committee MemberErnesto , Marques Jrmarques@cvr.pitt.eduMARQUES
Date: 29 September 2014
Date Type: Publication
Defense Date: 17 July 2014
Approval Date: 29 September 2014
Submission Date: 22 July 2014
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 69
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: dengue virus, plasmablast, memory b-cells
Date Deposited: 29 Sep 2014 19:56
Last Modified: 01 Sep 2019 05:15
URI: http://d-scholarship.pitt.edu/id/eprint/22477

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