Chikungunya virus life cycle

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.

Type I IFN signaling controls viral replication and pathogenesis during acute infection , — 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.

Atypical symptoms are most prevalent among vulnerable groups, including neonates, the elderly, and those with underlying comorbidities. In animal models reviewed in refs. 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 , , , The vast majority of patients experience chronic musculoskeletal disorders and usually respond to some extent to analgesics, antiinflammatory treatments, and physiotherapy.

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 , , 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 , — , , , — A meta-analysis of immune mediators from geographically distinct cohorts 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 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 , , the specific cellular targets of infection that contribute to the orchestration of these responses in vivo remain largely undefined.

Although many hematopoietic cells appear refractory to CHIKV infection 66 , 70 , , monocytes and macrophages are targeted by CHIKV and contribute to virus-induced pathogenesis in both humans and animals reviewed in ref. Activated macrophages are the primary infiltrating cell in infected tissues Figure 3 and refs. Depletion of macrophages in mice results in reduced CHIKV-associated musculoskeletal disease but significantly prolonged viremia , highlighting independent functions of macrophages in CHIKV disease.

These data suggest that macrophages are a source of persistent virus and contribute to CHIKV-induced arthropathy. However, these cells also may contribute to viral clearance In humans, IgM levels are detected within 5—7 days after the onset of symptoms , peak several weeks after infection , and begin to wane over the next several months An IgG response can be detected approximately 7—10 days after onset of illness, often after viremia has been cleared 37 , — 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 , — In addition, persistent IgM levels have been detected in patients and animals experiencing chronic arthritis 8 , , , , , Further investigation to identify specific CHIKV reservoirs and mechanisms of persistence will greatly inform illness management and development of therapeutics for chronic CHIKV pathologies.

The recent reemergence and worldwide spread of CHIKV render this virus an important public health threat. Although the mortality rate of CHIKV disease is modest, the debilitating and chronic nature of CHIKV disease and its associated economic burden are important considerations for the development of specific treatments. As traditional vector control has met with only limited success in CHIKV containment, there is a significant need for safe, efficacious, and economical CHIKV treatments or vaccines to mitigate viral spread and limit disease burden.

High-throughput screening of chemical libraries — , as well as synthesis of designer drugs , , has identified promising candidate CHIKV antivirals. Anti-CHIKV therapeutics also have been discovered or developed to directly target the viral replication cycle, including stages of entry, protein synthesis, genome replication, or enzymatic functions. Drugs indirectly targeting host factors required for efficient replication also have been identified reviewed in ref. Although compound discovery has unearthed a number of putative CHIKV antivirals, further testing in animal models and humans is required for clinical advancement of these drugs.

Furthermore, in postexposure therapeutic trials, monoclonal antibodies protect against CHIKV disease in mice, even when administered at late times of infection , , suggesting that immunotherapy would be effective for treatment of CHIKV infection. As evidence suggests that a single vaccine against CHIKV should protect against all CHIKV strains and provide lifelong immunity, and humans are the primary amplifying host during urban epidemics, rapidly deployed vaccination of at-risk populations could curtail mounting epidemics.

Furthermore, immunization of tourists and military personnel traveling to endemic or epidemic areas would protect travelers and decrease importation of the virus to naive populations. Various CHIKV vaccine strategies have been investigated, with many in preclinical and clinical studies reviewed in ref. Here, we summarize various vaccine candidates, focusing on those that have advanced to human studies Table 4.

Live-attenuated vaccines offer effective and lasting immunity, often with a single dose and low cost of production. Therefore, other strategies for development of live-attenuated vaccines for CHIKV have been investigated.

This modification decreases the expression of viral structural proteins , , which attenuates replication in mammalian cells and prevents replication in mosquito cells, as the IRES is not functional in insect cells Other live-attenuated CHIKV vaccine strategies include deletions in viral genes , , modification of glycosaminoglycan binding , alphavirus chimeras , , and codon alteration As reversion is a major safety concern with live-attenuated vaccines, a CHIKV vaccine containing a combination of attenuation strategies could diminish reversion and pathogenicity.

Virus-like particles VLPs represent another promising vaccine strategy Table 4. The expressed structural proteins form particles that are indistinguishable from intact virions but are replication-incompetent because of the lack of genomic vRNA In both mice and NHPs, the VLP vaccine elicits high-titer neutralizing antibodies that are protective against heterologous strains One uses a recombinant baculovirus-insect cell expression system that yields VLPs eliciting strong neutralizing antibodies, which are protective in mice In addition to these vaccine candidates, other recent CHIKV vaccine approaches investigated in preclinical studies include inactivated particles, subunit, and DNA- and recombinant virus—vectored vaccines reviewed in ref.

Although substantial progress has been made in the development of CHIKV vaccines, a number of difficulties will need to be overcome. As CHIKV epidemics have mostly occurred in developing nations, the most utilitarian vaccine should induce a robust and durable immune response with a single dose at a low cost.

However, even though vaccination is the most promising means to protect people in regions with endemic CHIKV, the challenging balance between vaccine safety, immunogenicity, and economical constraints of production may impede CHIKV vaccine development and licensing. The duplicity and varied manifestations of CHIKV immunopathology pose challenges to the development of effective treatments.

Although recent studies have contributed to a better understanding of the basic biology of CHIKV replication and disease, future work on virus-vector interactions, molecular mechanisms of viral replication, careful deconstruction of the multifaceted CHIKV-induced immune responses, and development of therapeutic interventions will be required to combat CHIKV transmission and illness.

We apologize to all whose work could not be referenced because of formatting and length restrictions. Conflict of interest: The authors have declared that no conflict of interest exists. Reference information: J Clin Invest. National Center for Biotechnology Information , U. Journal List J Clin Invest v.

J Clin Invest. Published online Mar 1. Laurie A. Silva and Terence S. Author information Copyright and License information Disclaimer. Address correspondence to: Terence S. Phone: This article has been cited by other articles in PMC.

Abstract Chikungunya virus CHIKV , a reemerging arbovirus, causes a crippling musculoskeletal inflammatory disease in humans characterized by fever, polyarthralgia, myalgia, rash, and headache. Ecology and epidemiology Chikungunya virus CHIKV is a mosquito-borne virus responsible for periodic and explosive outbreaks of a febrile disease that is characterized by severe and sometimes prolonged polyarthritis.

Open in a separate window. Figure 1. Figure 2. CHIKV replication cycle in mammalian cells. Disease mechanisms and host immune responses 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.

Figure 3. Footnotes Conflict of interest: The authors have declared that no conflict of interest exists. References 1. Lumsden WH. An epidemic of virus disease in Southern Province, Tanganyika Territory, in — General description and epidemiology.

Robinson MC. Clinical features. Ross RW. The Newala epidemic. The virus: isolation, pathogenic properties and relationship to the epidemic.

J Hyg Lond ; 54 2 — Thiberville SD, et al. Chikungunya fever: epidemiology, clinical syndrome, pathogenesis and therapy. Antiviral Res. Carey DE. Chikungunya and dengue: a case of mistaken identity?

J Hist Med Allied Sci. Halstead SB. Reappearance of chikungunya, formerly called dengue, in the Americas. Emerging Infect Dis. Couturier E, et al. Impaired quality of life after chikungunya virus infection: a 2-year follow-up study. Rheumatology Oxford ; 51 7 — Hoarau JJ, et al. Persistent chronic inflammation and infection by Chikungunya arthritogenic alphavirus in spite of a robust host immune response.

J Immunol. Schilte C, et al. Chikungunya virus-associated long-term arthralgia: a month prospective longitudinal study. Sissoko D, et al. Post-epidemic Chikungunya disease on Reunion Island: course of rheumatic manifestations and associated factors over a month period. Chikungunya-related fatality rates, Mauritius, India, and Reunion Island.

PLoS Med. Diallo D, et al. Landscape ecology of sylvatic chikungunya virus and mosquito vectors in southeastern Senegal. Vectors of Chikungunya virus in Senegal: current data and transmission cycles. Am J Trop Med Hyg. Aedes furcifer and other mosquitoes as vectors of chikungunya virus at Mica, northeastern Transvaal, South Africa.

J Am Mosq Control Assoc. Laboratory vector studies on six mosquito and one tick species with chikungunya virus. Inoue S, et al. Distribution of three arbovirus antibodies among monkeys Macaca fascicularis in the Philippines.

J Med Primatol. Experimental infection of Macaca radiata with Chikungunya virus and transmission of virus by mosquitoes. Indian J Med Res. McIntosh BM, et al. Further studies on the Chikungunya outbreak in Southern Rhodesia in Mosquitoes, wild primates and birds in relation to the epidemic.

Ann Trop Med Parasitol. In late , chikungunya virus was found for the first time in the Americas on islands in the Caribbean. There is a risk that the virus will be imported to new areas by infected travelers. There is no vaccine to prevent or medicine to treat chikungunya virus infection. Travelers can protect themselves by preventing mosquito bites.

When traveling to countries with chikungunya virus, use insect repellent, wear long sleeves and pants, and stay in places with air conditioning or that use window and door screens. Skip directly to site content Skip directly to page options Skip directly to A-Z link. Aedes albopictus in North America: probable introduction in used tires from northern Asia. Science , — Paupy, C. Aedes albopictus , an arbovirus vector: from the darkness to the light.

Microbes Infect. Gibbons, D. Visualization of the target-membrane-inserted fusion protein of Semliki Forest virus by combined electron microscopy and crystallography.

Cell , — Conformational change and protein-protein interactions of the fusion protein of Semliki Forest virus. Nature , — Kielian, M. Virus membrane-fusion proteins: more than one way to make a hairpin. Nature Rev. Microbiol 4 , 67—76 Chatterjee, P. Novel mutations that control the sphingolipid and cholesterol dependence of the Semliki Forest virus fusion protein. Development and characterization of a double subgenomic chikungunya virus infectious clone to express heterologous genes in Aedes aegypti mosquitoes.

Insect Biochem. Epistatic roles of E2 glycoprotein mutations in adaption of chikungunya virus to Aedes albopictus and Ae. Laurent, P. Development of a sensitive real-time reverse transcriptase PCR assay with an internal control to detect and quantify chikungunya virus. Carey, D. The chikungunya epidemic at Vellore, South India, including observations on concurrent dengue.

Brighton, S. Chikungunya virus infection. A retrospective study of cases. Isaacs, A. Virus interference. The interferon. B Biol. Myers, R. The epidemic of dengue-like fever in South India: isolation of chikungunya virus from human sera and from mosquitoes. Gifford, G.

Effect of actinomycin D on interferon production by 'active' and 'inactive' chikungunya virus in chick cells. Nature , 50—51 Transfer of interferon-producing macrophages: new approach to viral chemotherapy.

Levy, H. Effect of interferon on early interferon production. O'Neill, L. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Gilliet, M. Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Pichlmair, A. Innate recognition of viruses. Immunity 27 , — McCartney, S. Viral sensors: diversity in pathogen recognition. Akira, S. Toll-like receptor signalling.

Bieback, K. Hemagglutinin protein of wild-type measles virus activates Toll-like receptor 2 signaling. Compton, T. Human cytomegalovirus activates inflammatory cytokine responses via CD14 and Toll-like receptor 2. Kurt-Jones, E. Nature Immunol.

Rassa, J. Viruses and Toll-like receptors. Diebold, S. Alexopoulou, L. Kato, H. Dalod, M. Schulz, O. Toll-like receptor 3 promotes cross-priming to virus-infected cells. Muzio, M. Ichinohe, T. Inflammasome recognition of influenza virus is essential for adaptive immune responses. Allen, I. Immunity 30 , — Grandvaux, N. The interferon antiviral response: from viral invasion to evasion. Functional classification of interferon-stimulated genes identified using microarrays.

Lenschow, D. IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses. Natl Acad. USA , — Zhang, Y. Identification and characterization of interferon-induced proteins that inhibit alphavirus replication.

Bick, M. Expression of the zinc-finger antiviral protein inhibits alphavirus replication. Antalis, T. Brehin, A. Frolova, E. Breakwell, L. Semliki Forest virus nonstructural protein 2 is involved in suppression of the type I interferon response. Prophylaxis and therapy for chikungunya virus infection. Borgherini, G. Outbreak of chikungunya on Reunion Island: early clinical and laboratory features in adult patients. Kamphuis, E. Type I interferons directly regulate lymphocyte recirculation and cause transient blood lymphopenia.

Blood , — Harrison, V. Production and evaluation of a formalin-killed chikungunya vaccine. McClain, D. Immunologic interference from sequential administration of live attenuated alphavirus vaccines. Edelman, R. Marsh, M. Virus entry: open sesame. Chevillon, C. The chikungunya threat: an ecological and evolutionary perspective. Trends Microbiol 16 , 80—88 Salonen, A. Viral RNA replication in association with cellular membranes.

Garmashova, N. The Old World and New World alphaviruses use different virus-specific proteins for induction of transcriptional shutoff. Download references. We thank members of our laboratories and T. Couderc for critical reading of the manuscript. You can also search for this author in PubMed Google Scholar. Aedes aegypti. Aedes albopictus.

Olivier Schwartz's homepage. Matthew L. Albert's homepage. The site of cerebrospinal fluid production in the adult brain. It is formed by invagination of ependymal cells into the ventricles, which become highly vascularized. A rash consisting of small 1—2 mm red or purple spots on the body, the cause of which are minor haemorrhages resulting from disruption of the capillary bed. Stem cells that are localized at the basement membrane surrounding each myofibre and that give rise to regenerated muscle and to more satellite cells.

A molecular complex of several proteins that, following assembly, cleaves pro-interleukin-1 pro-IL-1 , thereby producing active IL Particles that are composed of assembled viral proteins and mimic the structure of viruses. They are non-infectious because they do not contain viral genetic material.

Reprints and Permissions. Schwartz, O. Biology and pathogenesis of chikungunya virus. Nat Rev Microbiol 8, — Download citation. Issue Date : July Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative. Advanced search. Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Skip to main content Thank you for visiting nature. This work was supported by institutional funds from CNRS. National Center for Biotechnology Information , U. Author manuscript; available in PMC Aug 4. Author information Copyright and License information Disclaimer. Copyright notice.

The publisher's final edited version of this article is available at Virology. See other articles in PMC that cite the published article. Abstract Arboviruses or arthropod-borne viruses , represent a threat for the new century.

Keywords: Chikungunya, Arbovirus, Virus—host interaction, Replicative cycle. Introduction Most of the emerging viral infections in humans, originate from known zoonosis. CHIKV, a member of arboviruses In the early s, workers at the Rockefeller Foundation demonstrated that arboviruses could be discriminated by serological tests. Open in a separate window. Genetic divergence of Chikungunya viruses in India — with special reference to the — explosive epidemic.

Solubilization and immunoprecipitation of alphavirus replication complexes. Health Geogr. Involvement of extracellular signal-regulated kinase module in HIV-mediated CD4 signals controlling activation of nuclear factor-kappa B and AP-1 transcription factors. Chloroquine phosphate treatment of chronic chikungunya arthritis. An open pilot study. Chikungunya and dengue: a case of mistaken identity? Allied Sci. Hemagglutination with arthropod-borne viruses.

Flavivirus genome organization, expression, and replication. Complete coding sequence of chikungunya virus from La Reunion island, human isolate GenBank. The chikungunya threat: an ecological and evolutionary perspective.

Trends Microbiol. Structure of Sindbis virus core protein reveals a chymotrypsin-like serine proteinase and the organization of the virion. Inhibition of enveloped RNA virus formation by peptides corresponding to glycoproteins sequences. Antiviral Chem. Venezuelan equine encephalitis virus infection of mosquito cells requires acidification as well as mosquito homologs of the endocytic proteins Rab5 and Rab7. A mouse model for chikungunya: young age and inefficient type-I interferon signaling are risk factors for severe disease.

PLoS Pathog. Ross River virus infection of human synovial cells in vitro. Dissection of Semliki Forest virus glycoprotein delivery from the trans-Golgi network to the cell surface in permeabilized BHK cells. Meeting of the Sentinelles. On chikungunya acute infection and chloroquine treatment.

Vector Borne Zoonotic Dis. Determining divergence times of the major kingdoms of living organisms with a protein clock. Inhibition of endocytosis by anti-clathrin antibodies. Persistent noncytolytic togavirus infection of primary mouse muscle cells.

Membrane protein lateral interactions control Semliki Forest virus budding. EMBO J. Mononuclear cell types in chronic synovial effusions of Ross River virus disease. The exanthem of Ross River virus infection: histology, location of virus antigen and nature of inflammatory infiltrate.

Eastern and Venezuelan equine encephalitis viruses differ in their ability to infect dendritic cells and macrophages: impact of altered cell tropism on pathogenesis.

The signal sequence of the p62 protein of Semliki Forest virus is involved in initiation but not in completing chain translocation. Cell Biol. Deletion analysis of the capsid protein of Sindbis virus: identification of the RNA binding region. Effect of anti-muchain-specific immunosuppression on Chikungunya virus encephalitis of mice. CCR5 deficiency increases risk of symptomatic West Nile virus infection. The role of low pH and disulfide shuffling in the entry and fusion of Semliki Forest virus and Sindbis virus.

An NTP-binding motif is the most conserved sequence in a highly diverged monophyletic group of proteins involved in positive strand RNA viral replication. A cis-acting mutation in the Sindbis virus junction region which affects subgenomic RNA synthesis. Site-directed mutagenesis of the proposed catalytic amino acids of the Sindbis virus capsid protein autoprotease.

Western equine encephalitis virus is a recombinant virus. Ross River virus transmission, infection, and disease: a cross-disciplinary review. Comparative immunogenicities of chikungunya vaccines prepared in avian and mammalian tissues. Production and evaluation of a formalin-killed Chikungunya vaccine. Isolation of chikungunya virus in Australia. Electron microscope study of development of Chikungunya virus in green monkey kidney stable VERO cells.

Chapter 14 Natural cycles of vector-borne pathogens. The Biology of Disease Vectors. Elsevier Academic Press; Peptide inhibitors of dengue virus and West Nile virus infectivity. Virol J. Site-directed mutations in the Sindbis virus E2 glycoprotein identify palmitoylation sites and affect virus budding.

In: Monath TP, editor. The Arboviruses: Epidemiology and Ecology. Prolonged infection of human synovial cells with Ross River virus. Chikungunya virus disease; pp. Complete nucleotide sequence of chikungunya virus and evidence for an internal polyadenylation site.

Japanese encephalitis vaccine including a preliminary report on dengue fever and Chikungunya vaccines. Efficient functional pseudotyping of oncoretroviral and lentiviral vectors by Venezuelan equine encephalitis virus envelope proteins.

Venezuelan equine encephalitis virus entry mechanism requires late endosome formation and resists cell membrane cholesterol depletion. AV mutation in virus during the chikungunya outbreak in Kerala, India. J Gen. Dendritic cell precursors are permissive to dengue virus and human immunodeficiency virus infection.

Stabilization of chikungunya virus infectivity by human blood platelets. Quantifying the specific binding between West Nile virus envelope domain III protein and the cellular receptor alphaVbeta3 integrin. A single mutation in the E2 glycoprotein important for neurovirulence influences binding of sindbis virus to neuroblastoma cells. The Fusion glycoprotein shell of Semliki Forest virus: an icosahedral assembly primed for fusogenic activation at endosomal pH.

Development of an attenuated strain of chikungunya virus for use in vaccine production. Phosphorylation of Sindbis virus nsP3 in vivo and in vitro. Persistence of Ross River virus in macrophages. Arbovirus Res. Antibody-dependent enhancement and persistence in macrophages of an arbovirus associated with arthritis.

Alphavirus-specific cytotoxic T lymphocytes recognize a cross-reactive epitope from the capsid protein and can eliminate virus from persistently infected macrophages. Mutations in the endo domain of Sindbis virus glycoprotein E2 block phosphorylation, reorientation of the endo domain, and nucleocapsid binding.

Phosphorylation and dephosphorylation events play critical roles in Sindbis virus maturation. Nucleocapsid-glycoprotein interactions required for assembly of alphaviruses.

The cholesterol requirement for Sindbis virus entry and exit and characterization of a spike protein region involved in cholesterol dependence. The crystal structures of chikungunya and Venezuelan equine encephalitis virus nsP3 macro domains define a conserved adenosine binding pocket. Biken J. Pathogenesis of Ross River virus infection in mice. Muscle, heart, and brown fat lesions. Concurrent isolation from patient of two arboviruses, chikungunya and dengue type 2. Biological and immunological studies on chikungunya virus: a comparative observation of two strains of African and Asian origins.

Kobe J. Dendritic-cell-specific ICAM3-grabbing non-integrin is essential for the productive infection of human dendritic cells by mosquito-cell-derived dengue viruses. EMBO Rep.