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Persistent Chronic Inflammation and Infection byChikungunya Arthritogenic Alphavirus in Spite of a Robust Host Immune
The Journal of Immunology, 2010, 184: 000-000.
Jean-Jacques Hoarau,*,†,1 Marie-Christine Jaffar Bandjee,*,†,‡,1 Pascale Krejbich Trotot,†,‡ Trina Das,†,‡ Ghislaine Li-Pat-Yuen,* Be´renge`re Dassa,* Me´lanie Denizot,†,‡ Elsa Guichard,* Anne Ribera,x Tawfiq Henni,{ Frank Tallet,* Marie Pierre Moiton,! Bernard Alex Gauze`re,†,# Sandrine Bruniquet,* Zaý¨noul Jaffar Bandjee,** Philippe Morbidelli,†† Ge´rard Martigny,†† Michel Jolivet,‡‡ Frederick Gay,xx Marc Grandadam,{{ Hugues Tolou,{{ Vincent Vieillard,!! Patrice Debre´,!! Brigitte Autran,!! and Philippe Gasque*,†,‡,!!
It is plausible that CHIKV persisting in immunoprivileged niches (called here sanctuaries) contributes directly to synovial tissue damage. CHIKV may trigger persistent joint pain and arthritis-like pathology with mechanisms possibly involving not only hostderived inflammatory cytokines but also the virus itself hijacking the "soldier" of the innate immune system, the resident tissue macrophages as described for RRV.
Patients with post-CHIKV RA-like arthritis are currently and efficiently treated with methotrexate (10-20 mg/wk for months), but this drug has also immunosuppressive activities that may complicate the issue of possible viral reactivation
Alphaviruses, including Chikungunya virus (CHIKV), produce a transient illness in humans, but severe forms leading to chronic incapacitating arthralgia/arthritis have been reported by mechanisms largely ill-characterized. The pathogenesis of CHIKV was addressed in a prospective cohort study of 49 hospitalized patients from Reunion Island subsequently categorized into two distinct groups at 12 mo postinfection.
Comprehensive analyses of the clinical and immunological parameters throughout the disease course were analyzed in either the “recovered” or the “chronic” groups to identify prognostic markers of arthritis-like pathology after CHIKV disease.
We found that the chronic group consisted mainly of more elderly patients (>60 y) and with much higher viral loads (up to 1010 viruses per milliliter of blood) during the acute phase. Remarkably, a rapid innate immune antiviral response was demonstrated by robust dendritic/NK/CD4/CD8 cell activation and accompanied by a rather weak Th1/Th2 cytokine response in both groups.
Interestingly, the antiviral immune response witnessed by high levels of IFN-a mRNA in PBMCs and circulating IL-12 persisted for months only in the chronic group.
CHIKV (RNA and proteins) was found in perivascular synovial macrophages in one chronic patient 18 mo postinfection surrounded by infiltrating NK and T cells (CD4++ but rare cytotoxic CD8). Fibroblast hyperplasia, strong angiogenesis, tissue lesions given the high levels of matrix metalloproteinase 2, and acute cell death [high cleaved poly (ADP-ribose) polymerase staining] were observed in the injured synovial tissue.
These observed cellular and molecular events may contribute to chronic arthralgia/arthritis targeted by methotrexate used empirically for effective treatment but with immunosuppressive function in a context of viral persistence.
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