CD8 T cells drive anorexia, dysbiosis, and blooms of a commensal with immunosuppressive potential after viral infection
Edited by Lora V. Hooper, University of Texas Southwestern Medical Center, Dallas, TX, and approved August 20, 2020 (received for review February 26, 2020)
Significance
Infections are known to perturb intestinal microbiome composition, but the underlying mechanisms and the implications of specific commensal species for antiviral immunity remain largely unknown. Here, we found that infection of mice with a fast-spreading and persistent, but not slow-spreading acute, viral isolate induced profound microbial dysbiosis, including blooming of Akkermansia muciniphila, that was largely caused by CD8 T cells and/or CD8 T cell-induced anorexia. Notably, administration of A. muciniphila into infected mice attenuated selected aspects of CD8 T cell responses, supporting its immunosuppressive potential in this context. Our findings bring about a role for CD8 T cells in promoting anorexia and microbial shifts after infection, including the enrichment of a fasting-associated commensal that can attenuate CD8 T cell responses.
Abstract
Infections elicit immune adaptations to enable pathogen resistance and/or tolerance and are associated with compositional shifts of the intestinal microbiome. However, a comprehensive understanding of how infections with pathogens that exhibit distinct capability to spread and/or persist differentially change the microbiome, the underlying mechanisms, and the relative contribution of individual commensal species to immune cell adaptations is still lacking. Here, we discovered that mouse infection with a fast-spreading and persistent (but not a slow-spreading acute) isolate of lymphocytic choriomeningitis virus induced large-scale microbiome shifts characterized by increased Verrucomicrobia and reduced Firmicute/Bacteroidetes ratio. Remarkably, the most profound microbiome changes occurred transiently after infection with the fast-spreading persistent isolate, were uncoupled from sustained viral loads, and were instead largely caused by CD8 T cell responses and/or CD8 T cell-induced anorexia. Among the taxa enriched by infection with the fast-spreading virus, Akkermansia muciniphila, broadly regarded as a beneficial commensal, bloomed upon starvation and in a CD8 T cell-dependent manner. Strikingly, oral administration of A. muciniphila suppressed selected effector features of CD8 T cells in the context of both infections. Our findings define unique microbiome differences after chronic versus acute viral infections and identify CD8 T cell responses and downstream anorexia as driver mechanisms of microbial dysbiosis after infection with a fast-spreading virus. Our data also highlight potential context-dependent effects of probiotics and suggest a model in which changes in host behavior and downstream microbiome dysbiosis may constitute a previously unrecognized negative feedback loop that contributes to CD8 T cell adaptations after infections with fast-spreading and/or persistent pathogens.
Data Availability
All 16S rRNA gene amplicon and shotgun metagenomics sequencing data are publicly available on the European Nucleotide Archive (https://www.ebi.ac.uk/ena/browser/home, accession number ERP123227) and on Qiita (https://qiita.ucsd.edu, study ID 11043).
Acknowledgments
We thank members of the Zúñiga laboratory for discussions and critical reading of the manuscript. We thank Dr. Julia M. Gauglitz for initial multinomial regression analyses; Dr. Clarisse A. Marotz and Dr. Pedro Belda-Ferre for key assistance with anaerobic cultures; Dr. Gail Ackermann for data upload and metadata curation on Qiita; Dr. Tomasz Kosciolek for guidance with Qiita/QIIME; “Qiita help” personnel for assistance with Qiita; as well as personnel at the animal facility and the IGM Genomics center sequencing core at UCSD.
Research was supported by NIH grants AI081923, AI113923, AI132122 and Seed Grant from the UC San Diego Center for Microbiome Innovation to E.I.Z., Office of Naval Research Multidisciplinary University Research Initiative (MURI) Award (N00014-15-1-2809) to R.K. M.R. is supported by Public Health Service Grants AI114625, AI126277, AI145325, by the Chiba University-UCSD Center for Mucosal Immunology, Allergy, and Vaccines and also holds an Investigator in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund. L.L-B was partly supported by ‘La Caixa’ fellowship for studies in North America and by the UCSD Frontiers of Innovation Scholars Program. R.G. was partly supported by a postdoctoral fellowship from the Max Kade Foundation.
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Information & Authors
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© 2020. Published under the PNAS license.
Data Availability
All 16S rRNA gene amplicon and shotgun metagenomics sequencing data are publicly available on the European Nucleotide Archive (https://www.ebi.ac.uk/ena/browser/home, accession number ERP123227) and on Qiita (https://qiita.ucsd.edu, study ID 11043).
Submission history
Published online: September 21, 2020
Published in issue: October 6, 2020
Change history
December 16, 2021: The Acknowledgments have been updated.
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Acknowledgments
We thank members of the Zúñiga laboratory for discussions and critical reading of the manuscript. We thank Dr. Julia M. Gauglitz for initial multinomial regression analyses; Dr. Clarisse A. Marotz and Dr. Pedro Belda-Ferre for key assistance with anaerobic cultures; Dr. Gail Ackermann for data upload and metadata curation on Qiita; Dr. Tomasz Kosciolek for guidance with Qiita/QIIME; “Qiita help” personnel for assistance with Qiita; as well as personnel at the animal facility and the IGM Genomics center sequencing core at UCSD.
Research was supported by NIH grants AI081923, AI113923, AI132122 and Seed Grant from the UC San Diego Center for Microbiome Innovation to E.I.Z., Office of Naval Research Multidisciplinary University Research Initiative (MURI) Award (N00014-15-1-2809) to R.K. M.R. is supported by Public Health Service Grants AI114625, AI126277, AI145325, by the Chiba University-UCSD Center for Mucosal Immunology, Allergy, and Vaccines and also holds an Investigator in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund. L.L-B was partly supported by ‘La Caixa’ fellowship for studies in North America and by the UCSD Frontiers of Innovation Scholars Program. R.G. was partly supported by a postdoctoral fellowship from the Max Kade Foundation.
Notes
This article is a PNAS Direct Submission.
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The authors declare no competing interest.
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CD8 T cells drive anorexia, dysbiosis, and blooms of a commensal with immunosuppressive potential after viral infection, Proc. Natl. Acad. Sci. U.S.A.
117 (40) 24998-25007,
https://doi.org/10.1073/pnas.2003656117
(2020).
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