Human-like NSG mouse glycoproteins sialylation pattern changes the phenotype of human lymphocytes and sensitivity to HIV-1 infection.
Raghubendra Singh Dagur, Amanda Branch-Woods, Saumi Mathews, Poonam S Joshi, Rolen M Quadros, Donald W Harms, Yan Cheng, Shana M Miles, Samuel J Pirruccello, Channabasavaiah B Gurumurthy, Santhi Gorantla, Larisa Y Poluektova
Author Information
Raghubendra Singh Dagur: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Amanda Branch-Woods: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Saumi Mathews: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Poonam S Joshi: Mouse Genome Engineering Core Facility, Vice Chancellor for Research Office, Omaha, NE, USA.
Rolen M Quadros: Mouse Genome Engineering Core Facility, Vice Chancellor for Research Office, Omaha, NE, USA.
Donald W Harms: Mouse Genome Engineering Core Facility, Vice Chancellor for Research Office, Omaha, NE, USA.
Yan Cheng: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Shana M Miles: Bellevue Medical Center, Bellevue, NE, USA.
Samuel J Pirruccello: Department of Pathology and Microbiology, Omaha, NE, USA.
Channabasavaiah B Gurumurthy: Mouse Genome Engineering Core Facility, Vice Chancellor for Research Office, Omaha, NE, USA.
Santhi Gorantla: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Larisa Y Poluektova: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA. lpoluekt@unmc.edu. ORCID
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 (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.
