Evasion of Innate Cytosolic DNA Sensing by a Gammaherpesvirus Facilitates Establishment of Latent Infection
Herpesviruses are DNA viruses harboring the capacity to establish lifelong latent-recurrent infections. There is limited knowledge about viruses targeting the innate DNA-sensing pathway, as well as how the innate system impacts on the latent reservoir of herpesvirus infections. In this article, we r...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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American Association of Immunologists
2017
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| Online Access: | http://hdl.handle.net/1721.1/108759 https://orcid.org/0000-0002-1090-6071 |
| _version_ | 1826192744259780608 |
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| author | Sun, Chenglong Schattgen, Stefan A. Pisitkun, Prapaporn Jorgensen, Joan P. Hilterbrand, Adam T. Wang, Lucas J. West, John A. Hansen, Kathrine Horan, Kristy A. Jakobsen, Martin R. O’Hare, Peter Adler, Heiko Sun, Ren Damania, Blossom Upton, Jason W. Fitzgerald, Katherine A. Paludan, Søren R. Ploegh, Hidde |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Sun, Chenglong Schattgen, Stefan A. Pisitkun, Prapaporn Jorgensen, Joan P. Hilterbrand, Adam T. Wang, Lucas J. West, John A. Hansen, Kathrine Horan, Kristy A. Jakobsen, Martin R. O’Hare, Peter Adler, Heiko Sun, Ren Damania, Blossom Upton, Jason W. Fitzgerald, Katherine A. Paludan, Søren R. Ploegh, Hidde |
| author_sort | Sun, Chenglong |
| collection | MIT |
| description | Herpesviruses are DNA viruses harboring the capacity to establish lifelong latent-recurrent infections. There is limited knowledge about viruses targeting the innate DNA-sensing pathway, as well as how the innate system impacts on the latent reservoir of herpesvirus infections. In this article, we report that murine gammaherpesvirus 68 (MHV68), in contrast to α- and β-herpesviruses, induces very limited innate immune responses through DNA-stimulated pathways, which correspondingly played only a minor role in the control of MHV68 infections in vivo. Similarly, Kaposi’s sarcoma–associated herpesvirus also did not stimulate immune signaling through the DNA-sensing pathways. Interestingly, an MHV68 mutant lacking deubiquitinase (DUB) activity, embedded within the large tegument protein open reading frame (ORF)64, gained the capacity to stimulate the DNA-activated stimulator of IFN genes (STING) pathway. We found that ORF64 targeted a step in the DNA-activated pathways upstream of the bifurcation into the STING and absent in melanoma 2 pathways, and lack of the ORF64 DUB was associated with impaired delivery of viral DNA to the nucleus, which, instead, localized to the cytoplasm. Correspondingly, the ORF64 DUB active site mutant virus exhibited impaired ability to establish latent infection in wild-type, but not STING-deficient, mice. Thus, gammaherpesviruses evade immune activation by the cytosolic DNA-sensing pathway, which, in the MHV68 model, facilitates establishment of infections. |
| first_indexed | 2024-09-23T09:28:34Z |
| format | Article |
| id | mit-1721.1/108759 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:28:34Z |
| publishDate | 2017 |
| publisher | American Association of Immunologists |
| record_format | dspace |
| spelling | mit-1721.1/1087592022-09-26T11:39:36Z Evasion of Innate Cytosolic DNA Sensing by a Gammaherpesvirus Facilitates Establishment of Latent Infection Sun, Chenglong Schattgen, Stefan A. Pisitkun, Prapaporn Jorgensen, Joan P. Hilterbrand, Adam T. Wang, Lucas J. West, John A. Hansen, Kathrine Horan, Kristy A. Jakobsen, Martin R. O’Hare, Peter Adler, Heiko Sun, Ren Damania, Blossom Upton, Jason W. Fitzgerald, Katherine A. Paludan, Søren R. Ploegh, Hidde Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Ploegh, Hidde Herpesviruses are DNA viruses harboring the capacity to establish lifelong latent-recurrent infections. There is limited knowledge about viruses targeting the innate DNA-sensing pathway, as well as how the innate system impacts on the latent reservoir of herpesvirus infections. In this article, we report that murine gammaherpesvirus 68 (MHV68), in contrast to α- and β-herpesviruses, induces very limited innate immune responses through DNA-stimulated pathways, which correspondingly played only a minor role in the control of MHV68 infections in vivo. Similarly, Kaposi’s sarcoma–associated herpesvirus also did not stimulate immune signaling through the DNA-sensing pathways. Interestingly, an MHV68 mutant lacking deubiquitinase (DUB) activity, embedded within the large tegument protein open reading frame (ORF)64, gained the capacity to stimulate the DNA-activated stimulator of IFN genes (STING) pathway. We found that ORF64 targeted a step in the DNA-activated pathways upstream of the bifurcation into the STING and absent in melanoma 2 pathways, and lack of the ORF64 DUB was associated with impaired delivery of viral DNA to the nucleus, which, instead, localized to the cytoplasm. Correspondingly, the ORF64 DUB active site mutant virus exhibited impaired ability to establish latent infection in wild-type, but not STING-deficient, mice. Thus, gammaherpesviruses evade immune activation by the cytosolic DNA-sensing pathway, which, in the MHV68 model, facilitates establishment of infections. 2017-05-08T19:58:21Z 2017-05-08T19:58:21Z 2015-02 2014-10 Article http://purl.org/eprint/type/JournalArticle 0022-1767 1550-6606 http://hdl.handle.net/1721.1/108759 Sun, Chenglong et al. “Evasion of Innate Cytosolic DNA Sensing by a Gammaherpesvirus Facilitates Establishment of Latent Infection.” The Journal of Immunology 194.4 (2015): 1819–1831. https://orcid.org/0000-0002-1090-6071 en_US http://dx.doi.org/10.4049/jimmunol.1402495 The Journal of Immunology Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association of Immunologists PMC |
| spellingShingle | Sun, Chenglong Schattgen, Stefan A. Pisitkun, Prapaporn Jorgensen, Joan P. Hilterbrand, Adam T. Wang, Lucas J. West, John A. Hansen, Kathrine Horan, Kristy A. Jakobsen, Martin R. O’Hare, Peter Adler, Heiko Sun, Ren Damania, Blossom Upton, Jason W. Fitzgerald, Katherine A. Paludan, Søren R. Ploegh, Hidde Evasion of Innate Cytosolic DNA Sensing by a Gammaherpesvirus Facilitates Establishment of Latent Infection |
| title | Evasion of Innate Cytosolic DNA Sensing by a Gammaherpesvirus Facilitates Establishment of Latent Infection |
| title_full | Evasion of Innate Cytosolic DNA Sensing by a Gammaherpesvirus Facilitates Establishment of Latent Infection |
| title_fullStr | Evasion of Innate Cytosolic DNA Sensing by a Gammaherpesvirus Facilitates Establishment of Latent Infection |
| title_full_unstemmed | Evasion of Innate Cytosolic DNA Sensing by a Gammaherpesvirus Facilitates Establishment of Latent Infection |
| title_short | Evasion of Innate Cytosolic DNA Sensing by a Gammaherpesvirus Facilitates Establishment of Latent Infection |
| title_sort | evasion of innate cytosolic dna sensing by a gammaherpesvirus facilitates establishment of latent infection |
| url | http://hdl.handle.net/1721.1/108759 https://orcid.org/0000-0002-1090-6071 |
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