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A germ-free humanized mouse model shows the contribution of resident microbiota to human-specific pathogen infection
Angela Wahl1,2,3, Wenbo Yao4,5,6, Baolin Liao4,5,6,7
1International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. awahl@med.unc.edu.
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.
Insights
The resident microbiome enhances Epstein-Barr virus (EBV) and human immunodeficiency virus (HIV) infection and disease progression in humanized mice. This highlights the microbiome's critical role in human-specific pathogen pathogenesis.
Area of Science:
- Immunology
- Microbiology
- Virology
Background:
- Germ-free (GF) mice lack resident microbiota, limiting their utility for studying human-specific pathogens.
- Humanized mouse models are crucial for investigating host-pathogen interactions.
- The role of the microbiome in the pathogenesis of human-specific viruses like EBV and HIV remains incompletely understood.
Purpose of the Study:
- To develop and utilize a novel humanized mouse model to investigate the impact of resident microbiota on the acquisition, replication, and pathogenesis of Epstein-Barr virus (EBV) and human immunodeficiency virus (HIV).
Main Methods:
- Generation of germ-free (GF) mice reconstituted with human immune cells.
- Comparison of GF humanized mice with conventional (CV) humanized mice harboring a resident microbiome.
- Assessment of EBV infection, EBV-induced tumorigenesis, and HIV acquisition, replication, and pathogenesis markers.
Main Results:
- Resident microbiota significantly enhanced EBV infection establishment and EBV-induced tumorigenesis in humanized mice.
- Conventional humanized mice exhibited increased mucosal HIV acquisition and replication compared to GF humanized mice.
- Higher plasma and tissue HIV RNA levels and increased frequencies of CCR5+ CD4+ T cells were observed in CV humanized mice, indicating microbiota's influence on HIV target cell availability.
Conclusions:
- Resident microbiota play a critical role in promoting the acquisition and pathogenesis of human-specific pathogens, including EBV and HIV.
- Humanized mouse models with a reconstituted microbiome provide a valuable platform for studying the complex interplay between host immunity, resident microbiota, and viral infections.
- Targeting the microbiome may represent a novel therapeutic strategy to control EBV and HIV infections.
