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

Dagur, R. S.; Branch Woods, A.; Mathews, S.; Joshi, P. S.; Quadros, R. M.; Harms, D. W.; Cheng, Y.; Miles, S. M.; Pirruccello, S. J.; Gurumurthy, C. B.; Gorantla, S.; Poluektova, L. Y.

doi:10.1101/404905

bioRxiv · 10.1101/404905

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

Dagur, R. S.·Branch Woods, A.·Mathews, S.·Joshi, P. S.·Quadros, R. M.·Harms, D. W.·Cheng, Y.·Miles, S. M.·Pirruccello, S. J.·Gurumurthy, C. B.·Gorantla, S.·Poluektova, L. Y.

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Abstract

BackgroundThe use of immunodeficient mice transplanted with human hematopoietic stem cells is an accepted approach to study human-specific infectious diseases, like 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 of mouse glycoproteins chemistry will affect phenotype and function of transplanted human hematopoietic stem cells and mature human immune cells in the course of HIV-1 infection is not known.\n\nResultsWe mutated mouse CMAH on the most widely human cells transplantation strain NOD/scid-IL2R{gamma} c-/- (NSG) mouse background 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 low effects on the clearance of human immunoglobulins and enhanced transduction efficiency of recombinant adeno-associated viral vector rAAV2/DJ8.\n\nConclusionNSG-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, might 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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Dagur, R. S., Branch Woods, A., Mathews, S., Joshi, P. S., Quadros, R. M., Harms, D. W., Cheng, Y., Miles, S. M., Pirruccello, S. J., Gurumurthy, C. B., Gorantla, S., Poluektova, L. Y.. 2018-08-31. Human-like NSG mouse glycoproteins sialylation pattern changes the phenotype of human lymphocytes and sensitivity to HIV-1 infection. https://doi.org/10.1101/404905

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