Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies (original) (raw)
Studies of CHIKV-infected humans and animals have defined symptoms and immune responses of acute and chronic CHIVK disease, but much of the molecular interplay between virus and host remains to be established. CHIKV-induced disease shares many similarities with illnesses caused by other arthritogenic alphaviruses, with some distinctions observed (reviewed in refs. 101–103). After deposition into the bloodstream or skin through a bite of an infected mosquito, CHIKV replicates at the site of inoculation in fibroblasts and possibly macrophages (Figure 3 and refs. 8, 70, 104, 105). Despite triggering innate immune responses, the virus spreads via lymphatics into the bloodstream, allowing dissemination to several sites of replication, most commonly lymphoid organs (lymph nodes and spleen), skin, and especially tissues where prominent disease symptoms occur (muscle, peripheral joints, and tendons) but also in brain and liver in more severe cases (72, 104–109). Replication of CHIKV in peripheral tissues results in remarkably high serum viral loads (>109 virus particles/ml; ref. 110). Such high-level viremia in humans is rare for most alphaviruses and allows CHIKV to be easily transmitted to mosquitoes via a bloodmeal.
Model of acute and chronic CHIKV pathogenesis. Acute CHIKV infection begins with transmission of the virus via a bite of an infected mosquito to the skin, where it replicates in susceptible cells, including fibroblasts and macrophages. The virus disseminates through lymphatics and bloodstream to typical (solid) and atypical (hatched) sites of primary replication (indicated in blue). Acute infection elicits an inflammatory response in infected tissues, characterized by an extensive infiltration of mainly macrophages and monocytes, but also neutrophils, NK cells, and lymphocytes in target tissues (indicated in blue), and by elaboration of a number of proinflammatory chemokines and cytokines. Within arthroskeletal tissues, synovial hyperplasia begins. Viral replication and host immune responses cause myalgia and polyarthralgia in distal joints. Chronic CHIKV disease can persist for months or years after acute infection but is often limited to more distal joints. Chronic disease is likely mediated by persistent virus and inflammation. Possible sites of CHIKV persistence include endothelial cells in the liver and other organs, mononuclear cells in the spleen, macrophages within the synovial fluid and surrounding tissues, and satellite cells within the muscle (indicated in purple). Within the chronically infected joint, the continued presence of a subset of infiltrating cells (mainly macrophages, monocytes, and lymphocytes) and specific proinflammatory mediators (IL-6, IL-8, and MCP-1) within the synovial fluid likely contribute to prolonged inflammatory disease. Chronic joint pathology resembles that in rheumatoid arthritis, with significant hyperplasia and angiogenesis. This model is based on human and animal studies.
Acute CHIKV infection elicits robust innate immune responses, leading to elevation of type I IFNs and numerous proinflammatory chemokines, cytokines, and growth factors (Table 2 and refs. 70, 111–115). Type I IFN signaling controls viral replication and pathogenesis during acute infection (104, 114–116). In humans, IFN-α appears early in infection and correlates with viral load (111, 114, 117). Coincident with rising viral loads and IFN-α responses, the vast majority of infected patients experience sudden onset of clinical illness (Table 1), with a small proportion of infected individuals (5%–28%) remaining asymptomatic (118, 119). Acute CHIKV infection is predominated by high fever (39°C–40°C), which can last up to a week and may occur in a biphasic manner (2, 120). After fever onset, most patients develop severe and often debilitating polyarthralgia that is usually bilateral and symmetric, most commonly in ankles, wrists, and phalanges. Other symptoms include arthritis, asthenia, conjunctivitis, gastrointestinal distress, headache, myalgia, and rash, which is usually maculopapular and pruritic (Table 1). In recent epidemics, more atypical and severe symptoms have been observed, including multiple dermatological manifestations, hemorrhage, hepatitis, myocarditis, neurological disorders, and ocular disease (Table 1 and refs. 110, 121–124). Atypical symptoms are most prevalent among vulnerable groups, including neonates, the elderly, and those with underlying comorbidities.
In animal models (reviewed in refs. 20 and 125), innate immune responses triggered by viral replication recruit inflammatory cells to infected musculoskeletal tissues, which are thought to contribute to muscular and articular damage resulting in pain and discomfort in muscles, joints, and tendons (Figure 3). Virus titers decline with the development of CHIKV-specific adaptive immunity. Although viremia is usually cleared 5–7 days after infection and most acute symptoms resolve within 2 weeks, rheumatic manifestations can persist for months to years in a subset of individuals (7–10, 37, 103, 126, 127). The percentage of CHIKV-infected patients reported to develop protracted illness varies greatly (~14% to ~87%), but an average prevalence of approximately 48% among infected patients has been estimated (128). Risk factors for chronic CHIKV disease include age (>45 years), preexisting chronic inflammatory arthropathy, and severity of symptoms during the acute phase (129, 130). Two types of persistent CHIKV-induced rheumatic disorders have been described (131). The vast majority of patients experience chronic musculoskeletal disorders and usually respond to some extent to analgesics, antiinflammatory treatments, and physiotherapy. However, approximately 5% of patients meet the criteria for chronic inflammatory rheumatism, which may be destructive and deforming (131). Thus, the underlying mechanisms of CHIKV disease may involve multiple distinct immunopathological processes. Early differentiation of chronic CHIKV infection would inform disease management, which may vary according to type.
Symptoms of acute CHIKV disease are caused by direct cellular damage and local inflammation, but the specific contributions of viral replication and the host immune response to CHIKV infection are yet to be completely unraveled. CHIKV infection is cytopathic and induces apoptosis, resulting in direct tissue injury (70, 132, 133). Numerous cell types, many of which are located at sites of disease, are susceptible to CHIKV, including chondrocytes, endothelial cells, fibroblasts, hepatocytes, macrophages, monocytes, muscle satellite cells, myocytes, and osteoblasts (8, 72, 75, 104–107, 113, 116, 134–139). A meta-analysis of immune mediators from geographically distinct cohorts (111) revealed a common signature profile during acute CHIKV disease in humans (Table 3). Several of these soluble factors are associated with the progression of rheumatoid arthritis (140). In multiple cohorts, elevated levels of IL-1β, IL-6, and monocyte chemoattractant protein-1 (MCP-1) correlate with disease severity (117, 141), and high levels of IL-6 and GM-CSF correlate with persistent arthralgia (refs. 104, 117, and Table 3). Thus, an imbalance of immune mediators required for effective antiviral defense also likely contributes to CHIKV pathogenesis. Although CHIKV infection is controlled by the innate immune response in both hematopoietic and nonhematopoietic cells (113, 114), the specific cellular targets of infection that contribute to the orchestration of these responses in vivo remain largely undefined.
Common elevated immune mediators associated with CHIKV disease in humans
Although many hematopoietic cells appear refractory to CHIKV infection (66, 70, 114), monocytes and macrophages are targeted by CHIKV and contribute to virus-induced pathogenesis in both humans and animals (reviewed in ref. 142). Activated macrophages are the primary infiltrating cell in infected tissues (Figure 3 and refs. 8, 72, 105–107), and elevated levels of MCP-1, the major chemoattractant for monocytes and macrophages, correlate with high viral loads in persons with acute CHIKV infection (8, 106, 111–113, 117, 143). Depletion of macrophages in mice results in reduced CHIKV-associated musculoskeletal disease but significantly prolonged viremia (106), highlighting independent functions of macrophages in CHIKV disease. Monocytes and macrophages have been detected in synovial fluid from chronic CHIKV patients (8) and animals (105), and CHIKV RNA and protein are detectable in synovial macrophages from humans (8) and nonhuman primates (NHPs) (105) during the chronic phase of infection. These data suggest that macrophages are a source of persistent virus and contribute to CHIKV-induced arthropathy. Plasmacytoid dendritic cells, NK cells, and neutrophils also infiltrate infected tissues during acute CHIKV infection (8, 143–146), but their role in CHIKV control remains to be clarified.
Acute infection in humans leads to activation and proliferation of CD8+ T cells, while a CD4+ T cell response is dominant during the chronic phase of CHIKV disease (8, 115). Although activated, CD8+ T cells do not appear to mediate CHIKV clearance or disease in animals (125). In contrast, studies using mice deficient in various types of lymphocytes implicate CD4+ T cells as inflammatory mediators in infected tissues (125, 147). However, these cells also may contribute to viral clearance (147). Tregs are involved in CHIKV pathology, as expansion of Tregs reduces CHIKV disease by selectively inhibiting CHIKV-specific CD4+ effector T cells (148). In addition, γδ T cells, which are abundant in skin, protect against CHIKV disease, as γδ T cell–deficient mice display exacerbated CHIKV infection (149).
Development of CHIKV-neutralizing antibodies is essential to control CHIKV viremia (125, 137, 147, 150, 151). CHIKV-infected humans, mice, and NHPs develop potent and neutralizing IgM and IgG antibodies that control viremia and confer cross-protection against secondary CHIKV infections in animal models (125, 137, 143, 147, 150–152). In humans, IgM levels are detected within 5–7 days after the onset of symptoms (153), peak several weeks after infection (154), and begin to wane over the next several months (154). An IgG response can be detected approximately 7–10 days after onset of illness, often after viremia has been cleared (37, 154–156). Many mouse and human IgM and IgG antibodies broadly and potently neutralize CHIKV (157–162). The most potently neutralizing antibodies target domains A and B of the E2 glycoprotein, with those targeting domain B often displaying broad neutralization against multiple strains of CHIKV and other related alphaviruses (157, 159–161). In B cell–deficient (μMT) mice, persistent, steady-state viremia occurs following CHIKV infection (147, 150), further highlighting the importance of neutralizing antibodies in mitigating CHIKV disease.
Although antibodies control viral load, CHIKV antigen and RNA have been detected in muscle and synovial biopsies from patients with chronic CHIKV disease, and muscle satellite cells and synovial macrophages have been proposed to be reservoirs for persistent CHIKV in humans (refs. 8, 72, and Figure 3). Persistent CHIKV infection also has been observed for weeks to months in experimentally infected mice (137, 147) and NHPs (105, 163), with vRNA detected in joint tissue (150), muscle, and spleen (105). In addition, persistent IgM levels have been detected in patients and animals experiencing chronic arthritis (8, 105, 126, 153, 164, 165). These data suggest that persistent CHIKV antigen, or perhaps infection, in protected cellular reservoirs triggers inflammation that culminates in chronic CHIKV rheumatic disease (Figure 3). Further investigation to identify specific CHIKV reservoirs and mechanisms of persistence will greatly inform illness management and development of therapeutics for chronic CHIKV pathologies.