Norovirus Changes Susceptibility to Type 1 Diabetes by Altering Intestinal Microbiota and Immune Cell Functions
Environmental factors contribute to Type 1 diabetes (T1D) susceptibility. The gut microbiome, which includes bacteria, viruses, and fungi, contributes to this environmental influence, and can induce immunological changes. The gut viral component of the microbiome, related to T1D has mostly focused o...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.02654/full |
| _version_ | 1828737596901031936 |
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| author | James A. Pearson Ningwen Tai Dilrukshi K. Ekanayake-Alper Dilrukshi K. Ekanayake-Alper Jian Peng Youjia Hu Karl Hager Susan Compton F. Susan Wong Peter C. Smith Li Wen |
| author_facet | James A. Pearson Ningwen Tai Dilrukshi K. Ekanayake-Alper Dilrukshi K. Ekanayake-Alper Jian Peng Youjia Hu Karl Hager Susan Compton F. Susan Wong Peter C. Smith Li Wen |
| author_sort | James A. Pearson |
| collection | DOAJ |
| description | Environmental factors contribute to Type 1 diabetes (T1D) susceptibility. The gut microbiome, which includes bacteria, viruses, and fungi, contributes to this environmental influence, and can induce immunological changes. The gut viral component of the microbiome, related to T1D has mostly focused on coxsackieviruses and rotavirus. The role of norovirus, another common enteric virus, in susceptibility to T1D was hitherto unknown. Norovirus is highly infectious and encountered by many children. We studied the mouse norovirus 4 (MNV4), related to human noroviruses, in the Non-obese diabetic (NOD) mouse model, to determine its role in influencing susceptibility to T1D. We infected MNV-free NOD mice with MNV4 by exposing the mice to MNV4-positive bedding from an endemically-infected mouse colony to mimic a natural infection. Control MNV-free NOD mice were exposed to MNV-free bedding from the same colony. Interestingly, MNV4 infection protected NOD mice from the development of T1D and was associated with an expansion of Tregs and reduced proinflammatory T cells. We also found MNV4 significantly modified the gut commensal bacteria composition, promoting increased α-diversity and Firmicutes/Bacteroidetes ratio. To elucidate whether T1D protection was directly related to MNV4, or indirectly through modulating gut microbiota, we colonized germ-free (GF) NOD mice with the MNV4-containing or non-MNV4-containing viral filtrate, isolated from filtered fecal material. We found that MNV4 induced significant changes in mucosal immunity, including altered Tuft cell markers, cytokine secretion, antiviral immune signaling markers, and the concentration of mucosal antibodies. Systemically, MNV4-infection altered the immune cells including B cell subsets, macrophages and T cells, and especially induced an increase in Treg number and function. Furthermore, in vitro primary exposure of the norovirus filtrate to naïve splenocytes identified significant increases in the proportion of activated and CTLA4-expressing Tregs. Our data provide novel knowledge that norovirus can protect NOD mice from T1D development by inducing the expansion of Tregs and reducing inflammatory T cells. Our study also highlights the importance of distinguishing the mucosal immunity mediated by bacteria from that by enteric viruses. |
| first_indexed | 2024-04-12T23:47:45Z |
| format | Article |
| id | doaj.art-16b9bced9fd94123963d27922e47e48d |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T23:47:45Z |
| publishDate | 2019-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-16b9bced9fd94123963d27922e47e48d2022-12-22T03:11:49ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-11-011010.3389/fimmu.2019.02654475249Norovirus Changes Susceptibility to Type 1 Diabetes by Altering Intestinal Microbiota and Immune Cell FunctionsJames A. Pearson0Ningwen Tai1Dilrukshi K. Ekanayake-Alper2Dilrukshi K. Ekanayake-Alper3Jian Peng4Youjia Hu5Karl Hager6Susan Compton7F. Susan Wong8Peter C. Smith9Li Wen10Endocrinology, Internal Medicine, School of Medicine, Yale University, New Haven, CT, United StatesEndocrinology, Internal Medicine, School of Medicine, Yale University, New Haven, CT, United StatesColombia Center for Transplant Immunology and Institute of Comparative Medicine, Columbia University Medical Center, Colombia University, New York, NY, United StatesDepartment of Comparative Medicine, School of Medicine, Yale University, New Haven, CT, United StatesEndocrinology, Internal Medicine, School of Medicine, Yale University, New Haven, CT, United StatesEndocrinology, Internal Medicine, School of Medicine, Yale University, New Haven, CT, United StatesDepartment of Lab Medicine, School of Medicine, Yale University, New Haven, CT, United StatesDepartment of Comparative Medicine, School of Medicine, Yale University, New Haven, CT, United StatesDiabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United KingdomDepartment of Comparative Medicine, School of Medicine, Yale University, New Haven, CT, United StatesEndocrinology, Internal Medicine, School of Medicine, Yale University, New Haven, CT, United StatesEnvironmental factors contribute to Type 1 diabetes (T1D) susceptibility. The gut microbiome, which includes bacteria, viruses, and fungi, contributes to this environmental influence, and can induce immunological changes. The gut viral component of the microbiome, related to T1D has mostly focused on coxsackieviruses and rotavirus. The role of norovirus, another common enteric virus, in susceptibility to T1D was hitherto unknown. Norovirus is highly infectious and encountered by many children. We studied the mouse norovirus 4 (MNV4), related to human noroviruses, in the Non-obese diabetic (NOD) mouse model, to determine its role in influencing susceptibility to T1D. We infected MNV-free NOD mice with MNV4 by exposing the mice to MNV4-positive bedding from an endemically-infected mouse colony to mimic a natural infection. Control MNV-free NOD mice were exposed to MNV-free bedding from the same colony. Interestingly, MNV4 infection protected NOD mice from the development of T1D and was associated with an expansion of Tregs and reduced proinflammatory T cells. We also found MNV4 significantly modified the gut commensal bacteria composition, promoting increased α-diversity and Firmicutes/Bacteroidetes ratio. To elucidate whether T1D protection was directly related to MNV4, or indirectly through modulating gut microbiota, we colonized germ-free (GF) NOD mice with the MNV4-containing or non-MNV4-containing viral filtrate, isolated from filtered fecal material. We found that MNV4 induced significant changes in mucosal immunity, including altered Tuft cell markers, cytokine secretion, antiviral immune signaling markers, and the concentration of mucosal antibodies. Systemically, MNV4-infection altered the immune cells including B cell subsets, macrophages and T cells, and especially induced an increase in Treg number and function. Furthermore, in vitro primary exposure of the norovirus filtrate to naïve splenocytes identified significant increases in the proportion of activated and CTLA4-expressing Tregs. Our data provide novel knowledge that norovirus can protect NOD mice from T1D development by inducing the expansion of Tregs and reducing inflammatory T cells. Our study also highlights the importance of distinguishing the mucosal immunity mediated by bacteria from that by enteric viruses.https://www.frontiersin.org/article/10.3389/fimmu.2019.02654/fullnorovirustype 1 diabetesnon-obese diabetic micegut microbiotaTuft cellsTreg |
| spellingShingle | James A. Pearson Ningwen Tai Dilrukshi K. Ekanayake-Alper Dilrukshi K. Ekanayake-Alper Jian Peng Youjia Hu Karl Hager Susan Compton F. Susan Wong Peter C. Smith Li Wen Norovirus Changes Susceptibility to Type 1 Diabetes by Altering Intestinal Microbiota and Immune Cell Functions Frontiers in Immunology norovirus type 1 diabetes non-obese diabetic mice gut microbiota Tuft cells Treg |
| title | Norovirus Changes Susceptibility to Type 1 Diabetes by Altering Intestinal Microbiota and Immune Cell Functions |
| title_full | Norovirus Changes Susceptibility to Type 1 Diabetes by Altering Intestinal Microbiota and Immune Cell Functions |
| title_fullStr | Norovirus Changes Susceptibility to Type 1 Diabetes by Altering Intestinal Microbiota and Immune Cell Functions |
| title_full_unstemmed | Norovirus Changes Susceptibility to Type 1 Diabetes by Altering Intestinal Microbiota and Immune Cell Functions |
| title_short | Norovirus Changes Susceptibility to Type 1 Diabetes by Altering Intestinal Microbiota and Immune Cell Functions |
| title_sort | norovirus changes susceptibility to type 1 diabetes by altering intestinal microbiota and immune cell functions |
| topic | norovirus type 1 diabetes non-obese diabetic mice gut microbiota Tuft cells Treg |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.02654/full |
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