Role of MXRA8 in Ross River Virus Disease Pathogenesis
ABSTRACT Arthritogenic alphaviruses such as Ross River virus (RRV) and Chikungunya virus (CHIKV) are responsible for large-scale epidemics that cause debilitating acute and chronic musculoskeletal diseases. MXRA8 was recently discovered as an entry receptor for multiple alphaviruses including CHIKV,...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2023-04-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.00588-23 |
| _version_ | 1827150269628022784 |
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| author | Wern Hann Ng Zheng L. Ling Andrew J. Kueh Marco J. Herold Nicholas P. West Nicholas J. C. King Suresh Mahalingam Xiang Liu |
| author_facet | Wern Hann Ng Zheng L. Ling Andrew J. Kueh Marco J. Herold Nicholas P. West Nicholas J. C. King Suresh Mahalingam Xiang Liu |
| author_sort | Wern Hann Ng |
| collection | DOAJ |
| description | ABSTRACT Arthritogenic alphaviruses such as Ross River virus (RRV) and Chikungunya virus (CHIKV) are responsible for large-scale epidemics that cause debilitating acute and chronic musculoskeletal diseases. MXRA8 was recently discovered as an entry receptor for multiple alphaviruses including CHIKV, RRV, Mayaro virus (MAYV), and O’nyong-nyong virus (ONNV). However, the role of MXRA8 in the development of alphavirus-induced musculoskeletal inflammation has not yet been fully studied. Here, we attempt to fully characterize the contribution of MXRA8 to RRV disease in an established mouse model. MXRA8 knockout (MXRA8−/−) mice generated on a C57BL/6J background, showed abrogated disease signs and reduced viral replication, which correlated with lower viral load, diminished proinflammatory cytokines, and limited cell infiltrates in inflamed tissues. Immunomodulation genes were upregulated to higher levels in RRV-infected wild-type (WT) mice than in MXRA8−/− mice. Intriguingly, Cdkn1a and Ifi44 genes in blood and CD127/IL7RA, CD45, BatF3, IFNGR, Ly6G/Ly6C, CD40, CD127, F4/80, and MHC-II genes in quadriceps were found to be upregulated in RRV-infected MXRA8−/− mice compared to WT mice. Our results showed an essential role of MXRA8 in the immune response of mice infected with RRV and, more importantly, demonstrated novel changes in immunomodulation genes, which shed light on the immunopathogenesis of alphavirus-induced disease. IMPORTANCE Previous studies have shown the importance of the cell surface protein MXRA8 as an entry receptor for several different prominent alphaviruses such as CHIKV, RRV, MAYV, and ONNV. In particular, the role of MXRA8 in the tissue tropism, viral pathogenesis, and immune response of a CHIKV mouse model have already been briefly characterized. However, the role of MXRA8 warrants further characterization in RRV disease background, since there are noticeable differences in the disease profile between CHIKV and RRV. For example, patients infected with CHIKV are usually affected by sudden onset of severe arthritis and fever, whereas RRV-infected patients generally only have minor joint pain and mild fever. Here, we characterized the role of MXRA8 in RRV disease and assessed several key mechanisms of MXRA8 that may contribute to the disease progression. |
| first_indexed | 2024-04-09T16:00:03Z |
| format | Article |
| id | doaj.art-d8bb7595bbe543b2b78b9672a9c14295 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2025-03-20T21:31:24Z |
| publishDate | 2023-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-d8bb7595bbe543b2b78b9672a9c142952024-08-11T18:27:32ZengAmerican Society for MicrobiologymBio2150-75112023-04-0114210.1128/mbio.00588-23Role of MXRA8 in Ross River Virus Disease PathogenesisWern Hann Ng0Zheng L. Ling1Andrew J. Kueh2Marco J. Herold3Nicholas P. West4Nicholas J. C. King5Suresh Mahalingam6Xiang Liu7Emerging Viruses, Inflammation and Therapeutics Group, Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, AustraliaViral Immunopathology Laboratory, Infection, Immunity and Inflammation Research Theme, Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, AustraliaSchool of Pharmacy and Medical Sciences, Griffith University, Gold Coast, Queensland, AustraliaEmerging Viruses, Inflammation and Therapeutics Group, Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, AustraliaEmerging Viruses, Inflammation and Therapeutics Group, Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, AustraliaEmerging Viruses, Inflammation and Therapeutics Group, Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, AustraliaABSTRACT Arthritogenic alphaviruses such as Ross River virus (RRV) and Chikungunya virus (CHIKV) are responsible for large-scale epidemics that cause debilitating acute and chronic musculoskeletal diseases. MXRA8 was recently discovered as an entry receptor for multiple alphaviruses including CHIKV, RRV, Mayaro virus (MAYV), and O’nyong-nyong virus (ONNV). However, the role of MXRA8 in the development of alphavirus-induced musculoskeletal inflammation has not yet been fully studied. Here, we attempt to fully characterize the contribution of MXRA8 to RRV disease in an established mouse model. MXRA8 knockout (MXRA8−/−) mice generated on a C57BL/6J background, showed abrogated disease signs and reduced viral replication, which correlated with lower viral load, diminished proinflammatory cytokines, and limited cell infiltrates in inflamed tissues. Immunomodulation genes were upregulated to higher levels in RRV-infected wild-type (WT) mice than in MXRA8−/− mice. Intriguingly, Cdkn1a and Ifi44 genes in blood and CD127/IL7RA, CD45, BatF3, IFNGR, Ly6G/Ly6C, CD40, CD127, F4/80, and MHC-II genes in quadriceps were found to be upregulated in RRV-infected MXRA8−/− mice compared to WT mice. Our results showed an essential role of MXRA8 in the immune response of mice infected with RRV and, more importantly, demonstrated novel changes in immunomodulation genes, which shed light on the immunopathogenesis of alphavirus-induced disease. IMPORTANCE Previous studies have shown the importance of the cell surface protein MXRA8 as an entry receptor for several different prominent alphaviruses such as CHIKV, RRV, MAYV, and ONNV. In particular, the role of MXRA8 in the tissue tropism, viral pathogenesis, and immune response of a CHIKV mouse model have already been briefly characterized. However, the role of MXRA8 warrants further characterization in RRV disease background, since there are noticeable differences in the disease profile between CHIKV and RRV. For example, patients infected with CHIKV are usually affected by sudden onset of severe arthritis and fever, whereas RRV-infected patients generally only have minor joint pain and mild fever. Here, we characterized the role of MXRA8 in RRV disease and assessed several key mechanisms of MXRA8 that may contribute to the disease progression.https://journals.asm.org/doi/10.1128/mbio.00588-23MXRA8Ross River virusalphaviruspathogenesis |
| spellingShingle | Wern Hann Ng Zheng L. Ling Andrew J. Kueh Marco J. Herold Nicholas P. West Nicholas J. C. King Suresh Mahalingam Xiang Liu Role of MXRA8 in Ross River Virus Disease Pathogenesis mBio MXRA8 Ross River virus alphavirus pathogenesis |
| title | Role of MXRA8 in Ross River Virus Disease Pathogenesis |
| title_full | Role of MXRA8 in Ross River Virus Disease Pathogenesis |
| title_fullStr | Role of MXRA8 in Ross River Virus Disease Pathogenesis |
| title_full_unstemmed | Role of MXRA8 in Ross River Virus Disease Pathogenesis |
| title_short | Role of MXRA8 in Ross River Virus Disease Pathogenesis |
| title_sort | role of mxra8 in ross river virus disease pathogenesis |
| topic | MXRA8 Ross River virus alphavirus pathogenesis |
| url | https://journals.asm.org/doi/10.1128/mbio.00588-23 |
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