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

Autor: Dagur RS; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Branch-Woods A; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Mathews S; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Joshi PS; Mouse Genome Engineering Core Facility, Vice Chancellor for Research Office, Omaha, NE, USA., Quadros RM; Mouse Genome Engineering Core Facility, Vice Chancellor for Research Office, Omaha, NE, USA., Harms DW; Mouse Genome Engineering Core Facility, Vice Chancellor for Research Office, Omaha, NE, USA., Cheng Y; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Miles SM; Bellevue Medical Center, Bellevue, NE, USA., Pirruccello SJ; Department of Pathology and Microbiology, Omaha, NE, USA., Gurumurthy CB; Mouse Genome Engineering Core Facility, Vice Chancellor for Research Office, Omaha, NE, USA.; Developmental Neuroscience, Munroe Meyer Institute for Genetics and Rehabilitation, of University of Nebraska Medical Center, Omaha, NE, USA., Gorantla S; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Poluektova LY; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA. lpoluekt@unmc.edu.
Jazyk: angličtina
Zdroj: BMC immunology [BMC Immunol] 2019 Jan 07; Vol. 20 (1), pp. 2. Date of Electronic Publication: 2019 Jan 07.
DOI: 10.1186/s12865-018-0279-3
Abstrakt: Background: 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.
Results: We mutated mouse CMAH in the NOD/scid-IL2Rγ c -/- (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.
Conclusion: 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.
Databáze: MEDLINE
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