Human-like NSG mouse glycoproteins sialylation pattern changes the phenotype of human lymphocytes and sensitivity to HIV-1 infection 11 Medical and Health Sciences 1107 Immunology

Raghubendra Singh Dagur, Amanda Branch-Woods, Saumi Mathews, Poonam S. Joshi, Rolen M. Quadros, Donald W. Harms, Yan Cheng, Shana M. Miles, Samuel Jay Pirruccello, Channabasavaiah B Gurumurthy, Santhi Gorantla, Larisa Y Poluektova

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number2
JournalBMC Immunology
Volume20
Issue number1
DOIs
StatePublished - Jan 7 2019

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Allergy and Immunology
HIV Infections
HIV-1
Glycoproteins
Lymphocytes
Phenotype
Health
Cell Transplantation
Hematopoietic Stem Cells
Immune System
B-Lymphocytes
Clustered Regularly Interspaced Short Palindromic Repeats
Tissue Transplantation
Hematopoietic Stem Cell Transplantation
N-Acetylneuraminic Acid
Communicable Diseases
Immunoglobulins

Keywords

  • CMP-N-acetylneuraminic acid hydroxylase
  • Hematopoietic stem cells
  • HIV-1
  • NOD/scid-IL2Rγ mice

ASJC Scopus subject areas

  • Immunology

Cite this

Human-like NSG mouse glycoproteins sialylation pattern changes the phenotype of human lymphocytes and sensitivity to HIV-1 infection 11 Medical and Health Sciences 1107 Immunology. / Dagur, Raghubendra Singh; Branch-Woods, Amanda; Mathews, Saumi; Joshi, Poonam S.; Quadros, Rolen M.; Harms, Donald W.; Cheng, Yan; Miles, Shana M.; Pirruccello, Samuel Jay; Gurumurthy, Channabasavaiah B; Gorantla, Santhi; Poluektova, Larisa Y.

In: BMC Immunology, Vol. 20, No. 1, 2, 07.01.2019.

Research output: Contribution to journalArticle

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abstract = "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.",
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T1 - Human-like NSG mouse glycoproteins sialylation pattern changes the phenotype of human lymphocytes and sensitivity to HIV-1 infection 11 Medical and Health Sciences 1107 Immunology

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

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.

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