Altered Immunity of Laboratory Mice in the Natural Environment Is Associated with Fungal Colonization

Overview

Journal Cell Host Microbe

Publisher Cell Press

Specialties Infectious Diseases
Microbiology

Date 2020 Mar 27

PMID 32209432

Citations 85

Authors

Frank Yeung

Ying-Han Chen

Jian-Da Lin

Jacqueline M Leung

Caroline McCauley

Joseph C Devlin

Christina Hansen

Alex Cronkite

Zac Stephens

Charlotte Drake-Dunn

Yi Fulmer

Bo Shopsin

Kelly V Ruggles

June L Round

Png Loke

Andrea L Graham

Ken Cadwell

Affiliations

Soon will be listed here.

Abstract

Free-living mammals, such as humans and wild mice, display heightened immune activation compared with artificially maintained laboratory mice. These differences are partially attributed to microbial exposure as laboratory mice infected with pathogens exhibit immune profiles more closely resembling that of free-living animals. Here, we examine how colonization by microorganisms within the natural environment contributes to immune system maturation by releasing inbred laboratory mice into an outdoor enclosure. In addition to enhancing differentiation of T cell populations previously associated with pathogen exposure, outdoor release increased circulating granulocytes. However, these "rewilded" mice were not infected by pathogens previously implicated in immune activation. Rather, immune system changes were associated with altered microbiota composition with notable increases in intestinal fungi. Fungi isolated from rewilded mice were sufficient in increasing circulating granulocytes. These findings establish a model to investigate how the natural environment impacts immune development and show that sustained fungal exposure impacts granulocyte numbers.

Citing Articles

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References

Kernbauer E, Ding Y, Cadwell K . An enteric virus can replace the beneficial function of commensal bacteria. Nature. 2014; 516(7529):94-8. PMC: 4257755. DOI: 10.1038/nature13960. View

Maurer K, Reyes-Robles T, Alonzo 3rd F, Durbin J, Torres V, Cadwell K . Autophagy mediates tolerance to Staphylococcus aureus alpha-toxin. Cell Host Microbe. 2015; 17(4):429-40. PMC: 4392646. DOI: 10.1016/j.chom.2015.03.001. View

Kernbauer E, Maurer K, Torres V, Shopsin B, Cadwell K . Gastrointestinal dissemination and transmission of Staphylococcus aureus following bacteremia. Infect Immun. 2014; 83(1):372-8. PMC: 4288891. DOI: 10.1128/IAI.02272-14. View

Wheeler M, Limon J, Bar A, Leal C, Gargus M, Tang J . Immunological Consequences of Intestinal Fungal Dysbiosis. Cell Host Microbe. 2016; 19(6):865-73. PMC: 4900921. DOI: 10.1016/j.chom.2016.05.003. View

Budischak S, Hansen C, Caudron Q, Garnier R, Kartzinel T, Pelczer I . Feeding Immunity: Physiological and Behavioral Responses to Infection and Resource Limitation. Front Immunol. 2018; 8:1914. PMC: 5766659. DOI: 10.3389/fimmu.2017.01914. View

Murthy A, Li Y, Peng I, Reichelt M, Katakam A, Noubade R . A Crohn's disease variant in Atg16l1 enhances its degradation by caspase 3. Nature. 2014; 506(7489):456-62. DOI: 10.1038/nature13044. View

Bokulich N, Kaehler B, Rideout J, Dillon M, Bolyen E, Knight R . Optimizing taxonomic classification of marker-gene amplicon sequences with QIIME 2's q2-feature-classifier plugin. Microbiome. 2018; 6(1):90. PMC: 5956843. DOI: 10.1186/s40168-018-0470-z. View

Wlodarska M, Kostic A, Xavier R . An integrative view of microbiome-host interactions in inflammatory bowel diseases. Cell Host Microbe. 2015; 17(5):577-91. PMC: 4498258. DOI: 10.1016/j.chom.2015.04.008. View

Lassen K, Kuballa P, Conway K, Patel K, Becker C, Peloquin J . Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense. Proc Natl Acad Sci U S A. 2014; 111(21):7741-6. PMC: 4040621. DOI: 10.1073/pnas.1407001111. View

10.

Amir A, McDonald D, Navas-Molina J, Kopylova E, Morton J, Xu Z . Deblur Rapidly Resolves Single-Nucleotide Community Sequence Patterns. mSystems. 2017; 2(2). PMC: 5340863. DOI: 10.1128/mSystems.00191-16. View

11.

Ramanan D, Tang M, Bowcutt R, Loke P, Cadwell K . Bacterial sensor Nod2 prevents inflammation of the small intestine by restricting the expansion of the commensal Bacteroides vulgatus. Immunity. 2014; 41(2):311-24. PMC: 4238935. DOI: 10.1016/j.immuni.2014.06.015. View

12.

Saitoh T, Fujita N, Jang M, Uematsu S, Yang B, Satoh T . Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature. 2008; 456(7219):264-8. DOI: 10.1038/nature07383. View

13.

Kim Y, Kamada N, Shaw M, Warner N, Chen G, Franchi L . The Nod2 sensor promotes intestinal pathogen eradication via the chemokine CCL2-dependent recruitment of inflammatory monocytes. Immunity. 2011; 34(5):769-80. PMC: 3103637. DOI: 10.1016/j.immuni.2011.04.013. View

14.

Neil J, Matsuzawa-Ishimoto Y, Kernbauer-Holzl E, Schuster S, Sota S, Venzon M . IFN-I and IL-22 mediate protective effects of intestinal viral infection. Nat Microbiol. 2019; 4(10):1737-1749. PMC: 6871771. DOI: 10.1038/s41564-019-0470-1. View

15.

Abubucker S, Segata N, Goll J, Schubert A, Izard J, Cantarel B . Metabolic reconstruction for metagenomic data and its application to the human microbiome. PLoS Comput Biol. 2012; 8(6):e1002358. PMC: 3374609. DOI: 10.1371/journal.pcbi.1002358. View

16.

Ramanan D, Bowcutt R, Lee S, Tang M, Kurtz Z, Ding Y . Helminth infection promotes colonization resistance via type 2 immunity. Science. 2016; 352(6285):608-12. PMC: 4905769. DOI: 10.1126/science.aaf3229. View

17.

Taylor D, Walters W, Lennon N, Bochicchio J, Krohn A, Caporaso J . Accurate Estimation of Fungal Diversity and Abundance through Improved Lineage-Specific Primers Optimized for Illumina Amplicon Sequencing. Appl Environ Microbiol. 2016; 82(24):7217-7226. PMC: 5118932. DOI: 10.1128/AEM.02576-16. View

18.

Marchiando A, Ramanan D, Ding Y, Gomez L, Hubbard-Lucey V, Maurer K . A deficiency in the autophagy gene Atg16L1 enhances resistance to enteric bacterial infection. Cell Host Microbe. 2013; 14(2):216-24. PMC: 3825684. DOI: 10.1016/j.chom.2013.07.013. View

19.

Cadwell K, Liu J, Brown S, Miyoshi H, Loh J, Lennerz J . A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature. 2008; 456(7219):259-63. PMC: 2695978. DOI: 10.1038/nature07416. View

20.

Akoumianaki T, Kyrmizi I, Valsecchi I, Gresnigt M, Samonis G, Drakos E . Aspergillus Cell Wall Melanin Blocks LC3-Associated Phagocytosis to Promote Pathogenicity. Cell Host Microbe. 2016; 19(1):79-90. DOI: 10.1016/j.chom.2015.12.002. View