Chikungunya virus infection disrupts MHC-I antigen presentation via nonstructural protein 2.
Infection by chikungunya virus (CHIKV), a mosquito-borne alphavirus, causes severe polyarthralgia and polymyalgia, which can last in some people for months to years. Chronic CHIKV disease signs and symptoms are associated with the persistence of viral nucleic acid and antigen in tissues. Like humans...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2024-03-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011794&type=printable |
| _version_ | 1797234296519393280 |
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| author | Brian C Ware M Guston Parks Mariana O L da Silva Thomas E Morrison |
| author_facet | Brian C Ware M Guston Parks Mariana O L da Silva Thomas E Morrison |
| author_sort | Brian C Ware |
| collection | DOAJ |
| description | Infection by chikungunya virus (CHIKV), a mosquito-borne alphavirus, causes severe polyarthralgia and polymyalgia, which can last in some people for months to years. Chronic CHIKV disease signs and symptoms are associated with the persistence of viral nucleic acid and antigen in tissues. Like humans and nonhuman primates, CHIKV infection in mice results in the development of robust adaptive antiviral immune responses. Despite this, joint tissue fibroblasts survive CHIKV infection and can support persistent viral replication, suggesting that they escape immune surveillance. Here, using a recombinant CHIKV strain encoding the fluorescent protein VENUS with an embedded CD8+ T cell epitope, SIINFEKL, we observed a marked loss of both MHC class I (MHC-I) surface expression and antigen presentation by CHIKV-infected joint tissue fibroblasts. Both in vivo and ex vivo infected joint tissue fibroblasts displayed reduced cell surface levels of H2-Kb and H2-Db MHC-I proteins while maintaining similar levels of other cell surface proteins. Mutations within the methyl transferase-like domain of the CHIKV nonstructural protein 2 (nsP2) increased MHC-I cell surface expression and antigen presentation efficiency by CHIKV-infected cells. Moreover, expression of WT nsP2 alone, but not nsP2 with mutations in the methyltransferase-like domain, resulted in decreased MHC-I antigen presentation efficiency. MHC-I surface expression and antigen presentation was rescued by replacing VENUS-SIINFEKL with SIINFEKL tethered to β2-microglobulin in the CHIKV genome, which bypasses the requirement for peptide processing and TAP-mediated peptide transport into the endoplasmic reticulum. Collectively, this work suggests that CHIKV escapes the surveillance of antiviral CD8+ T cells, in part, by nsP2-mediated disruption of MHC-I antigen presentation. |
| first_indexed | 2024-04-24T16:29:49Z |
| format | Article |
| id | doaj.art-dc18606325354d899c3e8a7944242b74 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-04-24T16:29:49Z |
| publishDate | 2024-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-dc18606325354d899c3e8a7944242b742024-03-30T05:32:28ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742024-03-01203e101179410.1371/journal.ppat.1011794Chikungunya virus infection disrupts MHC-I antigen presentation via nonstructural protein 2.Brian C WareM Guston ParksMariana O L da SilvaThomas E MorrisonInfection by chikungunya virus (CHIKV), a mosquito-borne alphavirus, causes severe polyarthralgia and polymyalgia, which can last in some people for months to years. Chronic CHIKV disease signs and symptoms are associated with the persistence of viral nucleic acid and antigen in tissues. Like humans and nonhuman primates, CHIKV infection in mice results in the development of robust adaptive antiviral immune responses. Despite this, joint tissue fibroblasts survive CHIKV infection and can support persistent viral replication, suggesting that they escape immune surveillance. Here, using a recombinant CHIKV strain encoding the fluorescent protein VENUS with an embedded CD8+ T cell epitope, SIINFEKL, we observed a marked loss of both MHC class I (MHC-I) surface expression and antigen presentation by CHIKV-infected joint tissue fibroblasts. Both in vivo and ex vivo infected joint tissue fibroblasts displayed reduced cell surface levels of H2-Kb and H2-Db MHC-I proteins while maintaining similar levels of other cell surface proteins. Mutations within the methyl transferase-like domain of the CHIKV nonstructural protein 2 (nsP2) increased MHC-I cell surface expression and antigen presentation efficiency by CHIKV-infected cells. Moreover, expression of WT nsP2 alone, but not nsP2 with mutations in the methyltransferase-like domain, resulted in decreased MHC-I antigen presentation efficiency. MHC-I surface expression and antigen presentation was rescued by replacing VENUS-SIINFEKL with SIINFEKL tethered to β2-microglobulin in the CHIKV genome, which bypasses the requirement for peptide processing and TAP-mediated peptide transport into the endoplasmic reticulum. Collectively, this work suggests that CHIKV escapes the surveillance of antiviral CD8+ T cells, in part, by nsP2-mediated disruption of MHC-I antigen presentation.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011794&type=printable |
| spellingShingle | Brian C Ware M Guston Parks Mariana O L da Silva Thomas E Morrison Chikungunya virus infection disrupts MHC-I antigen presentation via nonstructural protein 2. PLoS Pathogens |
| title | Chikungunya virus infection disrupts MHC-I antigen presentation via nonstructural protein 2. |
| title_full | Chikungunya virus infection disrupts MHC-I antigen presentation via nonstructural protein 2. |
| title_fullStr | Chikungunya virus infection disrupts MHC-I antigen presentation via nonstructural protein 2. |
| title_full_unstemmed | Chikungunya virus infection disrupts MHC-I antigen presentation via nonstructural protein 2. |
| title_short | Chikungunya virus infection disrupts MHC-I antigen presentation via nonstructural protein 2. |
| title_sort | chikungunya virus infection disrupts mhc i antigen presentation via nonstructural protein 2 |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011794&type=printable |
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