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

Data availability

Source data for Figs. 1–5 and Extended Data Figs. 1–8 are provided with the manuscript.

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Acknowledgements

We thank current and former members of the Garcia and Wahl laboratories for technical assistance and technicians at the UNC National Gnotobiotic Rodent Resource Center, Microbiome Core Facility, Division of Comparative Medicine, and Animal Histopathology and Clinical Chemistry Core for technical support. We also thank M. Kane, S. Lemon, J. Turpin and N. Raab-Traub for helpful comments and discussions. Figure 1a was created using BioRender.com. This work was supported by funding from NIH grants AI123010 (A.W.), DK131585 (A.W., J.V.G. and R.B.S), 1UM1AI126619 (current award 1UM1AI164567; J.V.G), P40OD010995 (R.B.S. and A.R.R.), P30DK034987 (R.B.S), U19AI082637 (I.M.) and FIC D43TW009532 (J.D.T). The UNC CFAR Biostatistics Core is supported by NIH-funded program P30AI050410. UNC Animal Histopathology & Clinical Chemistry is supported in part by an NCI Center Core Support Grant (5P30CA016080-42). The UNC Microbiome Core is funded in part by the Center for Gastrointestinal Biology and Disease (P30 DK034987) and the UNC Nutrition Obesity Research Center (P30 DK056350).

Author information

Author notes

These authors contributed equally: Angela Wahl, Wenbo Yao, Baolin Liao.

Authors and Affiliations

International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Angela Wahl, Wenbo Yao, Baolin Liao, Morgan Chateau, Cara Richardson, Lijun Ling, Adrienne Franks, Krithika Senthil, Genevieve Doyon & J. Victor Garcia

Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Angela Wahl, Wenbo Yao, Baolin Liao, Morgan Chateau, Cara Richardson, Lijun Ling, Adrienne Franks, Krithika Senthil, Genevieve Doyon, Joseph D. Tucker & J. Victor Garcia

Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Angela Wahl, Wenbo Yao, Baolin Liao, Morgan Chateau, Cara Richardson, Lijun Ling, Adrienne Franks, Krithika Senthil, Genevieve Doyon & J. Victor Garcia

Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, China

Baolin Liao

Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Fengling Li, Josh Frost, M. Andrea Azcarate-Peril, Allison R. Rogala, R. Balfour Sartor & J. Victor Garcia

Division of Comparative Medicine, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Josh Frost, Craig A. Fletcher & Allison R. Rogala

Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY, USA

Christopher B. Whitehurst

Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Joseph S. Pagano & R. Balfour Sartor

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Joseph S. Pagano

Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Joseph S. Pagano

Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

M. Andrea Azcarate-Peril & R. Balfour Sartor

UNC Microbiome Core, University of North Carolina, Chapel Hill, NC, USA

M. Andrea Azcarate-Peril

Department of Biostatistics, Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Michael G. Hudgens

Clinical Research Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK

Joseph D. Tucker

Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA

Ian McGowan

Orion Biotechnology, Ottawa, Ontario, Canada

Ian McGowan

Contributions

W.Y., B.L., C.R., M.C. and A.W. constructed BLT mice, necropsied mice, and performed flow cytometric analysis of peripheral blood and tissues. G.D. contributed to the flow cytometric analysis of tissues. W.Y. and A.W. performed the immunohistochemical analysis. A.W., A.F., K.S. and G.D. performed experiments with EBV-exposed BLT mice, and A.W. analyzed the data. C.B.W and J.S.P. contributed to the EBV studies. W.Y., C.R. and A.W. performed experiments with HIV-exposed BLT mice and analyzed data. L.L. assisted with rectal HIV exposures. F.L. and J.F. contributed to the rederivation of GF mice and microbial testing. M.A.A. contributed to the microbiome sequencing analysis. M.G.H assisted with statistical analyses and data presentation. A.R.R. and R.B.S contributed to the rederivation of GF mice, microbial testing and experimental design. I.M. contributed to the conceptualization of the study. C.A.F and J.D.T. contributed to data interpretation, and J.D.T also assisted with the supervision of B.L. J.V.G. and A.W. conceived and designed the study and experiments; supervised the work; and contributed to data interpretation, analysis, data presentation, and manuscript conceptualization and writing.

Corresponding authors

Correspondence to
Angela Wahl or J. Victor Garcia.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Biotechnology thanks the anonymous reviewers for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Fecal bacterial microbiome of CV-BLT mice.

The composition of the bacterial microbiome was analyzed by 16S amplicon sequencing in fecal pellets collected from CV-BLT mice (n=10). The mean relative abundance at the a, phylum and b, genus levels are shown. Taxa with a mean relative abundance
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