Low-dose interleukin 2 therapy halts the progression of post-streptococcal autoimmune complications in a rat model of rheumatic heart disease
ABSTRACT Acute rheumatic fever (ARF) is an autoimmune disease triggered by antibodies and T cells targeting the group A Streptococcus (GAS, Strep A) bacterium, often leading to rheumatic heart disease (RHD) and Sydenham’s chorea. Long-term monthly penicillin injections are recognized as a cornerston...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2025-04-01
|
| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.03823-24 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849731255603560448 |
|---|---|
| author | Rukshan Ahamed Mohamed Rafeek Natkunam Ketheesan Michael F. Good Manisha Pandey Ailin Lepletier |
| author_facet | Rukshan Ahamed Mohamed Rafeek Natkunam Ketheesan Michael F. Good Manisha Pandey Ailin Lepletier |
| author_sort | Rukshan Ahamed Mohamed Rafeek |
| collection | DOAJ |
| description | ABSTRACT Acute rheumatic fever (ARF) is an autoimmune disease triggered by antibodies and T cells targeting the group A Streptococcus (GAS, Strep A) bacterium, often leading to rheumatic heart disease (RHD) and Sydenham’s chorea. Long-term monthly penicillin injections are recognized as a cornerstone of public health programs to prevent Strep A reinfection and progression of ARF. However, compliance is poor, and better tools are required to slow disease progression. Preclinical evidence suggests that this can be achieved. Using a rat model that replicates post-streptococcal autoimmune complications, we explored the potential of low-dose interleukin-2 (LD-IL-2) as an immunotherapeutic intervention for ARF/RHD. In this model, injections of recombinant M protein from Strep A type 5 (rM5) to Lewis rats induce cardiac tissue inflammation, conduction abnormalities, and cross-reactive antibodies against cardiac and brain proteins central to disease pathogenesis. In animals injected with rM5 and treated with LD-IL-2, no cardiac functional or histological changes was observed. LD-IL-2 therapy effectively reduced the production of cross-reactive antibodies raised against host proteins and significantly increased regulatory T cells in the mediastinal lymph nodes. These novel findings suggest that LD-IL-2 will be an effective immunotherapeutic agent for treating ARF and has the potential to replace the standard monthly penicillin injections.IMPORTANCEPost-streptococcal autoimmune syndromes, including acute rheumatic fever, rheumatic heart disease, and Sydenham’s chorea, represent a significant yet often under-recognized health and economic burden. This is especially true in low-income countries and among Indigenous populations in high-income nations, where the disease burden is most severe. These conditions arise from an autoimmune response to group A Streptococcus infections, leading to long-term health complications, disability, and premature death. Despite their widespread impact, no vaccine is currently available to prevent reinfections, and no specific therapy exists to treat the resulting autoimmune process. This study uses a rat model of rheumatic heart disease to evaluate the potential of low-dose interleukin 2 therapy in improving clinical outcomes and reducing the incidence of autoimmune diseases triggered by streptococcal infections. |
| format | Article |
| id | doaj-art-af3bc8aa6f3c42c7b46e6481d271049f |
| institution | DOAJ |
| issn | 2150-7511 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj-art-af3bc8aa6f3c42c7b46e6481d271049f2025-08-20T03:08:36ZengAmerican Society for MicrobiologymBio2150-75112025-04-0116410.1128/mbio.03823-24Low-dose interleukin 2 therapy halts the progression of post-streptococcal autoimmune complications in a rat model of rheumatic heart diseaseRukshan Ahamed Mohamed Rafeek0Natkunam Ketheesan1Michael F. Good2Manisha Pandey3Ailin Lepletier4School of Science and Technology, University of New England, New South Wales, AustraliaSchool of Science and Technology, University of New England, New South Wales, AustraliaInstitute for Biomedicine and Glycomics, Griffith University, Gold Coast, Queensland, AustraliaSchool of Science and Technology, University of New England, New South Wales, AustraliaSchool of Science and Technology, University of New England, New South Wales, AustraliaABSTRACT Acute rheumatic fever (ARF) is an autoimmune disease triggered by antibodies and T cells targeting the group A Streptococcus (GAS, Strep A) bacterium, often leading to rheumatic heart disease (RHD) and Sydenham’s chorea. Long-term monthly penicillin injections are recognized as a cornerstone of public health programs to prevent Strep A reinfection and progression of ARF. However, compliance is poor, and better tools are required to slow disease progression. Preclinical evidence suggests that this can be achieved. Using a rat model that replicates post-streptococcal autoimmune complications, we explored the potential of low-dose interleukin-2 (LD-IL-2) as an immunotherapeutic intervention for ARF/RHD. In this model, injections of recombinant M protein from Strep A type 5 (rM5) to Lewis rats induce cardiac tissue inflammation, conduction abnormalities, and cross-reactive antibodies against cardiac and brain proteins central to disease pathogenesis. In animals injected with rM5 and treated with LD-IL-2, no cardiac functional or histological changes was observed. LD-IL-2 therapy effectively reduced the production of cross-reactive antibodies raised against host proteins and significantly increased regulatory T cells in the mediastinal lymph nodes. These novel findings suggest that LD-IL-2 will be an effective immunotherapeutic agent for treating ARF and has the potential to replace the standard monthly penicillin injections.IMPORTANCEPost-streptococcal autoimmune syndromes, including acute rheumatic fever, rheumatic heart disease, and Sydenham’s chorea, represent a significant yet often under-recognized health and economic burden. This is especially true in low-income countries and among Indigenous populations in high-income nations, where the disease burden is most severe. These conditions arise from an autoimmune response to group A Streptococcus infections, leading to long-term health complications, disability, and premature death. Despite their widespread impact, no vaccine is currently available to prevent reinfections, and no specific therapy exists to treat the resulting autoimmune process. This study uses a rat model of rheumatic heart disease to evaluate the potential of low-dose interleukin 2 therapy in improving clinical outcomes and reducing the incidence of autoimmune diseases triggered by streptococcal infections.https://journals.asm.org/doi/10.1128/mbio.03823-24acute rheumatic feverrheumatic heart diseasegroup A streptococcuslow-dose interleukin-2immunotherapyautoimmune diseases |
| spellingShingle | Rukshan Ahamed Mohamed Rafeek Natkunam Ketheesan Michael F. Good Manisha Pandey Ailin Lepletier Low-dose interleukin 2 therapy halts the progression of post-streptococcal autoimmune complications in a rat model of rheumatic heart disease mBio acute rheumatic fever rheumatic heart disease group A streptococcus low-dose interleukin-2 immunotherapy autoimmune diseases |
| title | Low-dose interleukin 2 therapy halts the progression of post-streptococcal autoimmune complications in a rat model of rheumatic heart disease |
| title_full | Low-dose interleukin 2 therapy halts the progression of post-streptococcal autoimmune complications in a rat model of rheumatic heart disease |
| title_fullStr | Low-dose interleukin 2 therapy halts the progression of post-streptococcal autoimmune complications in a rat model of rheumatic heart disease |
| title_full_unstemmed | Low-dose interleukin 2 therapy halts the progression of post-streptococcal autoimmune complications in a rat model of rheumatic heart disease |
| title_short | Low-dose interleukin 2 therapy halts the progression of post-streptococcal autoimmune complications in a rat model of rheumatic heart disease |
| title_sort | low dose interleukin 2 therapy halts the progression of post streptococcal autoimmune complications in a rat model of rheumatic heart disease |
| topic | acute rheumatic fever rheumatic heart disease group A streptococcus low-dose interleukin-2 immunotherapy autoimmune diseases |
| url | https://journals.asm.org/doi/10.1128/mbio.03823-24 |
| work_keys_str_mv | AT rukshanahamedmohamedrafeek lowdoseinterleukin2therapyhaltstheprogressionofpoststreptococcalautoimmunecomplicationsinaratmodelofrheumaticheartdisease AT natkunamketheesan lowdoseinterleukin2therapyhaltstheprogressionofpoststreptococcalautoimmunecomplicationsinaratmodelofrheumaticheartdisease AT michaelfgood lowdoseinterleukin2therapyhaltstheprogressionofpoststreptococcalautoimmunecomplicationsinaratmodelofrheumaticheartdisease AT manishapandey lowdoseinterleukin2therapyhaltstheprogressionofpoststreptococcalautoimmunecomplicationsinaratmodelofrheumaticheartdisease AT ailinlepletier lowdoseinterleukin2therapyhaltstheprogressionofpoststreptococcalautoimmunecomplicationsinaratmodelofrheumaticheartdisease |