Chikungunya Arthritis Mechanisms in the Americas

Chang, Aileen Y.; Martins, Karen; Encinales, Liliana; Reid, St Patrick; Acuña, Marlon; Encinales, Carlos; Matranga, Christian B.; Pacheco, Nelly; Cure, Carlos; Shukla, Bhavarth; Arteta, Teofilo Ruiz; Amdur, Richard L.; Cazares, Lisa H.; Gregory, Melissa K.; Ward, Michael D.; Porras, Alexandra; Rico-Mendoza, Alejandro; Liu, Dong; Kenny, Tara; Brueggemann, Ernie; Downey, Lydia G; Kamalapathy, Priyanka; Lichtenberger, Paola; Falls, Orlando; Simon, Gary L.; Bethony, Jeffrey M.; Firestein, Gary S.

doi:10.1002/art.40383

Cited by 65 publications

(32 citation statements)

References 35 publications

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“…Classically, patients acutely infected with CHIKV present with a febrile illness, polyarthralgia, myalgia and maculopapular rash that can last for several days [ 3 , 4 ]. Remarkably, severe complications in adults such as persistent arthralgia and destructive arthritis have been reported, consistent with chronic inflammatory rheumatisms (CIR)[ 5 – 8 ]. Symptoms can persist for months or even years following initial infection.…”

Section: Introductionmentioning

confidence: 95%

Immunomodulatory drug methotrexate used to treat patients with chronic inflammatory rheumatisms post-chikungunya does not impair the synovial antiviral and bone repair responses

Bedoui¹,

Giry²,

Jaffar‐Bandjee³

et al. 2018

PLoS Negl Trop Dis

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Chikungunya virus (CHIKV) is a mosquito-transmitted RNA alphavirus causing major outbreaks of infectious chronic inflammatory rheumatisms (CIR). Recently, methotrexate (MTX), a disease modifying anti-rheumatic drug has been used successfully to treat patients suffering from rheumatoid-like arthritis post-CHIK but its immunomodulatory activity in the context of viral persistence has been a matter of concerns. We herein used a model of primary human synovial fibroblasts (HSF) and the synthetic molecule polyriboinosinic:polyribocytidylic acid (PIC) to mimic chronic infectious settings in the joints of CHIKV infected patients. The innate antiviral immune and inflammatory responses were investigated in response to MTX used at the therapeutic concentration of 1 μM. We found that MTX did not affect cellular viability as indicated by the LDH release assay. By quantitative RT-PCR, we observed that HSF responded robustly to PIC by increasing ISG15 and IFNβ mRNA levels. Furthermore, PIC upregulated the mRNA expression of two of the major pattern recognition receptors, RIG-I and MDA5 involved in the innate immune detection of viral RNA. MTX did not impact the antiviral response of PIC on ISG15, IFNβ, RIG-I and MDA5 mRNA expressions. MTX alone or combined with PIC did not affect the expression of proinflammatory CCL2 and CXCL8 chemokines. PIC strongly upregulated the mRNA and protein expression of osteoclastogenic factors (IL-6, GM-CSF but not RANKL). Critically, MTX treatment alone or combined with PIC did not affect the expression of all three tested osteoclastogenic cytokines. We found that MTX alone did not increase the capacity of CHIKV to infect and replicate in HSF. In conclusion, our study argues for a beneficial effect of MTX to treat CIR post-CHIKV given that it does not critically impact the antiviral, the proinflammatory and the bone tissue remodeling responses of synovial cells.

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Section: Introductionmentioning

confidence: 95%

Immunomodulatory drug methotrexate used to treat patients with chronic inflammatory rheumatisms post-chikungunya does not impair the synovial antiviral and bone repair responses

Bedoui¹,

Giry²,

Jaffar‐Bandjee³

et al. 2018

PLoS Negl Trop Dis

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“…Patrick Reid (Pathology and Microbiology Department, University of Nebraska at Omaha, NE, USA) talked about integrating clinical and molecular data towards elucidating the mechanism underlying CHIKV-induced arthritis. Fever, polyarthralgia, and polyarthritis are the main symptoms of patients infected by CHIKV (Chang et al, 2018). Understanding the mechanism involved in these symptoms such as arthritis will help in the search for new therapeutics.…”

Section: Alphaviruses (Chikungunya): Molecular Biology Pathogenesismentioning

confidence: 99%

Third Tofo Advanced Study Week on Emerging and Re-emerging Viruses, 2018

et al. 2019

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Singapore, and the USA. Meeting sessions covered aspects of the epidemiology, diagnosis, molecular and structural biology, vaccine development, and antiviral drug discovery for emerging RNA viruses that are current threats in Africa and included flaviviruses (dengue and Zika), alphaviruses (chikungunya), coronaviruses, filoviruses (Ebola), influenza viruses, Crimean Congo hemorrhagic fever virus, Rift Valley fever Virus, Lassa virus, and others. Data were presented on recent flavivirus and/or chikungunyavirus outbreaks in Angola, Burkina Faso, and Mozambique. In addition, these viruses are endemic in many sub-Saharan countries. The TASW series on emerging viruses is unique in Africa and successful in promoting collaborations between researchers in Africa and other parts of the world, as well as among African scientists. This report summarizes the lectures held at the meeting and highlights advances in the field.

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“…Immune cell infiltration is a hallmark of acute CHIKV infection, including primarily macrophages, monocytes, but also neutrophils, dendritic cells, NK cells and lymphocytes 2 . In the chronic phase, CHIKV arthritis may progress without active viral replication, typified by elevated expression of cytokines and immune cell infiltration 2,13 . In particular, human arthritic disease severity is associated with a high level of serum chemoattractants for monocytes/macrophages/T cells, CXCL10 and CXCL9 14 .…”

Section: Introductionmentioning

confidence: 99%

STING deficiency-associated aberrant CXCL10 expression contributes to pathogenesis of arthritogenic alphaviruses

Lin

Geng

Harrison

et al. 2020

Preprint

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19Arthritogenic alphaviruses such as Chikungunya virus and O'nyong nyong virus cause acute 20 and chronic crippling arthralgia associated with inflammatory immune responses. However, the 21 physiological functions of individual immune signaling pathways in the pathogenesis of 22 alphaviral arthritis remain poorly understood. Here we report that a deficiency in the stimulator-23 of-interferon-genes (STING) led to enhanced viral loads, exacerbated inflammation and 24 selectively elevated expression of CXCL10, a chemoattractant for monocytes/macrophages/T 25 cells, in mouse feet. Cxcl10 -/mice had the same viremia as wild-type animals, but fewer 26 immune infiltrates and lower viral loads in footpads at the peak of arthritic disease (6-8 days 27 post infection). Macrophages constituted the largest immune cell population in footpads 28 following infection, which were significantly reduced in Cxcl10 -/mice. The viral RNA loads in 29 neutrophils and macrophages were reduced in Cxcl10 -/compared to wild-type mice. In 30 summary, our results demonstrate that STING signaling represses, while CXCL10 signaling 31 promotes, pathogenesis of alphaviral disease. 32 33 34 35 36 37 38 42 worldwide, particularly in tropical/subtropical regions. Many alphaviruses are arthritogenic, 43 including Chikungunya (CHIKV), O'nyong-nyong (ONNV) and Ross River viruses (RRV) etc. 44CHIKV is the causative agent of acute and chronic crippling arthralgia that was initially identified 45 in Tanzania in 1952 1 . Since then, several major epidemics have been recorded on the Indian 46Ocean islands, India, Southeast Asia, which resulted in over 6 million cases 2 . In late 2013, 47CHIKV emerged on the Caribbean islands, and has now spread to more than 50 countries 48 across the Central and South America, including autochthonous infections in the United States 49 and caused over 2.5 million infection cases (Sources: Pan America Health Organization). 50Approximately 50% of CHIKV-infected patients suffer from rheumatic manifestations that last 6 51 months to years, with ~5% of the victims having rheumatoid arthritis-like illnesses 3,4 . 52During the acute phase of infection in humans (~ two weeks), CHIKV infects many 53 organs and cell types 2 , induces apoptosis and direct tissue damage 5-7 . The acute phase is also 54 characteristic of robust innate immune responses, including high levels of type I IFNs, 55 proinflammatory cytokines/chemokines and growth factors 5,8-12 . Immune cell infiltration is a 56 hallmark of acute CHIKV infection, including primarily macrophages, monocytes, but also 57 neutrophils, dendritic cells, NK cells and lymphocytes 2 . In the chronic phase, CHIKV arthritis 58 may progress without active viral replication, typified by elevated expression of cytokines and 59 immune cell infiltration 2,13 . In particular, human arthritic disease severity is associated with a 60 high level of serum chemoattractants for monocytes/macrophages/T cells, CXCL10 and CXCL9 61 14 . In mice, CHIKV infection leads to a low viremia lasting usually 5-7 ...

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Chikungunya Arthritis Mechanisms in the Americas

Cited by 65 publications

References 35 publications

Immunomodulatory drug methotrexate used to treat patients with chronic inflammatory rheumatisms post-chikungunya does not impair the synovial antiviral and bone repair responses

Immunomodulatory drug methotrexate used to treat patients with chronic inflammatory rheumatisms post-chikungunya does not impair the synovial antiviral and bone repair responses

Third Tofo Advanced Study Week on Emerging and Re-emerging Viruses, 2018

STING deficiency-associated aberrant CXCL10 expression contributes to pathogenesis of arthritogenic alphaviruses

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