title: Persistent chronic inflammation and infection by Chikungunya arthritogenic alphavirus in spite of a robust host immune response.
abstract: 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 10(10) 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-alpha 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.
authors.affiliation: Biology Unit, Centre Hospitalier Régional Nord Félix-Guyon and Cyclotron Réunion Océan Indien, Université de la Réunion, St. Denis, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Hoarau
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Jaffar Bandjee
authors.forename: Pascale
authors.initials: P
authors.lastname: Krejbich Trotot
authors.forename: Trina
authors.initials: T
authors.lastname: Das
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Li-Pat-Yuen
authors.forename: Bérengère
authors.initials: B
authors.lastname: Dassa
authors.forename: Mélanie
authors.initials: M
authors.lastname: Denizot
authors.forename: Elsa
authors.initials: E
authors.lastname: Guichard
authors.forename: Anne
authors.initials: A
authors.lastname: Ribera
authors.forename: Tawfiq
authors.initials: T
authors.lastname: Henni
authors.forename: Frank
authors.initials: F
authors.lastname: Tallet
authors.forename: Marie Pierre
authors.initials: MP
authors.lastname: Moiton
authors.forename: Bernard Alex
authors.initials: BA
authors.lastname: Gauzère
authors.forename: Sandrine
authors.initials: S
authors.lastname: Bruniquet
authors.forename: Zaïnoul
authors.initials: Z
authors.lastname: Jaffar Bandjee
authors.forename: Philippe
authors.initials: P
authors.lastname: Morbidelli
authors.forename: Gérard
authors.initials: G
authors.lastname: Martigny
authors.forename: Michel
authors.initials: M
authors.lastname: Jolivet
authors.forename: Frederick
authors.initials: F
authors.lastname: Gay
authors.forename: Marc
authors.initials: M
authors.lastname: Grandadam
authors.forename: Hugues
authors.initials: H
authors.lastname: Tolou
authors.forename: Vincent
authors.initials: V
authors.lastname: Vieillard
authors.forename: Patrice
authors.initials: P
authors.lastname: Debré
authors.forename: Brigitte
authors.initials: B
authors.lastname: Autran
authors.forename: Philippe
authors.initials: P
authors.lastname: Gasque
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018354:Alphavirus Infections / Q000453:epidemiology / Q000276:immunology* / Q000473:pathology*; D018771:Arthralgia / Q000175:diagnosis / Q000276:immunology / Q000821:virology; D001170:Arthritis, Infectious / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D002646:Chikungunya virus / Q000276:immunology* / Q000472:pathogenicity; D002908:Chronic Disease; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007110:Immunity, Active; D007249:Inflammation / Q000453:epidemiology / Q000276:immunology / Q000821:virology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D017508:Reunion / Q000453:epidemiology; D019562:Viral Load / Q000276:immunology; D014766:Viremia / Q000175:diagnosis / Q000276:immunology / Q000473:pathology; D055815:Young Adult