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• W2094084149 abstract "After several decades of epidemiologic silence, chikungunya virus (CHIKV) has recently re-emerged, causing explosive outbreaks and reaching the 5 continents. Transmitted through the bite of Aedes species mosquitoes, CHIKV is responsible for an acute febrile illness accompanied by several characteristic symptoms, including cutaneous rash, myalgia, and arthralgia, with the latter sometimes persisting for months or years. Although CHIKV has previously been known as a relatively benign disease, more recent epidemic events have brought waves of increased morbidity and fatality, leading it to become a serious public health problem. The host's immune response plays a crucial role in controlling the infection, but it might also contribute to the promotion of viral spread and immunopathology. This review focuses on the immune responses to CHIKV in human subjects with an emphasis on early antiviral immune responses. We assess recent developments in the understanding of their possible Janus-faced effects in the control of viral infection and pathogenesis. Although preventive vaccination and specific therapies are yet to be developed, exploring this interesting model of virus-host interactions might have a strong effect on the design of novel therapeutic options to minimize immunopathology without impairing beneficial host defenses. After several decades of epidemiologic silence, chikungunya virus (CHIKV) has recently re-emerged, causing explosive outbreaks and reaching the 5 continents. Transmitted through the bite of Aedes species mosquitoes, CHIKV is responsible for an acute febrile illness accompanied by several characteristic symptoms, including cutaneous rash, myalgia, and arthralgia, with the latter sometimes persisting for months or years. Although CHIKV has previously been known as a relatively benign disease, more recent epidemic events have brought waves of increased morbidity and fatality, leading it to become a serious public health problem. The host's immune response plays a crucial role in controlling the infection, but it might also contribute to the promotion of viral spread and immunopathology. This review focuses on the immune responses to CHIKV in human subjects with an emphasis on early antiviral immune responses. We assess recent developments in the understanding of their possible Janus-faced effects in the control of viral infection and pathogenesis. Although preventive vaccination and specific therapies are yet to be developed, exploring this interesting model of virus-host interactions might have a strong effect on the design of novel therapeutic options to minimize immunopathology without impairing beneficial host defenses. Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com.First identified in the southern province of Tanzania in 1952, chikungunya virus (CHIKV) is believed to have originated in Africa.1Lumsden W.H. An epidemic of virus disease in Southern Province, Tanganyika Territory, in 1952-53. II. General description and epidemiology.Trans R Soc Trop Med Hyg. 1955; 49: 33-57Abstract Full Text PDF PubMed Scopus (288) Google Scholar, 2Robinson M.C. An epidemic of virus disease in Southern Province, Tanganyika Territory, in 1952-53: clinical features.Trans R Soc Trop Med Hyg. 1955; 49: 28Abstract Full Text PDF PubMed Scopus (662) Google Scholar Its name, chikungunya, is derived from a Makonde word meaning “that which bends up,” in reference to the frequent and debilitating joint pains associated with infection. CHIKV is a member of the Togaviridae family and of the Old World alphavirus group. This group comprises 31 viruses, 7 of which can cause human joint disorders, namely CHIKV, Semliki Forest, O'Nyong-Nyong (Central Africa), Ross River and Barmah Forest (Australia and the Pacific), Sindbis (cosmopolitan), and Mayaro (South America and French Guyana) viruses.3Suhrbier A. Jaffar-Bandjee M.C. Gasque P. Arthritogenic alphaviruses—an overview.Nat Rev Rheumatol. 2012; 8: 420-429Crossref PubMed Scopus (291) Google ScholarCHIKV is composed of a phospholipid envelope, a 60- to 70-nm-diameter capsid, and a single-strand positive-sense RNA of approximately 12 kb containing 2 open reading frames (ORFs). The ORF at the 5′ end encodes 4 nonstructural proteins (nsP1-nsP4), and the ORF at the 3′ end encodes the structural proteins capsid protein, envelope glycoproteins E1 and E2, and 2 small cleavage products (E3 and 6K).The replication cycle of CHIKV is essentially similar of that of other alphaviruses.4Solignat M. Gay B. Higgs S. Briant L. Devaux C. Replication cycle of chikungunya: a re-emerging arbovirus.Virology. 2009; 393: 183-197Crossref PubMed Scopus (225) Google Scholar It begins with the attachment of E1 with unknown cellular receptors, which leads to the fusion of the viral particle to the host cell membrane. Of note, several receptors have been suggested, but to date, their putative roles have not been firmly established.5Schwartz O. Albert M.L. Biology and pathogenesis of chikungunya virus.Nat Rev Microbiol. 2010; 8: 491-500Crossref PubMed Scopus (478) Google Scholar, 6Silva L.A. Khomandiak S. Ashbrook A.W. Weller R. Heise M.T. Morrison T.E. et al.A single-amino-acid polymorphism in Chikungunya virus E2 glycoprotein influences glycosaminoglycan utilization.J Virol. 2014; 88: 2385-2397Crossref PubMed Scopus (89) Google Scholar After virus entry, the positive-sense genomic RNA acts directly as mRNA to produce nsPs, which are responsible for synthesis of further structural proteins required for viral encapsidation and budding.7Spuul P. Balistreri G. Hellström K. Golubtsov A.V. Jokitalo E. Ahola T. Assembly of alphavirus replication complexes from RNA and protein components in a novel trans-replication system in mammalian cells.J Virol. 2011; 85: 4739-4751Crossref PubMed Scopus (68) Google ScholarIn Africa the virus is maintained in a sylvatic transmission cycle between nonhuman primates, bats, rodents, and other unidentified vertebrates; these animals have viremia but no pronounced physical manifestations. CHIKV infection is transmitted to the human population by Aedes aegypti or Aedes africanus mosquitoes and, since 2006, Aedes albopictus mosquitoes; this new vector has invaded most of the world over the past 30 years.8Waldock J. Chandra N.L. Lelieveld J. Proestos Y. Michael E. Christophides G. et al.The role of environmental variables on Aedes albopictus biology and chikungunya epidemiology.Pathog Glob Health. 2013; 107: 224-241Crossref PubMed Scopus (115) Google ScholarThis infection can be both endemic and epidemic. Schematically, the endemic form appears to be mainly rural, with continuous sporadic transmission to largely immune populations, and can be associated with small content outbreaks or isolated cases. During epidemics, CHIKV can circulate directly through a human-mosquito-human transmission cycle, without the need for animal reservoirs. Genetic changes in the E1 glycoprotein, which mediates viral entry at low pH and affects viral fusion, assembly, and/or cell tropism, have enabled the virus to replicate efficiently in A albopictus, consequently modifying the epidemiologic pattern of CHIKV. More recently, a second mutation was identified in the E2 gene E2-I211T, which was probably acquired by CHIKV strains around 2004-2005. This mutation has been shown to be a first necessary step to allow the subsequent E1-A226V substitution, providing a suitable background to allow CHIKV adaptation to A albopictus.9Tsetsarkin K.A. McGee C.E. Volk S.M. Vanlandingham D.L. Weaver S.C. Higgs S. Epistatic roles of E2 glycoprotein mutations in adaption of chikungunya virus to Aedes albopictus and Ae. aegypti mosquitoes.PLoS One. 2009; 4: e6835Crossref PubMed Scopus (164) Google Scholar The combination of second-step adaptive mutations compels us to expect future emergence of CHIKV strains with even greater efficiency of transmission in the most endemic regions of the world.10Tsetsarkin K.A. Chen R. Yun R. Rossi S.L. Plante K.S. Guerbois M. et al.Multi-peaked adaptive landscape for chikungunya virus evolution predicts continued fitness optimization in Aedes albopictus mosquitoes.Nat Commun. 2014; 5: 4084Crossref PubMed Scopus (155) Google ScholarThe most recent epidemic events mainly emerged in urban populations with weak specific immunity. In this setting the disease is characterized by an abrupt epidemic peak, with seroprevalence rates reaching up to 70% and then decreasing gradually as an increasing proportion of the population develops immunity.CHIKV epidemics most certainly occurred before the virus was discovered, as suggested by descriptions of epidemic fevers accompanied by pronounced arthralgia. These fevers were attributed to other viral infections. On the basis of recent phylogenetic analyses, the evolutionary timescale of CHIKV suggests that sylvatic African CHIKV probably first emerged as a human pathogen in the 18th century and certainly re-emerged periodically with relatively low prevalence in Africa but also in Asia, with the earliest outbreak in the Philippines in 1954.11Tsetsarkin K.A. Chen R. Sherman M.B. Weaver S.C. Chikungunya virus: evolution and genetic determinants of emergence.Curr Opin Virol. 2011; 1: 310-317Crossref PubMed Scopus (121) Google Scholar Since 2000, after an epidemiologic silent period, CHIKV prevalence has exploded worldwide. An urban epidemic of CHIKV was described in the Democratic Republic of Congo after an absence of about 40 years and then in Indonesia, causing 24 distinct outbreaks after a more than 20-year hiatus. In 2005, CHIKV emerged for the first time in the islands of the Indian Ocean. By June 2006, a third of the population of La Reunion was infected by CHIKV; approximately 266,000 clinical cases and 203 deaths were associated with the disease.12Borgherini G. Poubeau P. Staikowsky F. Lory M. Le Moullec N. Becquart J.P. et al.Outbreak of chikungunya on Reunion Island: early clinical and laboratory features in 157 adult patients.Clin Infect Dis. 2007; 44: 1401-1407Crossref PubMed Scopus (363) Google Scholar, 13Renault P. Solet J.L. Sissoko D. Balleydier E. Larrieu S. Filleul L. et al.A major epidemic of chikungunya virus infection on Reunion Island, France, 2005-2006.Am J trop Med Hyg. 2007; 77: 727-731Crossref PubMed Scopus (388) Google Scholar During this period, CHIKV was also reported in India,14Arankulle V.A. Shrivastava S. Chrian S. Gunjikar R.S. Walimbe A.M. Jadhav S.M. Genetic divergence of chikungunya viruses in India (1963-2006) with special reference to the 2005–2006 explosive epidemic.J Gen Virol. 2007; 88: 1967-1976Crossref PubMed Scopus (251) Google Scholar and several other countries in Southeast Asia, resulting in an estimated 1.9 million cases reported by the World Health Organization. Minor outbreaks have been observed in Africa until 2012.15Leroy E.M. Nkoghe D. Ollomo B. Nze-Nkogue C. Becquart P. Grard G. et al.Concurrent chikungunya and dengue virus infections during simultaneous outbreaks, Gabon, 2007.Emerg Infect Dis. 2009; 15: 591-593Crossref PubMed Scopus (174) Google Scholar, 16Caron M. Paupy C. Grard G. Becquart P. Mombo I. Nso B.B. et al.Recent introduction and rapid dissemination of Chikungunya virus and Dengue virus serotype 2 associated with human and mosquito coinfections in Gabon, central Africa.Clin Infect Dis. 2012; 55: e45-e53Crossref PubMed Scopus (127) Google Scholar, 17Nkoghe D. Kassa R.F. Caron M. Grard G. Mombo I. Bikié B. et al.Clinical forms of chikungunya in Gabon, 2010.PLoS Negl Trop Dis. 2012; 6: e1517Crossref PubMed Scopus (49) Google Scholar, 18Ansumana R. Jacobsen K.H. Leski T.A. Covington A.L. Bangura U. Hodges M.H. et al.Reemergence of chikungunya virus in Bo, Sierra Leone.Emerg Infect Dis. 2013; 19: 1108-1110Crossref PubMed Scopus (20) Google Scholar The first evidence of autochthonous CHIKV transmission in Europe was recorded in Italy in 200719Rezza G. Nicoletti L. Angelini R. Romi R. Finarelli A.C. Panning M. et al.Infection with chikungunya virus in Italy: an outbreak in a temperate region.Lancet. 2007; 370: 1840-1846Abstract Full Text Full Text PDF PubMed Scopus (1110) Google Scholar and in the Americas in December 2013.20Leparc-Goffart I. Nougairede A. Cassadou S. Prat C. de Lamballerie X. Chikungunya in the Americas.Lancet. 2014; 383: 514Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar, 21Staples J.E. Fischer M. Chikungunya virus in the Americas—what a vectorborne pathogen can do.N Engl J Med. 2014; 371: 887-889Crossref PubMed Scopus (104) Google Scholar, 22Olowokure B. Francis L. Polson-Edwards K. Nasci R. Quénel P. Aldighieri S. et al.The Caribbean response to chikungunya.Lancet Infect Dis. 2014; 14: 1039-1040Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar As of August 29, 2014, the Pan American Health Organization has recorded 776,000 cases and 152 deaths attributed to CHIKV infection in 33 countries and territories of the Americas (http://www.paho.org/chikungunya). The United States ArboNET, the national surveillance system for arthropod-borne diseases, reported 11 locally transmitted cases in Florida, as well as 3984 cases from Puerto Rico and the US Virgin Islands. The main CHIKV vectors are found to be increasingly present in temperate regions, such as Europe and the Americas. At the same time, the potential for viremic travelers returning from epidemic regions is on the increase. As an example, in the United States 109 imported cases of CHIKV were identified between 1995 and 2009, and 115 cases were identified between 2010 and 2013.23Gibney K.B. Fischer M. Prince H.E. Kramer L.D. St George K. Kosoy O.L. et al.Chikungunya fever in the United States: a fifteen year review of cases.Clin Infect Dis. 2011; 52: e121-e126Crossref PubMed Scopus (88) Google Scholar, 24Lindsey N.P. Prince H.E. Kosoy O. Laven J. Messenger S. Staples J.E. et al.Chikungunya virus infections among travelers—United States, 2010-2013.Am J Trop Med Hyg. 2015; 92: 82-87Crossref PubMed Scopus (25) Google Scholar As of December 16, 2014, 2021 cases were identified in 46 of 50 US states in travelers returning from the Americas (n = 1989), Asia (n = 11), or the Pacific Islands (n = 10; Fig 1, A). It is reasonable to augur that these patients could present sufficient levels of viremia to infect competent mosquitoes and act as Trojan horses for the introduction and spread of CHIKV infection in nonendemic areas. The risk of emergence of CHIKV in US territories is higher yet, considering the wide distribution of A aegypti and A albopictus in the country (Fig 1, B).To date, CHIKV infection has been identified in nearly 80 countries across 5 continents and caused more than 6 million confirmed cases. Considering the explosive nature of the epidemics in completely susceptible populations and the rapidly increasing counts, CHIKV has become a major public health issue. As such, in 2008, CHIKV was listed as a US National Institute of Allergy and Infectious Diseases category C priority pathogen. Intriguingly, outbreaks were mostly reported to be unpredictable, with an interval of several decades between major events. The precise factors of CHIKV emergence are unclear, but we can hypothesize that, in addition to ecologic and virus-linked factors, the immune status of the affected populations plays a key role both in the intensity and periodicity of recurrence.Recent progress in understanding CHIKV pathogenesisWhat of the acute infection?After intradermal inoculation by an infected female mosquito, CHIKV enters the subcutaneous capillaries, where it immediately starts to replicate within permissive cells of the skin, such as macrophages, fibroblasts, and endothelial cells (Fig 2). In a zebrafish model Palha et al25Palha N. Guivel-Benhassine F. Briolat V. Lutfalla G. Sourisseau M. Ellett F. et al.Real-time whole-body visualization of Chikungunya Virus infection and host interferon response in zebrafish.PLoS Pathog. 2013; 9: e1003619Crossref PubMed Scopus (120) Google Scholar have shown that infected cells rapidly appear in various organs within a median of approximately 14 hours after infection. Although the host is mounting a response to control the virus in the dermis, the virus disseminates rapidly to the blood circulatory system (Fig 2). During this silent incubation period, which lasts 3 to 7 days on average (range, 1-12 days), blood-circulating viral loads increase rapidly to reach tremendous concentrations detectable in the first few days of symptoms, sometimes reaching greater than 1010 copies/mL of plasma, which is uncommon in other arboviral diseases.26Chow A. Her Z. Ong E.K. Chen J.M. Dimatatac F. Kwek D.J. et al.Persistent arthralgia induced by Chikungunya virus infection is associated with interleukin-6 and granulocyte macrophage colony-stimulating factor.J Infect Dis. 2011; 203: 149-157Crossref PubMed Scopus (251) Google Scholar The peak viral titer was detected in the first 5 to 6 days after onset of symptoms in southern Thailand and Singapore in 200826Chow A. Her Z. Ong E.K. Chen J.M. Dimatatac F. Kwek D.J. et al.Persistent arthralgia induced by Chikungunya virus infection is associated with interleukin-6 and granulocyte macrophage colony-stimulating factor.J Infect Dis. 2011; 203: 149-157Crossref PubMed Scopus (251) Google Scholar, 27Leo Y.S. Chow A.L. Tan L.K. Lye D.C. Lin L. Ng L.C. Chikungunya outbreak, Singapore, 2008.Emerg Infect Dis. 2009; 15: 836-837Crossref PubMed Scopus (91) Google Scholar but as early as in the first 1 to 3 days in patients from La Reunion Island in 2006.28Thiberville S.D. Boisson V. Gaudart J. Simon F. Flahault A. de Lamballerie X. Chikungunya fever: a clinical and virological investigation of outpatients on Reunion Island, South-West Indian Ocean.PLoS Negl Trop Dis. 2013; 7: e2004Crossref PubMed Scopus (118) Google Scholar As in other viral infections, the acute phase of CHIKV infection is accompanied by an early IFN-α response,29Hoarau J.J. Jaffar Bandjee M.C. Krejbich Trotot P. Das T. Li-Pat-Yuen G. Dassa B. et al.Persistent chronic inflammation and infection by Chikungunya arthritogenic alphavirus in spite of a robust host immune response.J Immunol. 2010; 184: 5914-5927Crossref PubMed Scopus (400) Google Scholar, 30Wauquier N. Becquart P. Nkoghe D. Padilla C. Ndjoyi-Mbiguino A. Leroy E.M. The acute phase of chikungunya virus infection in humans is associated with strong innate immunity and T CD8 cell activation.J Infect Dis. 2011; 204: 115-123Crossref PubMed Scopus (162) Google Scholar which is detected as early as the first day of infection. IFN-α concentrations correlate with plasmatic viral load. In interferon response factor–deficient mice, it was demonstrated that inadequate IFN-α responses after CHIKV infection can be sufficient to induce hemorrhagic fever and shock,31Rudd P.A. Wilson J. Gardner J. Larcher T. Babarit C. Le T.T. Interferon response factors 3 and 7 protect against Chikungunya virus hemorrhagic fever and shock.J Virol. 2012; 86: 9888-9898Crossref PubMed Scopus (127) Google Scholar a finding that further highlights the importance of these cytokines in the pathology of CHIKV infection. Concurrently with the increase in viral load and IFN-α responses, a very high proportion of CHIKV-infected patients (72% to 97%) experience clinical symptoms compared with those with other arbovirus infections.32Staples J.E. Breiman R.F. Powers A.M. Chikungunya fever: an epidemiological review of a re-emerging infectious disease.Clin Infect Dis. 2009; 49: 942-948Crossref PubMed Scopus (460) Google Scholar Clinical onset is abrupt and most often characterized by high fever (typically >39°C [102°F]) associated with a wide range of other acute and nonspecific manifestations combining headache, myalgia, diarrhea, vomiting, abdominal pain, and rash. Intense polyarthralgia, the hallmark symptom of CHIKV infection, affects mainly the extremities (ankles, wrists, and phalanges) but can also affect the large joints (http://www.cdc.gov/chikungunya/pdfs/CHIKV_Clinicians.pdf, Table I).33Dupuis-Maguiraga L. Noret M. Brun S. Le Grand R. Gras G. Roques P. Chikungunya disease: infection-associated markers from the acute to the chronic phase of arbovirus-induced arthralgia.PLoS Negl Trop Dis. 2012; 6: e1446Crossref PubMed Scopus (165) Google ScholarFig 2Viral dissemination, clinical manifestations, and chronic persistence in CHIKV-infected patients. CHIKV is transmitted through the bite of a female mosquito. The virus infects susceptible cells of the dermis, such as endothelial cells, fibroblasts, and macrophages, and replicates rapidly. Locally produced viral particles are transported through the circulatory system to secondary lymphoid organs and then disseminated to different organs, including the brain, spleen, liver, joints, and muscles. This acute phase of infection is associated with a high release of type 1 interferons, followed by upmodulation or downmodulation of many other cytokines, chemokines, and proinflammatory mediators. CHIKV can persist for weeks after primary infection in patients with a chronic disease. Infection of macrophages in the joints is accompanied by local and long-lasting inflammation of the synovial tissues.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table IClinical symptoms and laboratory findings of CHIKV infectionClinical symptomsLaboratory findingsMajorMinorAtypicalFeverArthritisBullous skin lesionsMyelitisLymphopenia Abrupt onsetConjunctivitisCranial nerve palsiesMyocarditisThrombocytopenia Typically >39°CHeadacheGuillain-BarreNephritisCreatinine +++Joint painMyalgiaHemorrhageUveitisTransaminase +++ Severe and debilitatingNauseaHepatitisRetinitis Multiple jointsRashMeningoencephalitis Bilateral and symmetricVomiting Open table in a new tab CHIKV infection is often confused with dengue virus (DENV) infection. Both diseases present with high temperatures and myalgias in persons living in or returning from tropical areas and are transmitted by the same species of mosquitoes. Despite certain clinical similarities, the prevalence of specific symptoms might help with the initial differential diagnosis; prominent and prolonged arthralgias affecting multiple joints are more consistent with CHIKV, and hemorrhage is more common in cases of DENV infection (Table II). Other alphaviruses can also induce fever and arthralgias, and therefore the traveler's itinerary is important to consider while identifying probable cause (Table III). CHIKV infection is confirmed in the laboratory by means of viral isolation, detection of viral nucleic acid in serum samples with RT-PCR, or detection of an IgM antibody response (http://www.cdc.gov/chikungunya/hc/diagnostic.html, Table III).Table IIClinical and laboratory features of CHIKV infection compared with those of DENV infectionCHIKVDENVClinical features Fever (>39°C)+++++ Arthralgia++++/− Arthritis+− Headache++++ Rash+++ Myalgia+++ Hemorrhage+/−++ Shock−+Laboratory features Lymphopenia+++++ Neutropenia++++ Thrombocytopenia++++ Hemoconcentration−+++Symbols indicate the percentage of patients exhibiting each feature: +++, 70% to 100% of patients; ++, 40% to 69%; +, 10% to 39%; +/−, <10%; −, 0%. Open table in a new tab Table IIIDiagnostic criteria for CHIKV infectionActions1: Clinical criteria Residing or visiting an epidemic area within 15 d before onset of symptoms (high fever and/or severe arthralgia)Determination of clinical symptoms (Table I)2: Differential diagnosis CHIKV coexists with other infectious diseases, such as dengue, other alphavirus infections, or endemic malariaComparative analysis of clinical and laboratory features (Table II)3: Laboratory criteria after onset of symptoms Confirmation of infection through:Optimal timing after illness onset:Isolation of virus≤ 3 dPresence of viral RNA (PCR)≤ 8 dDetection of specific antibodies (IgM)≥ 4 d Open table in a new tab Persisting symptoms seem to be a direct consequence of the viral infection and the associated proinflammatory immune response, as reported in different studies showing the early detection of various proinflammatory cytokines. Viral load has been linked to concentrations of IFN-α but also IL-1RA (IL-1 receptor antagonist), IL-6, IL-12, CCL2, and CXCL10.26Chow A. Her Z. Ong E.K. Chen J.M. Dimatatac F. Kwek D.J. et al.Persistent arthralgia induced by Chikungunya virus infection is associated with interleukin-6 and granulocyte macrophage colony-stimulating factor.J Infect Dis. 2011; 203: 149-157Crossref PubMed Scopus (251) Google Scholar, 29Hoarau J.J. Jaffar Bandjee M.C. Krejbich Trotot P. Das T. Li-Pat-Yuen G. Dassa B. et al.Persistent chronic inflammation and infection by Chikungunya arthritogenic alphavirus in spite of a robust host immune response.J Immunol. 2010; 184: 5914-5927Crossref PubMed Scopus (400) Google Scholar, 30Wauquier N. Becquart P. Nkoghe D. Padilla C. Ndjoyi-Mbiguino A. Leroy E.M. The acute phase of chikungunya virus infection in humans is associated with strong innate immunity and T CD8 cell activation.J Infect Dis. 2011; 204: 115-123Crossref PubMed Scopus (162) Google Scholar, 34Ng L.F. Chow A. Sun Y.J. Kwek D.J. Lim P.L. Dimatatac F. et al.IL-1beta, IL-6, and RANTES as biomarkers of Chikungunya severity.PLoS One. 2009; 4: e4261Crossref PubMed Scopus (216) Google Scholar, 35Kelvin A.A. Banner D. Silvi G. Moro M.L. Spataro N. Galbani P. et al.Inflammatory cytokine expression is associated with chikungunya virus resolution and symptom severity.PLoS Negl Trop Dis. 2011; 5: e1279Crossref PubMed Scopus (113) Google Scholar The TH1 cytokine response is essential to promote immune cell activation but might also cause tissue injuries. Surprisingly, proinflammatory cytokines, such as TNF-α, IL-1β, and IL-8, were poorly expressed in the acute phase of CHIKV infection, and TH2 (IL-4, IL-6, IL-10, and IL-13) cytokines were only expressed in a few CHIKV-infected patients (Fig 2).34Ng L.F. Chow A. Sun Y.J. Kwek D.J. Lim P.L. Dimatatac F. et al.IL-1beta, IL-6, and RANTES as biomarkers of Chikungunya severity.PLoS One. 2009; 4: e4261Crossref PubMed Scopus (216) Google Scholar, 36Venugopalan A. Ghorpade R.P. Chopra A. Cytokines in acute chikungunya.PLoS One. 2014; 9: e111305Crossref PubMed Scopus (57) Google Scholar IFN-γ and IL-12 are known to act synergistically to promote innate immune cell activation, and levels both were highly increased in the majority of CHIKV-infected patients.30Wauquier N. Becquart P. Nkoghe D. Padilla C. Ndjoyi-Mbiguino A. Leroy E.M. The acute phase of chikungunya virus infection in humans is associated with strong innate immunity and T CD8 cell activation.J Infect Dis. 2011; 204: 115-123Crossref PubMed Scopus (162) Google Scholar, 34Ng L.F. Chow A. Sun Y.J. Kwek D.J. Lim P.L. Dimatatac F. et al.IL-1beta, IL-6, and RANTES as biomarkers of Chikungunya severity.PLoS One. 2009; 4: e4261Crossref PubMed Scopus (216) Google Scholar However, results related to cytokines in patients with CHIKV infection are usually contradictory. Discrepancies between studies for some markers could reflect different genetic backgrounds, heterogeneous sanitary conditions, and patient management strategies, as well as differences in laboratory techniques. In an experimental infection of macaques with CHIKV, early production of IFN-α, IL-6, and CCL2, followed by IFN-γ, TNF-α, CCL3, and CCL4, was detected.37Labadie K. Larcher T. Joubert C. Mannioui A. Delache B. Guigand L. et al.Chikungunya disease in nonhuman primates involves long-term viral persistence in macrophages.J Clin Invest. 2010; 120: 894-906Crossref PubMed Scopus (368) Google ScholarWhat of the chronic infection?The acute signs and symptoms of CHIKV infection usually resolve within 1 to 3 weeks, but the arthralgia can persist for months or even years in some patients. This chronic phase, which is usually characterized by fluctuations in intensity and relapses, is generally less severe than the acute phase, but many patients still experience a pronounced loss in movement and quality of life. The proportion of patients with chronic signs attributable to CHIKV 3 months after infection differed between outbreaks. In Singapore 13% of infected patients still had chronic arthralgia, whereas nearly half of the patients with persistent rheumatic pain were impaired in carrying out daily or household activities.26Chow A. Her Z. Ong E.K. Chen J.M. Dimatatac F. Kwek D.J. et al.Persistent arthralgia induced by Chikungunya virus infection is associated with interleukin-6 and granulocyte macrophage colony-stimulating factor.J Infect Dis. 2011; 203: 149-157Crossref PubMed Scopus (251) Google Scholar These manifestations were independently associated with older age, severe initial pain, and the presence of comorbid osteoarthritis.38Sissoko D. Malvy D. Ezzedine K. Renault P. Moscetti F. Ledrans M. et al.Post-epidemic Chikungunya disease on Reunion Island: course of rheumatic manifestations and associated factors over a 15-month period.PLoS Negl Trop Dis. 2009; 3: e389Crossref PubMed Scopus (255) Google Scholar Children are also at risk for severe manifestations of the disease with common clinical features, such as chronic swollen ankles or wrists.39Sebastian M.R. Lodha R. Kabra S.K. Chikungunya infection in children.Indian J Pediatr. 2009; 76: 185-189Crossref PubMed Scopus (54) Google Scholar, 40Lewthwaite P. Vasanthapuram R. Osborne J.C. Begum A. Plank J.L. Shankar M.V. et al.Chikungunya virus and central nervous system infections in children, India.Emerg Infect Dis. 2009; 15: 329-331Crossref PubMed Scopus (81) Google Scholar It is plausible that CHIKV persisting in immune-privileged niches directly inflicts damage t" @default.
• W2094084149 created "2016-06-24" @default.
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• W2094084149 date "2015-04-01" @default.
• W2094084149 modified "2023-10-11" @default.
• W2094084149 title "Control of immunopathology during chikungunya virus infection" @default.
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• W2094084149 doi "https://doi.org/10.1016/j.jaci.2015.01.039" @default.
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