Humanized DRAGA mice immunized with Plasmodium falciparum sporozoites and chloroquine elicit protective pre-erythrocytic immunity

Majji, Sai; Wijayalath, Wathsala; Shashikumar, Soumya; Brumeanu, Teodor‐D.; Casares, Sofía

doi:10.1186/s12936-018-2264-y

Cited by 18 publications

(30 citation statements)

References 43 publications

(76 reference statements)

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“…DRAGA mice express HLA-A2.1 and HLA-DR0401 molecules on a Rag1KO.IL2RγcKO.NOD (NRG) background, and they have been described previously [52][53][54][55] . HLA-A2.…”

Section: His-reconstitution Of Draga Micementioning

confidence: 99%

“…Technologies, Vancouver, BC, Canada) containing approximately 10 5 human HSC (CD34 + ) as measured by FACS using a mouse anti-human CD34 antibody (BD Biosciences, San Jose, CA, USA) as described [49][50][51][52][53][54] . The procedures for assessing human T and B cell reconstitution in peripheral blood by FACS have been described [49][50][51][52]72 . As documented in our previous studies, >90% of DRAGA mice are fully reconstituted.…”

Section: His-reconstitution Of Draga Micementioning

confidence: 99%

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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

Brumeanu

Vir

Shashikumar

et al. 2020

Preprint

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The current SARS-CoV-2 pandemic is accompanied by high morbidity and mortality rates, and there is a compelling need for effective vaccines and therapeutic agents to lessen the severity of COVID-19 disease. Appropriate animal models are essential for testing of vaccines and therapeutics and for mechanistic studies of infection and the host response. The Spike (S) protein of SARS-COV-2 has a high affinity for the human ACE2 receptor, which is expressed on multiple cell types including alveolar epithelial and vascular endothelial cells. Wild-type mice are not susceptible to developing coronavirus-mediated diseases. Accordingly, several human (h)ACE2 transgenic mouse models have been developed for coronavirus research. However, these mice have failed to closely mimic important aspects of the human immunopathological responses to SARS-CoV-2. We report herein that DRAGA (HLA-A2.HLA-DR4.Rag1KO.IL-2R. gammac KO.NOD) mice infused with human hematopoietic stem cells from cord blood reconstitute a fully functional human immune system, as well as engraft human epithelial and endothelial cells, sustain SARS-CoV-2 infection, and develop severe COVID-19-like symptoms. In pilot experiments, infected mice developed parenchymal and epithelial lung infiltrations with granzyme B+ and perforin+ CD8+ T cells and alveolar CD61+ microthrombi, mimicking human immunopathological responses to SARS-CoV-2. We propose the DRAGA mouse as a novel pre-clinical tool for studying COVID-19 immunopathology and human immune responses to SARS-CoV-2, including events leading to the cytokine storm and coagulopathies, as well as for testing of candidate vaccines and therapeutics.

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“…DRAGA mice express HLA-A2.1 and HLA-DR0401 molecules on a Rag1KO.IL2RγcKO.NOD (NRG) background, and they have been described previously [52][53][54][55] . HLA-A2.…”

Section: His-reconstitution Of Draga Micementioning

confidence: 99%

Section: His-reconstitution Of Draga Micementioning

confidence: 99%

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

Brumeanu

Vir

Shashikumar

et al. 2020

Preprint

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“…With respect to T cell responses, this work has largely been limited to either HLA transgenic humanized mice that universally express HLA-A*02 or to the BLT humanized mice used in this study. These studies have demonstrated the ability to induce T cell responses following infection with live or inactivated microbes (43,44,114) or through delivery of protein or peptide antigens (115,116). Here, we build on these results by demonstrating that the engrafted human immune system in BLT mice is also responsive to immunization that can accelerate the development of functional antigen-specific responses able to mediate control of HIV-1.…”

Section: Figmentioning

confidence: 87%

“…To date, a number of studies have demonstrated with varying success the ability to immunize different humanized mouse models and induce humoral and cellular immunity (30,43,44,(110)(111)(112)(113)(114)(115)(116). With respect to T cell responses, this work has largely been limited to either HLA transgenic humanized mice that universally express HLA-A*02 or to the BLT humanized mice used in this study.…”

Section: Figmentioning

confidence: 99%

Immunization of BLT Humanized Mice Redirects T Cell Responses to Gag and Reduces Acute HIV-1 Viremia

Claiborne

Dudek

Maldini

et al. 2019

J Virol

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BLT (bone marrow-liver-thymus) humanized mice, which reconstitute a functional human immune system, develop prototypic human virus-specific CD8+ T cell responses following infection with human immunodeficiency virus type 1 (HIV-1). We explored the utility of the BLT model for HIV-1 vaccine development by immunizing BLT mice against the conserved viral Gag protein, utilizing a rapid prime-boost protocol of poly(lactic-co-glycolic) acid microparticles and a replication-defective herpes simplex virus (HSV) recombinant vector. After HIV-1 challenge, the mice developed broad, proteome-wide gamma interferon-positive (IFN-γ+) T cell responses against HIV-1 that reached magnitudes equivalent to what is observed in HIV-1-infected individuals. The functionality of these responses was underscored by the consistent emergence of escape mutations in multiple CD8+ T cell epitopes during the course of infection. Although prechallenge vaccine-induced responses were largely undetectable, the Gag immunization increased both the magnitude and the kinetics of anamnestic Gag-specific T cell responses following HIV-1 infection, and the magnitude of these postchallenge Gag-specific responses was inversely correlated with acute HIV-1 viremia. Indeed, Gag immunization was associated with a modest but significant 0.5-log reduction in HIV-1 viral load when analyzed across four experimental groups of BLT mice. Notably, the HSV vector induced elevated plasma concentrations of polarizing cytokines and chemotactic factors, including interleukin-12p70 (IL-12p70) and MIP-1α, which were positively correlated with the magnitude of Gag-specific responses. Overall, these results support the ability of BLT mice to recapitulate human pathogen-specific T cell responses and to respond to immunization; however, additional improvements to the model are required to develop a robust system for testing HIV-1 vaccine efficacy. IMPORTANCE Advances in the development of humanized mice have raised the possibility of a small-animal model for preclinical testing of an HIV-1 vaccine. Here, we describe the capacity of BLT humanized mice to mount broadly directed HIV-1-specific human T cell responses that are functionally active, as indicated by the rapid emergence of viral escape mutations. Although immunization of BLT mice with the conserved viral Gag protein did not result in detectable prechallenge responses, it did increase the magnitude and kinetics of postchallenge Gag-specific T cell responses, which was associated with a modest but significant reduction in acute HIV-1 viremia. Additionally, the BLT model revealed immunization-associated increases in the plasma concentrations of immunomodulatory cytokines and chemokines that correlated with more robust T cell responses. These data support the potential utility of the BLT humanized mouse for HIV-1 vaccine development but suggest that additional improvements to the model are warranted.

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“…Earlier generations of human immune system humanized mice showed poor ability to support reconstitution and development of functional human T cells or B cells that are able to secrete IgG ( 17 ). With the introduction of HLA transgenes in the Rag1KO.IL2RγcKO.NOD (NRG) background, the DRAG mice (HLA-DR4.Rag1KO.IL2RγcKO.NOD), and DRAGA mice (HLA-A2.HLA-DR4.Rag1KO.IL2RγcKO.NOD) infused with HLA-matched human hematopoietic stem cells (HSC) have been shown to repopulate the mouse thymus and to reconstitute functional human T cells that support human B cell immunoglobulin class switching and secretion of human IgG ( 18 – 24 ). These mice have been used successfully for supporting infection with human pathogens, such as Plasmodium falciparum (malaria), HIV, Zika, and influenza A virus, and for analyzing human immune responses upon infection or vaccination ( 20 – 25 ).…”

Section: Introductionmentioning

confidence: 99%

Dissemination of Orientia tsutsugamushi, a Causative Agent of Scrub Typhus, and Immunological Responses in the Humanized DRAGA Mouse

et al. 2018

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Scrub typhus is caused by Orientia tsutsugamushi, an obligated intracellular bacterium that affects over one million people per year. Several mouse models have been used to study its pathogenesis, disease immunology, and for testing vaccine candidates. However, due to the intrinsic differences between the immune systems in mouse and human, these mouse models could not faithfully mimic the pathology and immunological responses developed by human patients, limiting their value in both basic and translational studies. In this study, we have tested for the first time, a new humanized mouse model through footpad inoculation of O. tsutsugamushi in DRAGA (HLA-A2.HLA-DR4.Rag1KO.IL2RγcKO.NOD) mice with their human immune system reconstituted by infusion of HLA-matched human hematopoietic stem cells from umbilical cord blood. Upon infection, Orientia disseminated into various organs of DRAGA mice resulted in lethality in a dose-dependent manner, while all C3H/HeJ mice infected by the same route survived. Tissue-specific lesions associated with inflammation and/or necroses were observed in multiple organs of infected DRAGA mice. Consistent with the intracellular nature of Orientia, strong Th1, but subdued Th2 responses were elicited as reflected by the human cytokine profiles in sera from infected mice. Interestingly, the percentage of both activated and regulatory (CD4+FOXP3+) human T cells were elevated in spleen tissues of infected mice. After immunization with irradiated whole cell Orientia, humanized DRAGA mice showed a significant activation of human T cells as evidenced by increased number of human CD4+ and CD8+ T cells. Specific human IgM and IgG antibodies were developed after repetitive immunization. The humanized DRAGA mouse model represents a new pre-clinical model for studying Orientia-human interactions and also for testing vaccines and novel therapeutics for scrub typhus.

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Humanized DRAGA mice immunized with Plasmodium falciparum sporozoites and chloroquine elicit protective pre-erythrocytic immunity

Cited by 18 publications

References 43 publications

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

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

Immunization of BLT Humanized Mice Redirects T Cell Responses to Gag and Reduces Acute HIV-1 Viremia

Dissemination of Orientia tsutsugamushi, a Causative Agent of Scrub Typhus, and Immunological Responses in the Humanized DRAGA Mouse

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