Please use this identifier to cite or link to this item:
http://hdl.handle.net/11375/27361
Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.advisor | Gillgrass, Amy | - |
dc.contributor.author | Lepard, Madeleine | - |
dc.date.accessioned | 2022-02-07T16:25:12Z | - |
dc.date.available | 2022-02-07T16:25:12Z | - |
dc.date.issued | 2022 | - |
dc.identifier.uri | http://hdl.handle.net/11375/27361 | - |
dc.description | Infection & Immunity | en_US |
dc.description.abstract | Currently, there are 38 million people living with human immunodeficiency virus (HIV-1) worldwide and there were 680,000 HIV-related deaths in 2020 alone. The greatest cause of mortality in people living with HIV (PLHIV) is infection with opportunistic pathogens such as tuberculosis (TB), which accounts for one third of HIV-related deaths. PLHIV are 20 times more susceptible to TB and co-infection leads to significantly worsened outcomes in terms of both diseases. Humanized mouse (hu-mouse) models, which possess human immune cells for HIV to infect, have been useful for HIV research. Our aim is to create hu- mouse models of HIV, TB and co-infection to investigate disease progression, immune responses, therapeutics, prevention and vaccination. NOD-Rag1null-IL2rgnull (NRG) mice are highly immunocompromised mice that are traditionally used to generate hu-mouse models. We are also developing NRG mice that are transgenic for human HLA-DR4 and HLA-A2 (DRAG-A2) and similar mice have been reported to have improved immune responses. NRG and DRAG-A2 mice were humanized with hematopoietic stem cells obtained from human umbilical cord blood. DRAG-A2 mice had significantly higher engraftment success rates (defined as the percentage of mice with >10% hCD45+) as well as higher overall CD45+ leukocyte, CD4+ T cell, CD19+ B cell and CD14+ monocyte reconstitution in the blood compared to huNRGs. huNRG mice were permissive to infection with JR-CSF or NL4.3-Bal-Env HIV-1 intravaginally or systemically. huDRAG-A2 mice were also infected intravaginally with NL4.3-Bal-Env HIV-1. huDRAG-A2 mice, but not huNRGs, produced HIV-specific IgG, indicating improved immune responses. huNRG mice were infected intranasally with mCherry-Erdman, YFP-H37Rv or H37Rv Mtb. huDRAG-A2 mice were also infected with H37Rv. Human immune cell involvement and human-like granuloma formation was observed using flow cytometry and immunohistopathology. These findings show that the DRAG-A2 model may be optimal for investigating HIV, TB and co-infection, which continue to be serious global health concerns. | en_US |
dc.language.iso | en | en_US |
dc.subject | HIV | en_US |
dc.subject | TB | en_US |
dc.subject | Humanized mice | en_US |
dc.subject | Co-infection | en_US |
dc.title | Developing and Utilizing a Next-Generation Humanized Mouse Model for Investigating HIV and Tuberculosis | en_US |
dc.type | Thesis | en_US |
dc.contributor.department | Medical Sciences | en_US |
dc.description.degreetype | Thesis | en_US |
dc.description.degree | Master of Science (MSc) | en_US |
dc.description.layabstract | Human immunodeficiency virus (HIV) and tuberculosis (TB) are infectious diseases that affect millions of people worldwide every year. The greatest cause of death in people living with HIV is co-infection with TB and HIV-positive individuals are much more likely to get TB. Humanized mouse (hu-mouse) models possess human immune cells for HIV to infect and are useful for studying HIV. Our goal is to create hu-mouse models of HIV, TB and HIV/TB co-infection that will allow us to study how these diseases interact. We are currently developing a traditional hu-mouse model (known as NRG), as well as an improved next-generation model (known as DRAG-A2) with a more functional immune system. Both models have been successfully infected with HIV or TB. Only DRAG-A2 mice were able to make antibodies against HIV. The improved DRAG-A2 model will enable future studies on HIV, TB and co-infection, which continue to be understudied global problems. | en_US |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
Lepard_Madeleine_finalsubmission2022January_M.Sc_MedicalSciences_Infection&Immunity.pdf | 2.8 MB | Adobe PDF | View/Open |
Items in MacSphere are protected by copyright, with all rights reserved, unless otherwise indicated.