A Germ-Free Humanized Mouse Model Shows the Contribution of Resident Microbiota to Human-Specific Pathogen Infection

Authors

Angela Wahl, The University of North Carolina at Chapel Hill
Wenbo Yao, The University of North Carolina at Chapel Hill
Baolin Liao, The University of North Carolina at Chapel Hill
Morgan Chateau, The University of North Carolina at Chapel Hill
Cara Richardson, The University of North Carolina at Chapel Hill
Lijun Ling, The University of North Carolina at Chapel Hill
Adrienne Franks, The University of North Carolina at Chapel Hill
Krithika Senthil, The University of North Carolina at Chapel Hill
Genevieve Doyon, The University of North Carolina at Chapel Hill
Fengling Li, UNC School of Medicine
Josh Frost, UNC School of Medicine
Christopher B. Whitehurst, New York Medical College
Joseph S. Pagano, UNC School of Medicine
Craig A. Fletcher, UNC School of Medicine
M. Andrea Azcarate-Peril, UNC School of Medicine
Michael G. Hudgens, UNC Gillings School of Global Public Health
Allison R. Rogala, UNC School of Medicine
Joseph D. Tucker, UNC School of Medicine
Ian McGowan, University of Pittsburgh School of Medicine
R. Balfour Sartor, UNC School of Medicine
J. Victor Garcia, The University of North Carolina at Chapel Hill

Author Type(s)

Faculty

DOI

10.1038/s41587-023-01906-5

Journal Title

Nature Biotechnology

First Page

905

Last Page

915

Document Type

Article

Publication Date

6-1-2024

Department

Pathology, Microbiology and Immunology

Disciplines

Medicine and Health Sciences

Abstract

Germ-free (GF) mice, which are depleted of their resident microbiota, are the gold standard for exploring the role of the microbiome in health and disease; however, they are of limited value in the study of human-specific pathogens because they do not support their replication. Here, we develop GF mice systemically reconstituted with human immune cells and use them to evaluate the role of the resident microbiome in the acquisition, replication and pathogenesis of two human-specific pathogens, Epstein–Barr virus (EBV) and human immunodeficiency virus (HIV). Comparison with conventional (CV) humanized mice showed that resident microbiota enhance the establishment of EBV infection and EBV-induced tumorigenesis and increase mucosal HIV acquisition and replication. HIV RNA levels were higher in plasma and tissues of CV humanized mice compared with GF humanized mice. The frequency of CCR5⁺ CD4⁺ T cells throughout the intestine was also higher in CV humanized mice, indicating that resident microbiota govern levels of HIV target cells. Thus, resident microbiota promote the acquisition and pathogenesis of two clinically relevant human-specific pathogens.

Recommended Citation

Wahl, A., Yao, W., Liao, B., Chateau, M., Richardson, C., Ling, L., Franks, A., Senthil, K., Doyon, G., Li, F., Frost, J., Whitehurst, C., Pagano, J., Fletcher, C., Azcarate-Peril, M., Hudgens, M., Rogala, A., Tucker, J., McGowan, I., Sartor, R., & Garcia, J. (2024). A Germ-Free Humanized Mouse Model Shows the Contribution of Resident Microbiota to Human-Specific Pathogen Infection. Nature Biotechnology, 42 (6), 905-915. https://doi.org/10.1038/s41587-023-01906-5