TY - JOUR
T1 - Human-like NSG mouse glycoproteins sialylation pattern changes the phenotype of human lymphocytes and sensitivity to HIV-1 infection
AU - Dagur, Raghubendra Singh
AU - Branch-Woods, Amanda
AU - Mathews, Saumi
AU - Joshi, Poonam S.
AU - Quadros, Rolen M.
AU - Harms, Donald W.
AU - Cheng, Yan
AU - Miles, Shana M.
AU - Pirruccello, Samuel Jay
AU - Gurumurthy, Channabasavaiah B
AU - Gorantla, Santhi
AU - Poluektova, Larisa Y
N1 - Publisher Copyright:
© 2019 The Author(s).
PY - 2019/1/7
Y1 - 2019/1/7
N2 - 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-IL2Rγc -/- (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.
AB - 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-IL2Rγc -/- (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.
KW - CMP-N-acetylneuraminic acid hydroxylase
KW - HIV-1
KW - Hematopoietic stem cells
KW - NOD/scid-IL2Rγ mice
UR - http://www.scopus.com/inward/record.url?scp=85059742876&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85059742876&partnerID=8YFLogxK
U2 - 10.1186/s12865-018-0279-3
DO - 10.1186/s12865-018-0279-3
M3 - Article
C2 - 30616506
AN - SCOPUS:85059742876
SN - 1471-2172
VL - 20
JO - BMC Immunology
JF - BMC Immunology
IS - 1
M1 - 2
ER -