NYMC Faculty Publications

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

Angela Wahl, International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. awahl@med.unc.edu.
Wenbo Yao, International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Baolin Liao, International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Morgan Chateau, International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Cara Richardson, International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Lijun Ling, International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Adrienne Franks, International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Krithika Senthil, International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Genevieve Doyon, International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Fengling Li, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Josh Frost, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Christopher B. Whitehurst, Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY, USA.
Joseph S. Pagano, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Craig A. Fletcher, Division of Comparative Medicine, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
M Andrea Azcarate-Peril, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Michael G. Hudgens, Department of Biostatistics, Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Allison R. Rogala, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Joseph D. Tucker, Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Ian McGowan, Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA.
R Balfour Sartor, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
J Victor Garcia, International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. victor_garcia@med.unc.edu.

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

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.

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