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Review
. 2012;6(3):e1446.
doi: 10.1371/journal.pntd.0001446. Epub 2012 Mar 27.

Chikungunya disease: infection-associated markers from the acute to the chronic phase of arbovirus-induced arthralgia

Affiliations
Review

Chikungunya disease: infection-associated markers from the acute to the chronic phase of arbovirus-induced arthralgia

Laurence Dupuis-Maguiraga et al. PLoS Negl Trop Dis. 2012.

Abstract

At the end of 2005, an outbreak of fever associated with joint pain occurred in La Réunion. The causal agent, chikungunya virus (CHIKV), has been known for 50 years and could thus be readily identified. This arbovirus is present worldwide, particularly in India, but also in Europe, with new variants returning to Africa. In humans, it causes a disease characterized by a typical acute infection, sometimes followed by persistent arthralgia and myalgia lasting months or years. Investigations in the La Réunion cohort and studies in a macaque model of chikungunya implicated monocytes-macrophages in viral persistence. In this Review, we consider the relationship between CHIKV and the immune response and discuss predictive factors for chronic arthralgia and myalgia by providing an overview of current knowledge on chikungunya pathogenesis. Comparisons of data from animal models of the acute and chronic phases of infection, and data from clinical series, provide information about the mechanisms of CHIKV infection-associated inflammation, viral persistence in monocytes-macrophages, and their link to chronic signs.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Virus dissemination and target organs.
Following inoculation with CHIKV through a mosquito bite, the virus directly enters the subcutaneous capillaries, with some viruses infecting susceptible cells in the skin, such as macrophages or fibroblasts and endothelial cells. Local viral replication seems to be minor and limited in time, with the locally produced virus probably being transported to secondary lymphoid organs close to the site of inoculation. The blood carries most viruses, as free virions or in the form of infected monocytes, to the target organs, the liver, muscle, joints, and remote lymphoid organs. In these tissues, infection is associated with a marked infiltration of mononuclear cells, including macrophages, particularly when viral replication occurs. The pathological events associated with tissue infection are mostly subclinical in the liver (hepatocyte apoptosis) and lymphoid organs (adenopathy), whereas mononuclear cell infiltration and viral replication in the muscles and joints are associated with very strong pain, with some of the patients presenting arthritis. * Guillain-Barré syndrome and encephalitis are very rare events. † True arthritis remains a rare event (from 2% to 10%); see Table 2.
Figure 2
Figure 2. Mechanisms of CHIKV persistence and tissue inflammation in patients with chronic disease.
(1) Months after the acute infection, monocytes, T cells, and natural killer (NK) cells are still attracted to the inflamed joint, where they become activated. (2) The infection of macrophages in joints is associated with local inflammation and the production of cytokines, chemokines, and pro-inflammatory effectors, such as MCP-1/CCL-2, IL-8, IL-6, IFN-α, and MMP2. (3) The phagocytosis of apoptotic bodies from infected cells probably contributes to viral persistence. Nevertheless, the beneficial or deleterious effect of local inflammation on viral persistence remains unclear. (4) When it occurs, arthritis is accompanied by high rates of fibroblast apoptosis and cartilage destruction. Chronic inflammation probably plays a major role in this damage and associated pain. (5) The potential relationship between local inflammation of the joint and a state of systemic activation, as demonstrated by the presence of inflammation markers in plasma and blood cells, remains unclear.
Figure 3
Figure 3. The macrophage is central to chronic signs of chikungunya disease.
Macrophage infiltration, under the control of MCP-1/CCL-2, is a critical feature of damaged tissues. The inflammatory effectors IL-6, IL-8, MCP-1/CCL-2, MMP2, and INF-α are specifically expressed in the tissues of patients with chronic chikungunya, who have high IFN-α and IL-12 mRNA levels in their circulating leukocytes. This classical inflammatory process may be regulated by HGF and eotaxin, which have different expression profiles during the recovery phase in patients with chikungunya, depending on whether or not these patients go on to develop chronic disease. HGF also promotes muscle regeneration. Once they have infiltrated the joint or muscle, the macrophages are activated and regulate the local Th1/Th2 balance as a function of their own activation status (classical/M1 or alternative/M2). GM-CSF and HGF, which have M1 and M2 effector activities, respectively, may modulate this balance as they are differentially expressed in acute and chronic chikungunya. CHIKV persists in infected macrophages only in patients with a chronic rheumatic syndrome. The reciprocal influences connecting viral persistence and local inflammation are not known. Solid arrows: activation. Solid stopped lines: regulation. Dotted arrows: expression.

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