Taddonio, Jocelyn M.
(2024)
Exploring Ancestry-Related Differences in Dengue Virus Infection in Human Skin.
Master's Thesis, University of Pittsburgh.
(Unpublished)
Abstract
Dengue is the most prevalent arboviral infection in the world, and the number of clinical cases and global spread are rising. Recent data have demonstrated a link between genetic ancestry and susceptibility to dengue virus (DENV) infection; individuals with European ancestry (EA) have a higher rate of infection and inflammatory response to dengue than those of African ancestry (AA). Immunofluorescence staining of skin – the site of dengue virus transmission – has illustrated differences in cytokine expression in EA and AA donors following infection ex vivo. Single nucleotide polymorphisms (SNPs) of various innate immune genes, including RXRA, have been associated with susceptibility to DENV infections and genetic ancestry. Retinoid X receptor alpha (RXRα) is known to promote proinflammatory responses by limiting interferon production and inducing inflammatory and chemokine gene expression. This inhibits host antiviral defenses, which makes the immune system more susceptible to viral infection. The possible role of RXRα in DENV infections is unknown, but it could influence the ancestry-related differences observed in immune responses to DENV infections. This study aims to examine RXRα expression in the epidermis, as well as identify the cells responsible for production of proinflammatory and antiviral cytokines during DENV infections. To investigate this, human skin explants donated by the University of Pittsburgh Medical Center (UPMC) were infected with DENV. Chemiluminescent western blotting and flow cytometry techniques were used to identify and quantify RXRα expression within infected cells. Full-thickness cell lysates (epidermal and dermal cells) suggested a difference in RXRα expression between ancestry donors 24-hours post infection, while epidermal cell lysates showed no protein difference. Interleukin-1β (IL-1β) and interferon alpha (IFNα) concentrations were measured by ELISA to evaluate cytokine production in response to infection. Secreted cytokines were not detectable by ELISA 24-hours post infection, while preliminary data for intercellular cytokine levels showed no difference in concentration. This project was unable to identify the epidermal cells responsible for cytokine production in response to DENV infections. By understanding ancestry-related differences in DENV infections and the forces which drive the immune responses, therapeutics can be developed to modulate these responses that increase risk of disease in susceptible populations.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
26 June 2024 |
| Date Type: |
Publication |
| Defense Date: |
6 June 2024 |
| Approval Date: |
26 June 2024 |
| Submission Date: |
21 June 2024 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
62 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Infectious Diseases and Microbiology |
| Degree: |
MS - Master of Science |
| Thesis Type: |
Master's Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
dengue, virus, DENV, infection, ancestry, innate immunity, immune response, RXRa, skin |
| Date Deposited: |
26 Jun 2024 19:54 |
| Last Modified: |
26 Jun 2024 19:54 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46601 |
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