@article{6fc08c83de9d4d54b4cf24fbedcc5c4e,
title = "Human-Immune-System (HIS) humanized mouse model (DRAGA: HLA-A2.HLA-DR4.Rag1KO.IL-2RγcKO.NOD) for COVID-19",
abstract = "We report a Human Immune System (HIS)-humanized mouse model (“DRAGA”: HLA-A2.HLA-DR4.Rag1KO.IL-2 RγcKO.NOD) for COVID-19 research. DRAGA mice express transgenically HLA-class I and class-II molecules in the mouse thymus to promote human T cell development and human B cell Ig-class switching. When infused with human hematopoietic stem cells from cord blood reconstitute a functional human immune system, as well as human epi/endothelial cells in lung and upper respiratory airways expressing the human ACE2 receptor for SARS-CoV-2. The DRAGA mice were able to sustain SARS-CoV-2 infection for at least 25 days. Infected mice showed replicating virus in the lungs, deteriorating clinical condition, and human-like lung immunopathology including human lymphocyte infiltrates, microthrombi and pulmonary sequelae. Among the intra-alveolar and peri-bronchiolar lymphocyte infiltrates, human lung-resident (CD103+) CD8+ and CD4+ T cells were sequestered in epithelial (CD326+) lung niches and secreted granzyme B and perforin, suggesting anti-viral cytotoxic activity. Infected mice also mounted human IgG antibody responses to SARS-CoV-2 viral proteins. Hence, HIS-DRAGA mice showed unique advantages as a surrogate in vivo human model for studying SARS-CoV-2 immunopathological mechanisms and testing the safety and efficacy of candidate vaccines and therapeutics.",
keywords = "COVID-19, DRAGA mice, Human immune system, SARS-CoV-2, human antibodies, human lung-resident CD8 T cells, humanized mice, lung immunopathology",
author = "Brumeanu, {Teodor D.} and Pooja Vir and Karim, {Ahmad Faisal} and Swagata Kar and Dalia Benetiene and Megan Lok and Jack Greenhouse and Tammy Putmon-Taylor and Christopher Kitajewski and Chung, {Kevin K.} and Pratt, {Kathleen P.} and Casares, {Sofia A.}",
note = "Funding Information: This work was supported by the Department of Medicine, Sanford Endowment intramural funds under grant #312028-1.00-61517 (T-D.B. and K.P.P.), the Military Infectious Diseases Research Program #F0600_20_NM work unit number A1210 under grant #F0600_20_NM (S.A.C), and by the National Institutes of Health under grants #HL 130448, #HL 12767B, and the Collaborative Health Initiative Research Program at Uniformed Services University under grant # NHLBIIAAA-A-HL-007.001 (K.P.P). We thank Ms. Soumya Sashikumar for maintaining the DRAGA mice colony at NMRC and Dr. Cara Olsen at USUH for statistical analyses. T-D.B, KPP, KKC, and SAC are US Federal employees. The work of these individuals was prepared as part of official government duties. Title 17 U.S.C. §105 provides that “copyright protection under this title is not available for any work of the United States Government.” Title 17 U.S.C. §101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person{\textquoteright}s official duties. The views expressed are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of the Army, Department of Defense, nor the U.S. Government. Publisher Copyright: {\textcopyright} This work was authored as part of the Contributor{\textquoteright}s official duties as an Employee of the United States Government and is therefore a work of the United States Government. In accordance with 17 U.S.C. 105, no copyright protection is available for such works under U.S. Law.",
year = "2022",
doi = "10.1080/21645515.2022.2048622",
language = "English",
volume = "18",
journal = "Human Vaccines and Immunotherapeutics",
issn = "2164-5515",
number = "5",
}