scholarly journals Humanized Mouse Models for the Study of Hepatitis C and Host Interactions

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 604 ◽  
Author(s):  
Kylie Su Mei Yong ◽  
Zhisheng Her ◽  
Qingfeng Chen
Keyword(s):  
Hepatitis C ◽  
Drug Testing ◽  
Humanized Mice ◽  
In Vivo Studies ◽  
Mammalian Host ◽  
Humanized Mouse ◽  
Host Tropism ◽  
Host Interactions ◽  
Humanized Mouse Models

Hepatitis C virus (HCV) infection is commonly attributed as a major cause of chronic hepatotropic diseases, such as, steatosis, cirrhosis and hepatocellular carcinoma. As HCV infects only humans and primates, its narrow host tropism hampers in vivo studies of HCV-mammalian host interactions and the development of effective therapeutics and vaccines. In this context, we will focus our discussion on humanized mice in HCV research. Here, these humanized mice are defined as animal models that encompass either only human hepatocytes or both human liver and immune cells. Aspects related to immunopathogenesis, anti-viral interventions, drug testing and perspectives of these models for future HCV research will be discussed.

scholarly journals Perspectives on Non-BLT Humanized Mouse Models for Studying HIV Pathogenesis and Therapy

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 776
Author(s):  
Kazutaka Terahara ◽  
Ryutaro Iwabuchi ◽  
Yasuko Tsunetsugu-Yokota
Keyword(s):  
Mouse Models ◽  
Humanized Mice ◽  
Lymphoid Tissues ◽  
Humanized Mouse ◽  
Hiv Pathogenesis ◽  
Hematopoietic Stem ◽  
Critical Issues ◽  
In Vivo Animal Models ◽  
Humanized Mouse Models

A variety of humanized mice, which are reconstituted only with human hematopoietic stem cells (HSC) or with fetal thymus and HSCs, have been developed and widely utilized as in vivo animal models of HIV-1 infection. The models represent some aspects of HIV-mediated pathogenesis in humans and are useful for the evaluation of therapeutic regimens. However, there are several limitations in these models, including their incomplete immune responses and poor distribution of human cells to the secondary lymphoid tissues. These limitations are common in many humanized mouse models and are critical issues that need to be addressed. As distinct defects exist in each model, we need to be cautious about the experimental design and interpretation of the outcomes obtained using humanized mice. Considering this point, we mainly characterize the current conventional humanized mouse reconstituted only with HSCs and describe past achievements in this area, as well as the potential contributions of the humanized mouse models for the study of HIV pathogenesis and therapy. We also discuss the use of various technologies to solve the current problems. Humanized mice will contribute not only to the pre-clinical evaluation of anti-HIV regimens, but also to a deeper understanding of basic aspects of HIV biology.

scholarly journals Exploiting species specificity to understand the tropism of a human-specific toxin

2020 ◽  
Vol 6 (11) ◽  
pp. eaax7515 ◽  
Author(s):  
K. M. Boguslawski ◽  
A. N. McKeown ◽  
C. J. Day ◽  
K. A. Lacey ◽  
K. Tam ◽  
...  
Keyword(s):  
Virulence Factors ◽  
Gene Editing ◽  
Humanized Mice ◽  
In Vivo Studies ◽  
Humanized Mouse ◽  
Toxin Binding ◽  
Biochemical Studies ◽  
Specific Virulence ◽  
Human Specific

Many pathogens produce virulence factors that are specific toward their natural host. Clinically relevant methicillin-resistant Staphylococcus aureus (MRSA) isolates are highly adapted to humans and produce an array of human-specific virulence factors. One such factor is LukAB, a recently identified pore-forming toxin that targets human phagocytes by binding to the integrin component CD11b. LukAB exhibits strong tropism toward human, but not murine, CD11b. Here, phylogenetics and biochemical studies lead to the identification of an 11-residue domain required for the specificity of LukAB toward human CD11b, which is sufficient to render murine CD11b compatible with toxin binding. CRISPR-mediated gene editing was used to replace this domain, resulting in a “humanized” mouse. In vivo studies revealed that the humanized mice exhibit enhanced susceptibility to MRSA bloodstream infection, a phenotype mediated by LukAB. Thus, these studies establish LukAB as an important toxin for MRSA bacteremia and describe a new mouse model to study MRSA pathobiology.

scholarly journals Development of an Inflammatory CD14+ Dendritic Cell Subset in Humanized Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Ryutaro Iwabuchi ◽  
Keigo Ide ◽  
Kazutaka Terahara ◽  
Ryota Wagatsuma ◽  
Rieko Iwaki ◽  
...  
Keyword(s):  
Mouse Models ◽  
Cell Subset ◽  
Experimental Models ◽  
Transcriptional Analysis ◽  
Humanized Mice ◽  
Dendritic Cell Subset ◽  
Humanized Mouse ◽  
Gm Csf ◽  
Humanized Mouse Models

Humanized mouse models are attractive experimental models for analyzing the development and functions of human dendritic cells (DCs) in vivo. Although various types of DC subsets, including DC type 3 (DC3s), have been identified in humans, it remains unclear whether humanized mice can reproduce heterogeneous DC subsets. CD14, classically known as a monocyte/macrophage marker, is reported as an indicator of DC3s. We previously observed that some CD14+ myeloid cells expressed CD1c, a pan marker for bona fide conventional DC2 (cDC2s), in humanized mouse models in which human FLT3L and GM-CSF genes were transiently expressed using in vivo transfection (IVT). Here, we aimed to elucidate the identity of CD14+CD1c+ DC-like cells in humanized mouse models. We found that CD14+CD1c+ cells were phenotypically different from cDC2s; CD14+CD1c+ cells expressed CD163 but not CD5, whereas cDC2s expressed CD5 but not CD163. Furthermore, CD14+CD1c+ cells primed and polarized naïve CD4+ T cells toward IFN-γ+ Th1 cells more profoundly than cDC2s. Transcriptional analysis revealed that CD14+CD1c+ cells expressed several DC3-specific transcripts, such as CD163, S100A8, and S100A9, and were clearly segregated from cDC2s and monocytes. When lipopolysaccharide was administered to the humanized mice, the frequency of CD14+CD1c+ cells producing IL-6 and TNF-α was elevated, indicating a pro-inflammatory signature. Thus, humanized mice are able to sustain development of functional CD14+CD1c+ DCs, which are equivalent to DC3 subset observed in humans, and they could be useful for analyzing the development and function of DC3s in vivo.

scholarly journals HUMANIZED MICE: CREATION, MODELS AND USE IN EXPERIMENTAL ONCOLOGY (REVIEW)

Biomeditsina ◽  
2019 ◽  
pp. 67-81
Author(s):  
O. I. Kit ◽  
A. Yu. Maksimov ◽  
T. P. Protasova ◽  
A. S. Goncharova ◽  
D. S. Kutilin ◽  
...  
Keyword(s):  
Cancer Biology ◽  
Human Cancer ◽  
Transgenic Animals ◽  
Humanized Mice ◽  
Humanized Mouse ◽  
Antitumour Agents ◽  
Human Genes ◽  
Oncology Review ◽  
Wide Range ◽  
Humanized Mouse Models

Research laboratories in various countries are constantly endeavouring to improve the existing and to create new biological objects to simulate various human diseases. Immunodefi cient mice with transplanted human functional cells and tissues, as well as transgenic animals with the relevant human genes integrated in their genome — i. e. humanized mice — are increasingly used as test systems in biomedical studies. Humanized mouse models are constantly being improved to fi nd application in studies investigating human biological reactions and identifying the pathogenetic mechanisms behind a wide range of diseases, or as preclinical tools for medicine testing. In particular, such animals play an increasingly important role both in studies of human-specifi c infectious agents, cancer biology research and in the development of new antitumour agents. In addition, humanized mice are increasingly used as translational models in many areas of clinical research, including transplantology, immunology and oncology. Ultimately, the use of humanized animals can lead to the introduction of a truly personalized medicine into clinical practice. In this review, we discuss modern advances in the creation and use of humanized mice, emphasizing their usefulness for the pathogenesis study, as well as the development of new methods for human cancer treatment.

scholarly journals HSC extrinsic sex-related and intrinsic autoimmune disease–related human B-cell variation is recapitulated in humanized mice

2017 ◽  
Vol 1 (23) ◽  
pp. 2007-2018 ◽  
Author(s):  
Chiara Borsotti ◽  
Nichole M. Danzl ◽  
Grace Nauman ◽  
Markus A. Hölzl ◽  
Clare French ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Autoimmune Disease ◽  
B Cell ◽  
Humanized Mice ◽  
Male Mice ◽  
Humanized Mouse ◽  
Key Points ◽  
Humanized Mouse Models ◽  
Cell Variation ◽  
Human B Cell

Key Points Increased human B-cell reconstitution is seen in female compared to male mice in multiple humanized mouse models. The PI mouse model recapitulates HSC-intrinsic autoimmune defects from T1D and RA bone marrow donors.

scholarly journals Human hematopoietic stem cell maintenance and myeloid cell development in next-generation humanized mouse models

2019 ◽  
Vol 3 (3) ◽  
pp. 268-274 ◽  
Author(s):  
Trisha R. Sippel ◽  
Stefan Radtke ◽  
Tayla M. Olsen ◽  
Hans-Peter Kiem ◽  
Anthony Rongvaux
Keyword(s):  
Myeloid Cell ◽  
Humanized Mice ◽  
Next Generation ◽  
Humanized Mouse ◽  
Hematopoietic Stem ◽  
Stem Cell Maintenance ◽  
Key Points ◽  
Humanized Mouse Models ◽  
Cell Maintenance

Key Points Next-generation humanized mice differentially support human HSPC maintenance and myelopoiesis. MISTRG mice support long-term human HSPC maintenance demonstrated by quaternary transplantation and development of human tissue macrophages.

In Vivo Efficacy of Bcl11a Erythroid-Enhancer Deletion in Humanized Mouse Models of Anemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2465-2465 ◽  
Author(s):  
Thomas M Ryan ◽  
Suean Daimia Fontenard ◽  
Shanrun Liu ◽  
Jonathan Lockhart ◽  
Michael Berlett
Keyword(s):  
Mouse Models ◽  
Fetal Hemoglobin ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Globin Genes ◽  
Humanized Mouse ◽  
Gamma Globin ◽  
Hemoglobin Switching ◽  
Humanized Mouse Models

Abstract Autologous cell therapy holds great promise for the treatment of beta thalassemia major and hemoglobinopathies like sickle cell anemia. Gene editing of a patient's own stem cells to reactivate the silenced gamma globin gene is one approach under active development. Prior to directly testing these new therapies in patients, we can answer some basic questions about their in vivo efficiency and efficacy in humanized mouse models of anemia. These models have their endogenous adult alpha and beta globin genes replaced with human alpha, gamma, and beta globin genes. These mice synthesize high level of human fetal hemoglobin during fetal life and complete their fetal-to-adult hemoglobin switch after birth. Experimental strategies designed to reactivate the silenced fetal gamma globin genes in adult erythroid cells are easily tested in vivo in these humanized hemoglobin switching mouse models. The silenced human fetal gamma globin genes can be activated by mutating the erythroid-specific enhancer of Bcl11a by gene editing. CRISPR sgRNAs, designed to target the +62 kb DNase I hypersensitive site in the second intron of Bcl11a, were microinjected along with Cas9 mRNA, into fertilized mouse embryos collected from humanized hemoglobin (Hb A) mice. The indel mutations that were generated in the founder animals were characterized and bred to homozygosity. The data demonstrates that the sgRNAs tested were successful in creating multiple unique mutations at the erythroid enhancer target sites. These mutations were transmitted through the germline allowing the effect of individual edited alleles to be analyzed. The majority of the mutations showed marginal increases in the number of F-cells over control animals. Significantly, despite having homozygous mutation of the erythroid-enhancer in all cells, fetal hemoglobin expression remains heterocellular. Importantly, the therapeutic efficacy of reactivating fetal hemoglobin with specific Bcl11a erythroid-enhancer mutations for the treatment of beta thalassemia major and sickle cell anemia was directly measured in vivo in these humanized models of disease. The reactivation of gamma globin in these humanized mouse models provides us with an opportunity to further interrogate the Bcl11a enhancer element, identify additional factors involved in hemoglobin switching and elucidate the mechanism driving pancellular vs heterocellular fetal hemoglobin expression. Disclosures No relevant conflicts of interest to declare.

scholarly journals Humanized Mouse Models for the Advancement of Innate Lymphoid Cell-Based Cancer Immunotherapies

2021 ◽  
Vol 12 ◽  
Author(s):  
Nina B. Horowitz ◽  
Imran Mohammad ◽  
Uriel Y. Moreno-Nieves ◽  
Ievgen Koliesnik ◽  
Quan Tran ◽  
...  
Keyword(s):  
Nk Cells ◽  
Mouse Models ◽  
Human Cell Line ◽  
Lymphoid Cells ◽  
Humanized Mouse ◽  
Cancer Treatments ◽  
Human Genes ◽  
Humanized Mouse Models ◽  
And Behavior

Innate lymphoid cells (ILCs) are a branch of the immune system that consists of diverse circulating and tissue-resident cells, which carry out functions including homeostasis and antitumor immunity. The development and behavior of human natural killer (NK) cells and other ILCs in the context of cancer is still incompletely understood. Since NK cells and Group 1 and 2 ILCs are known to be important for mediating antitumor immune responses, a clearer understanding of these processes is critical for improving cancer treatments and understanding tumor immunology as a whole. Unfortunately, there are some major differences in ILC differentiation and effector function pathways between humans and mice. To this end, mice bearing patient-derived xenografts or human cell line-derived tumors alongside human genes or human immune cells represent an excellent tool for studying these pathways in vivo. Recent advancements in humanized mice enable unparalleled insights into complex tumor-ILC interactions. In this review, we discuss ILC behavior in the context of cancer, the humanized mouse models that are most commonly employed in cancer research and their optimization for studying ILCs, current approaches to manipulating human ILCs for antitumor activity, and the relative utility of various mouse models for the development and assessment of these ILC-related immunotherapies.

scholarly journals Modelling of human herpesvirus infections in humanized mice

2014 ◽  
Vol 95 (10) ◽  
pp. 2106-2117 ◽  
Author(s):  
Bradford K. Berges ◽  
Anne Tanner
Keyword(s):  
Mouse Models ◽  
Immune Cells ◽  
Human Herpesvirus ◽  
Antiviral Drugs ◽  
Humanized Mice ◽  
Great Promise ◽  
Humanized Mouse ◽  
Herpes Simplex Viruses ◽  
Human Immune ◽  
Humanized Mouse Models

The human herpesviruses (HHVs) are remarkably successful human pathogens, with some members of the family successfully establishing infection in the vast majority of humans worldwide. Although many HHV infections result in asymptomatic infection or mild disease, there are rare cases of severe disease and death found with nearly every HHV. Many of the pathogenic mechanisms of these viruses are poorly understood, and in many cases, effective antiviral drugs are lacking. Only a single vaccine exists for the HHVs and researchers have been unable to develop treatments to cure the persistent infections associated with HHVs. A major hindrance to HHV research has been the lack of suitable animal models, with the notable exception of the herpes simplex viruses. One promising area for HHV research is the use of humanized mouse models, in which human cells or tissues are transplanted into immunodeficient mice. Current humanized mouse models mostly transplant human haematopoietic stem cells (HSCs), resulting in the production of a variety of human immune cells. Although all HHVs are thought to infect human immune cells, the beta- and gammaherpesviruses extensively infect and establish latency in these cells. Thus, mice humanized with HSCs hold great promise to study these herpesviruses. In this review, we provide a historical perspective on the use of both older and newer humanized mouse models to study HHV infections. The focus is on current developments in using humanized mice to study mechanisms of HHV-induced pathogenesis, human immune responses to HHVs and effectiveness of antiviral drugs.

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