Persistent Chronic Inflammation and Infection by Chikungunya Arthritogenic Alphavirus in Spite of a Robust Host Immune Response

Abstract

International audienceAlphaviruses, 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 (\textgreater60 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-α 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

A Mouse Model of Chikungunya Virus–Induced Musculoskeletal Inflammatory Disease

“…Furthermore, Gardner et al did not report any evidence for CHIKV persistence in their model, although this has been reported both in CHIKV-infected humans and nonhuman primates. 21,34 In contrast, we observed ongoing inflammation in joint tissues at least 3 weeks after inoculation, as well as joint-specific persistence of CHIKV RNA. These differences may reflect the differences in mouse age or the virus isolate used in the two studies and require further investigation.…”

Arthrogenic Alphaviruses and Inflammatory Myopathies

“…This is the first in vivo study to show that CHIKV persistence in macrophages may be responsible for the long-lasting symptoms observed in humans. A study of viral persistence in macrophages during human infection has demonstrated evidence of CHIKV antigens in perivascular synovial macrophages in a CHIKV patient 18 months after the initial infection (Hoarau et al, 2010). Thus, it is reasonable to speculate that viral persistence in macrophages may trigger low levels of macrophage activation long term, which may contribute to chronic disease symptoms.…”

“…Similar to studies with RRV, analysis of serum samples from CHIKV-infected patients has also shown elevated levels of cytokines and chemokines. Of particular interest is the upregulation of IL-6, TNF-, IL-1, IFN-, interferon-inducible protein-10 (IP-10) and monokine induced by IFN- (MIG) (Hoarau et al, 2010;Ng et al, 2009b). There has been an association between high levels of viraemia in acute CHIKV-infected patients and a higher production of pro-inflammatory cytokines such as IL-6 and TNF- (Chow et al, 2011).…”

“…As muscle inflammation is one of the primary symptoms of the acute and sub-acute stages of viral infection, it is thought that the onset of an idiopathic inflammatory myopathy could be triggered by a chronic underlying viral infection. The ability of alphaviruses to cause persistent and chronic infections has been recently studied with the demonstration of the presence of viral antigens in the muscle and synovial tissue of infected patients (Hoarau et al, 2010;Ozden et al, 2007). Invading pathogens can cause muscle tissue damage in both direct (by means of infection), and indirect (involving immune mediated damage) mechanisms.…”

Chikungunya and Its Interaction With the Host Cell

“…Several studies have tried to identify the factors associated with chronic Chikungunya disease in groups of patients in Singapore [83], La Réunion [84], Dakshina Kannada (India) [85,86], and Emilia Romagna (Italy) [87]. Regulatory mechanisms silencing the vigorous (even localized) inflammatory response seem to be required to prevent the establishment of chronic disease weeks or even months after viral clearance from the blood.…”