A germ-free humanized mouse model shows the contribution of resident microbiota to human-specific pathogen infection

Angela Wahl; Wenbo Yao; Baolin Liao; Morgan Chateau; Cara Richardson; Lijun Ling; Adrienne Franks; Krithika Senthil; Genevieve Doyon; Fengling Li; Josh Frost; Christopher B Whitehurst; Joseph S Pagano; Craig A Fletcher; M Andrea Azcarate-Peril; Michael G Hudgens; Allison R Rogala; Joseph D Tucker; Ian McGowan; R Balfour Sartor; J Victor Garcia

doi:10.1038/s41587-023-01906-5

A germ-free humanized mouse model shows the contribution of resident microbiota to human-specific pathogen infection

Nat Biotechnol. 2023 Aug 10. doi: 10.1038/s41587-023-01906-5. Online ahead of print.

Authors

Angela Wahl^#^{1

2

3}, Wenbo Yao^#^{4

5

6}, Baolin Liao^#^{4

5

6

7}, Morgan Chateau^{4

5

6}, Cara Richardson^{4

5

6}, Lijun Ling^{4

5

6}, Adrienne Franks^{4

5

6}, Krithika Senthil^{4

5

6}, Genevieve Doyon^{4

5

6}, Fengling Li⁸, Josh Frost^{8

9}, Christopher B Whitehurst¹⁰, Joseph S Pagano^{11

12

13}, Craig A Fletcher⁹, M Andrea Azcarate-Peril^{8

14

15}, Michael G Hudgens¹⁶, Allison R Rogala^{8

9}, Joseph D Tucker^{5

17}, Ian McGowan^{18

19}, R Balfour Sartor^{8

11

14}, J Victor Garcia^{20

21

22

23}

Affiliations

¹ International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. awahl@med.unc.edu.
² Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. awahl@med.unc.edu.
³ Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. awahl@med.unc.edu.
⁴ International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵ Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶ Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁷ Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China.
⁸ Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁹ Division of Comparative Medicine, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁰ Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY, USA.
¹¹ Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹² Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹³ Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁴ Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁵ UNC Microbiome Core, University of North Carolina, Chapel Hill, NC, USA.
¹⁶ Department of Biostatistics, Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁷ Clinical Research Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK.
¹⁸ Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA.
¹⁹ Orion Biotechnology, Ottawa, Ontario, Canada.
²⁰ International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. victor_garcia@med.unc.edu.
²¹ Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. victor_garcia@med.unc.edu.
²² Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. victor_garcia@med.unc.edu.
²³ Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. victor_garcia@med.unc.edu.

^# Contributed equally.

PMID: 37563299
DOI: 10.1038/s41587-023-01906-5

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.

Abstract

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