Human-like NSG mouse glycoproteins sialylation pattern changes the phenotype of human lymphocytes and sensitivity to HIV-1 infection

• Published in: BMC immunology 2019-01, Vol.20 (1), p.2-2, Article 2
• Main Authors: Dagur, Raghubendra Singh, Branch-Woods, Amanda, Mathews, Saumi, Joshi, Poonam S, Quadros, Rolen M, Harms, Donald W, Cheng, Yan, Miles, Shana M, Pirruccello, Samuel J, Gurumurthy, Channabasavaiah B, Gorantla, Santhi, Poluektova, Larisa Y
• Format: Article
• Language: English
• Subjects: Acids; Age; Analysis; Animal models; Animals; Antibodies; B cells; Bone marrow; Care and treatment; Cell culture; Cell proliferation; Cells (Biology); CMP-N-acetylneuraminic acid hydroxylase; Communicable diseases; CRISPR; CRISPR-Cas Systems; Disease Models, Animal; Genes; Genetic Loci; Genotype & phenotype; Glycoproteins; Glycoproteins - metabolism; Health aspects; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hematopoietic Stem Cells - immunology; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - virology; HIV; HIV infections; HIV Infections - genetics; HIV Infections - immunology; HIV Infections - metabolism; HIV Infections - virology; HIV-1; Human immunodeficiency virus; Hydroxylase; Immune clearance; Immune system; Immune System - cytology; Immune System - immunology; Immune System - metabolism; Immunodeficiency; Immunoglobulins; Immunologic research; Immunophenotyping; Infectious diseases; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Lymphocytes; Lymphocytes - immunology; Lymphocytes - metabolism; Lymphocytes - virology; Lymphocytes B; Mammals; Medical research; Mice; Mice, Knockout; Mutation; N-Acetylneuraminic acid; NOD/scid-IL2Rγc −/− mice; Pathogens; Peripheral blood; Phenotype; Phenotypes; Physiological aspects; Proteins; Sialic acids; Spleen; Stem cell transplantation; Stem cells; Surgery; Vectors (Biology)
• ISSN: 1471-2172; 1471-2172
• DOI: 10.1186/s12865-018-0279-3

The use of immunodeficient mice transplanted with human hematopoietic stem cells is an accepted approach to study human-specific infectious diseases such as HIV-1 and to investigate multiple aspects of human immune system development. However, mouse and human are different in sialylation patterns of proteins due to evolutionary mutations of the CMP-N-acetylneuraminic acid hydroxylase (CMAH) gene that prevent formation of N-glycolylneuraminic acid from N-acetylneuraminic acid. How changes in the mouse glycoproteins' chemistry affect phenotype and function of transplanted human hematopoietic stem cells and mature human immune cells in the course of HIV-1 infection are not known. We mutated mouse CMAH in the NOD/scid-IL2Rγ (NSG) mouse strain, which is widely used for the transplantation of human cells, using the CRISPR/Cas9 system. The new strain provides a better environment for human immune cells. Transplantation of human hematopoietic stem cells leads to broad B cells repertoire, higher sensitivity to HIV-1 infection, and enhanced proliferation of transplanted peripheral blood lymphocytes. The mice showed no effect on the clearance of human immunoglobulins and enhanced transduction efficiency of recombinant adeno-associated viral vector rAAV2/DJ8. NSG-cmah mice expand the mouse models suitable for human cells transplantation, and this new model has advantages in generating a human B cell repertoire. This strain is suitable to study different aspects of the human immune system development, provide advantages in patient-derived tissue and cell transplantation, and could allow studies of viral vectors and infectious agents that are sensitive to human-like sialylation of mouse glycoproteins.