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http://hdl.handle.net/11375/27675
Title: | Investigating Immune Responses and Pathology During HIV/Mtb Co-Infection Within Humanized Mice |
Authors: | Yang, Jack (Xiaozhi) |
Advisor: | Gillgrass, Amy |
Department: | Medical Sciences (Molecular Virology and Immunology Program) |
Keywords: | HIV;TB;humanized mouse models;co-infection;granuloma;TB vaccine;HIV/TB co-infection pre-clinical model;in vivo HIV/TB co-infection |
Publication Date: | 2022 |
Abstract: | There are an estimated 2 billion individuals infected with Mtb, and 37.7 million people living with HIV (PLWH) worldwide. HIV/Mtb co-infection increases the risk of developing active tuberculosis by over 20-fold, and 210,000 of 1.5 million deaths from TB were among co-infected PLWH in 2020. Therefore, development of effective TB vaccination, particularly within the vulnerable PLWH population, is an urgent global issue. With limited in vivo models to study co-infection, humanized NRG (huNRG) mice and humanized DRAG-A2 mice (a next-generation of huNRG mice expressing HLA class I and II transgenes with improved human immune reconstitution, huDRAG-A2) are promising tools for HIV and TB reserach as they develop robust human immune cell populations and recapitulate many aspects of HIV or TB clinical disease. HIV/Mtb co-infection was investigated using huNRG and hu-DRAG-A2 mice in separate experiments where intravaginal (with DMPA pre-treatment) or intraperitoneal HIV-1 infection was administered, respectively, and intranasal infection of Mtb was administered 3.5 weeks later. Both huNRG and huDRAG-A2 mice recapitulated hallmark features of HIV/Mtb co-infection such as severe granuloma pathology, hCD4+ T cell depletion in lung and spleen tissue, and human like lung pathology such as Mtb-infected foamy macrophages in the granuloma. Co-infected huDRAG-A2 mice also displayed significantly higher bacterial burden in the lungs, increased extrapulmonary dissemination into spleen and liver, and significantly lower hCD4+ T cells in the peripheral blood post-Mtb infection when compared to the Mtb-only infected group. To investigate TB vaccine immunogenicity, huNRG and huDRAG-A2 mice were immunized with a novel trivalent vaccine, AdCh68MV. Upon intranasal immunization, both models showed trends of developing higher Mtb antigen-specific hCD4+ T cell responses in the lung and spleen. Overall, this project sets the initial stages of a pre-clinical HIV/Mtb co-infection model in huNRG and huDRAG-A2 mice appropriate for immune investigations, therapeutic and vaccination development. |
URI: | http://hdl.handle.net/11375/27675 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Yang_Jack(Xiaozhi)_2022June_MSc.pdf | 6.81 MB | Adobe PDF | View/Open |
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