A Human-Immune-System (HIS) humanized mouse model (DRAGA: HLA-A2. HLA-DR4. Rag1 KO.IL-2Rγc KO. NOD) for COVID-19

Brumeanu, Teodor‐D.; Vir, Pooja; Karim, Ahmad Faisal; Kar, Swagata; Benetiene, Dalia; Lok, Megan; Greenhouse, Jack; Putmon-Taylor, Tammy; Kitajewski, Christopher; Chung, Kevin K.; Pratt, Kathleen P.; Casares, Sofía

doi:10.21203/rs.3.rs-225156/v1

“…Humanized DRAGA mice DRAGA mice expressing transgenically HLA-A2.1 and HLA-DR0401 molecules on a Rag1KO.IL2RgcKO.NOD (NRG) background have been previously described (Wijayalath et al, 2014;Allam et al, 2015;Majji et al, 2016;Kim et al, 2017;Allam et al, 2018;Jiang et al, 2018;Majji et al, 2018;Mendoza et al, 2018Mendoza et al, , 2020Brumeanu et al, 2022;Ollerton et al, 2022). Mice were bred at the Veterinary Service Program at WRAIR/NMRC.…”

Section: Methodsmentioning

confidence: 99%

“…DRAGA mice infused with hHSCs from umbilical cord blood (thereafter termed as HIS-DRAGA) reconstitute functional human T and B cells and respond to vaccination by eliciting specific human cellular and antibody responses (Danner et al, 2011;Majji et al, 2016Majji et al, , 2018Mendoza et al, 2018;Ollerton et al, 2022). The HIS-DRAGA mice also reconstitute human epithelial and endothelial cells in the lung and other organs (Mendoza et al, 2020;Brumeanu et al, 2022) as well as human Kupffer cells and hepatocytes (Wijayalath et al, 2014), which allows to sustain infection with human pathogens including P. falciparum (Wijayalath et al, 2014;Majji et al, 2018), HIV (Allam et al, 2015;Kim et al, 2017;Allam et al, 2018;Ollerton et al, 2022), Orienta tsusugamushi (scrub typhus) (Jiang et al, 2018), influenza A (Mendoza et al, 2018(Mendoza et al, , 2020, SARS-CoV-2 (Brumeanu et al, 2022), and Zika virus (Yi et al, 2017). Herein, we have examined human cell reconstitution in the brain of HIS-DRAGA mice.…”

Section: Introductionmentioning

confidence: 99%

Reconstitution of human microglia and resident T cells in the brain of humanized DRAGA mice

Ghosh Roy,

Karim,

Brumeanu

et al. 2024

Front. Cell. Infect. Microbiol.

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Humanized mouse models are valuable tools for investigating the human immune system in response to infection and injury. We have previously described the human immune system (HIS)-DRAGA mice (HLA-A2.HLA-DR4.Rag1KO.IL-2RgKO.NOD) generated by infusion of Human Leukocyte Antigen (HLA)-matched, human hematopoietic stem cells from umbilical cord blood. By reconstituting human cells, the HIS-DRAGA mouse model has been utilized as a “surrogate in vivo human model” for infectious diseases such as Human Immunodeficiency Virus (HIV), Influenza, Coronavirus Disease 2019 (COVID-19), scrub typhus, and malaria. This humanized mouse model bypasses ethical concerns about the use of fetal tissues for the humanization of laboratory animals. Here in, we demonstrate the presence of human microglia and T cells in the brain of HIS-DRAGA mice. Microglia are brain-resident macrophages that play pivotal roles against pathogens and cerebral damage, whereas the brain-resident T cells provide surveillance and defense against infections. Our findings suggest that the HIS-DRAGA mouse model offers unique advantages for studying the functions of human microglia and T cells in the brain during infections, degenerative disorders, tumors, and trauma, as well as for testing therapeutics in these pathological conditions.

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“…Humanized DRAGA mice DRAGA mice expressing transgenically HLA-A2.1 and HLA-DR0401 molecules on a Rag1KO.IL2RgcKO.NOD (NRG) background have been previously described (Wijayalath et al, 2014;Allam et al, 2015;Majji et al, 2016;Kim et al, 2017;Allam et al, 2018;Jiang et al, 2018;Majji et al, 2018;Mendoza et al, 2018Mendoza et al, , 2020Brumeanu et al, 2022;Ollerton et al, 2022). Mice were bred at the Veterinary Service Program at WRAIR/NMRC.…”

Section: Methodsmentioning

confidence: 99%

“…DRAGA mice infused with hHSCs from umbilical cord blood (thereafter termed as HIS-DRAGA) reconstitute functional human T and B cells and respond to vaccination by eliciting specific human cellular and antibody responses (Danner et al, 2011;Majji et al, 2016Majji et al, , 2018Mendoza et al, 2018;Ollerton et al, 2022). The HIS-DRAGA mice also reconstitute human epithelial and endothelial cells in the lung and other organs (Mendoza et al, 2020;Brumeanu et al, 2022) as well as human Kupffer cells and hepatocytes (Wijayalath et al, 2014), which allows to sustain infection with human pathogens including P. falciparum (Wijayalath et al, 2014;Majji et al, 2018), HIV (Allam et al, 2015;Kim et al, 2017;Allam et al, 2018;Ollerton et al, 2022), Orienta tsusugamushi (scrub typhus) (Jiang et al, 2018), influenza A (Mendoza et al, 2018(Mendoza et al, , 2020, SARS-CoV-2 (Brumeanu et al, 2022), and Zika virus (Yi et al, 2017). Herein, we have examined human cell reconstitution in the brain of HIS-DRAGA mice.…”

Section: Introductionmentioning

confidence: 99%

Presentation_1.pptx

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Comparing Current and Next-Generation Humanized Mouse Models for Advancing HIV and HIV/Mtb Co-Infection Studies

Lepard

¹

,

Yang

²

,

Afkhami

³

et al. 2022

Viruses

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In people living with HIV, Mycobacterium tuberculosis (Mtb) is the major cause of death. Due to the increased morbidity/mortality in co-infection, further research is urgently required. A limiting factor to research in HIV and HIV/Mtb co-infection is the lack of accessible in vivo models. Next-generation humanized mice expressing HLA transgenes report improved human immune reconstitution and functionality, which may better recapitulate human disease. This study compares well-established huNRG mice and next-generation HLA I/II-transgenic (huDRAG-A2) mice for immune reconstitution, disease course, and pathology in HIV and TB. HuDRAG-A2 mice have improved engraftment of key immune cell types involved in HIV and TB disease. Upon intravaginal HIV-1 infection, both models developed significant HIV target cell depletion in the blood and tissues. Upon intranasal Mtb infection, both models sustained high bacterial load within the lungs and tissue dissemination. Some huDRAG-A2 granulomas appeared more classically organized, characterized by focal central necrosis, multinucleated giant cells, and foamy macrophages surrounded by a halo of CD4+ T cells. HIV/Mtb co-infection in huNRG mice trended towards worsened TB pathology and showed potential for modeling co-infection. Both huNRG and huDRAG-A2 mice are viable options for investigating HIV and TB, but the huDRAG-A2 model may offer advantages.

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A Human-Immune-System (HIS) humanized mouse model (DRAGA: HLA-A2. HLA-DR4. Rag1 KO.IL-2Rγc KO. NOD) for COVID-19

Cited by 3 publications

References 61 publications

Reconstitution of human microglia and resident T cells in the brain of humanized DRAGA mice

Reconstitution of human microglia and resident T cells in the brain of humanized DRAGA mice

Presentation_1.pptx

Comparing Current and Next-Generation Humanized Mouse Models for Advancing HIV and HIV/Mtb Co-Infection Studies

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