Persistent chronic inflammation and infection by Chikungunya arthritogenic alphavirus in spite of a robust host immune response.
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.
Hoarau
Jean-Jacques
JJ
Biology Unit, Centre Hospitalier Régional Nord Félix-Guyon and Cyclotron Réunion Océan Indien, Université de la Réunion, St. Denis, France.
Jaffar Bandjee
Marie-Christine
MC
Krejbich Trotot
Pascale
P
Das
Trina
T
Li-Pat-Yuen
Ghislaine
G
Dassa
Bérengère
B
Denizot
Mélanie
M
Guichard
Elsa
E
Ribera
Anne
A
Henni
Tawfiq
T
Tallet
Frank
F
Moiton
Marie Pierre
MP
Gauzère
Bernard Alex
BA
Bruniquet
Sandrine
S
Jaffar Bandjee
Zaïnoul
Z
Morbidelli
Philippe
P
Martigny
Gérard
G
Jolivet
Michel
M
Gay
Frederick
F
Grandadam
Marc
M
Tolou
Hugues
H
Vieillard
Vincent
V
Debré
Patrice
P
Autran
Brigitte
B
Gasque
Philippe
P
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