Human Cytomegalovirus Induces Cellular and Humoral Virus-specific Immune Responses in Humanized BLT Mice

Abstract

The strict species specificity of Human Cytomegalovirus (HCMV) has impeded our understanding of antiviral adaptive immune responses in the context of a human immune system. We have previously shown that HCMV infection of human hematopoietic progenitor cells engrafted in immune deficient mice (huNSG) results in viral latency that can be reactivated following G-CSF treatment. In this study, we characterized the functional human adaptive immune responses in HCMV latently-infected huBLT (humanized Bone marrow-Liver-Thymus) mice. Following infection, huBLT mice generate human effector and central memory CD4+ and CD8+ T-cell responses reactive to peptides corresponding to both IE and pp65 proteins. Additionally, both HCMV specific IgM and IgG B-cell responses with the ability to neutralize virus were detected. These results indicate that the HCMV huBLT mouse model may provide a valuable tool to study viral latency and reactivation as well as evaluate HCMV vaccines and immune responses in the context of a functional human immune system.

A Hitchhiker's guide to humanized mice: new pathways to studying viral infections

“…Similarly, injection of recombinant human IL‐4 and GM‐CSF before tetanus toxoid immunization stimulates memory B‐cell clonal expansion, induces improved B‐cell class switching capacity and provokes increased total IgG, IgM and tetanus‐specific IgG responses (Table ). Additionally, humanized mouse models have been used for the study of antigen‐specific antibody responses to various infections …”

“…Additionally, humanized mouse models have been used for the study of antigen-specific antibody responses to various infections. 15,59 The addition of human Il6 gene knock-in has demonstrated improved haematopoiesis, class switching and a high frequency of somatic hypermutation. 26 Due to this, a further advancement of the MISTRG mouse was created, with the addition of the human Il6 by gene knock-in, resulting in the new MISTRG-6 strain.…”

Precision mouse models with expanded tropism for human pathogens

“…Although commonly used, inbred mouse strains do not faithfully recapitulate important aspects of human disease and the human immune response 10 . Furthermore, many human pathogens do not replicate in wild-type mice 1,5,[11][12][13][14][15][16][17][18][19][20][21] . The availability of highly immunodeficient mouse strains allows for the creation of human/ mouse chimeric models (humanized mice) that are locally or systemically reconstituted with human hematopoietic cells following engraftment of human tissues and/or stem cells.…”

“…The availability of highly immunodeficient mouse strains allows for the creation of human/ mouse chimeric models (humanized mice) that are locally or systemically reconstituted with human hematopoietic cells following engraftment of human tissues and/or stem cells. Humanized mice have been used to study human immune development and human-specific pathogens that replicate in human hematopoietic cells (for example, Epstein-Barr virus, dengue virus, human immunodeficiency virus, Kaposi's sarcoma herpesvirus) and to test the efficacy of preventative and therapeutic agents 5,[11][12][13][14][15][16][17][18][19]22,23 . Bone marrow/liver/thymus (BLT) humanized mice are generated by bone marrow transplantation of immunodeficient mice implanted with autologous human thymus/liver tissue.…”

Human immune system mouse models of Ebola virus infection

“…Despite limitations in some models, vaccine studies are currently being performed using HIS mice [47,48]. Furthermore, recent reports demonstrating virus-specific and neutralization-capable IgM and IgG responses supports the use of huBLT models in vaccines studies [49,50]. Development of HIS mouse models with advanced humoral immune function is a focus in the field.…”