ArticlePLoS pathogens2017
RNA-Seq analysis of chikungunya virus infection and identification of granzyme A as a major promoter of arthritic inflammation.
Article in PLoS pathogens, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT00281294 (A Phase 2 Study to Evaluate the Safety, Tolerability, and Activity of Fontolizumab in Subjects With Active Rheumatoid Arthritis), which is not on this map. Cited by 87 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Phase 2 Study to Evaluate the Safety, Tolerability, and Activity of Fontolizumab in Subjects With Active Rheumatoid Arthritis
Who cites it
87 citing papers in PubMed, 117 citations in OpenAlex.
- Systems analysis of subjects acutely infected with the Chikungunya virus.PLoS pathogens · 2019Trial
- Glutamine antagonist DON attenuates chikungunya virus-induced myositis by suppressing inflammatory activation in a murine model.Emerging microbes & infections · 2026Article
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- Chikungunya virus persists in joint-associated macrophages and promotes chronic disease in mice.Nature microbiology · 2026Article
- Hidden in Plain Sight: Alphavirus Persistence and Its Potential for Driving Chronic Pathogenesis.Viruses · 2025Review
- Advances and perspectives for animal models of chikungunya virus infection.Biosafety and health · 2025Review
- Chikungunya virus and other emerging arthritogenic alphaviruses.Nature reviews. Microbiology · 2025Review
- Pathotype-Specific Expression of Granzyme-Perforin Pathway Genes and Their Association With Clinical Disease Activity in Early Rheumatoid Arthritis and in a Randomized Clinical Trial.Immune network · 2025Article
- Transcriptomic insights into early mechanisms underlying post-chikungunya chronic inflammatory joint disease.Scientific reports · 2025Article
- Pro-inflammatory granzyme K contributes extracellularly to disease.Frontiers in immunology · 2025Review
- Mutations in chikungunya virus nsP4 decrease viral fitness and sensitivity to the broad-spectrum antiviral 4'-Fluorouridine.PLoS pathogens · 2025Article
- Multiorgan proteomic analysis of infected animal models predict potential host factors for chikungunya virus.MedComm · 2025Article
- Obesity-Associated Changes in Immune Cell Dynamics During Alphavirus Infection Revealed by Single Cell Transcriptomic Analysis.bioRxiv : the preprint server for biology · 2024Article
- Safety concern of recombination between self-amplifying mRNA vaccines and viruses is mitigated in vivo.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Chronic chikungunya disease (CCD): clinical insights, immunopathogenesis and therapeutic perspectives.QJM : monthly journal of the Association of Physicians · 2024Review
- Long chikungunya? An overview to immunopathology of persistent arthralgia.World journal of virology · 2024Review
- Article
- Granzyme serine proteases in inflammation and rheumatic diseases.Nature reviews. Rheumatology · 2024Review
- Current challenges in the discovery of treatments against Mayaro fever.Expert opinion on therapeutic targets · 2024Review
27 more citing papers are in PubMed but not listed here.
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Authors and funding
19 authors at 8 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Chikungunya virus (CHIKV) is an arthritogenic alphavirus causing epidemics of acute and chronic arthritic disease. Herein we describe a comprehensive RNA-Seq analysis of feet and lymph nodes at peak viraemia (day 2 post infection), acute arthritis (day 7) and chronic disease (day 30) in the CHIKV adult wild-type mouse model. Genes previously shown to be up-regulated in CHIKV patients were also up-regulated in the mouse model. CHIKV sequence information was also obtained with up to ≈8% of the reads mapping to the viral genome; however, no adaptive viral genome changes were apparent. Although day 2, 7 and 30 represent distinct stages of infection and disease, there was a pronounced overlap in up-regulated host genes and pathways. Type I interferon response genes (IRGs) represented up to ≈50% of up-regulated genes, even after loss of type I interferon induction on days 7 and 30. Bioinformatic analyses suggested a number of interferon response factors were primarily responsible for maintaining type I IRG induction. A group of genes prominent in the RNA-Seq analysis and hitherto unexplored in viral arthropathies were granzymes A, B and K. Granzyme A-/- and to a lesser extent granzyme K-/-, but not granzyme B-/-, mice showed a pronounced reduction in foot swelling and arthritis, with analysis of granzyme A-/- mice showing no reductions in viral loads but reduced NK and T cell infiltrates post CHIKV infection. Treatment with Serpinb6b, a granzyme A inhibitor, also reduced arthritic inflammation in wild-type mice. In non-human primates circulating granzyme A levels were elevated after CHIKV infection, with the increase correlating with viral load. Elevated granzyme A levels were also seen in a small cohort of human CHIKV patients. Taken together these results suggest granzyme A is an important driver of arthritic inflammation and a potential target for therapy.
trial registrationClinicalTrials.gov NCT00281294.
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