RESUMEN
A flagship recommendation of the citizen's steering committee on immunization, the mandatory immunization for infants extended to 11 vaccines, introduced in January 2018, is part of a set of recommendations that must be considered as a whole, each component being indispensable to the achievement of objectives: restore confidence in vaccination and increase immunization coverage. Roundtable # 6 participants identified a decade of concrete initiatives that could address, at least in part, the committee's recommendations, including: developing information systems and data generation; simplify the vaccination journey and increase vaccination opportunities; developing training of health professionals; learning vaccines at school; using motivational interviewing in educational intervention; undertaking local initiatives; improving supply and communicate on the value of vaccines. To carry out these actions, it has been proposed that a joint ministerial task-force bringing together the different stakeholders at the national level should be set up to promote their implementation and follow-up, and at regional level, the establishment of an Agences régionales de santé awareness plan making vaccination a priority.
Asunto(s)
Aceptación de la Atención de Salud , Vacunas , Comunicación , Francia , Educación en Salud/tendencias , Humanos , Programas de Inmunización/tendencias , Programas Obligatorios , Motivación , Farmacovigilancia , Salud Pública , Instituciones Académicas , Vacunación/tendencias , Cobertura de VacunaciónRESUMEN
OBJECTIVE: To compare the oxidative stress induced by IV iron infusion in critically ill patients and in healthy volunteers. DESIGN: Multicenter, interventional study. SETTING: Two ICUs and one clinical research center. SUBJECTS: Anemic critically ill patients treated with IV iron and healthy volunteers. INTERVENTIONS: IV infusion of 100 mg of iron sucrose. MEASUREMENTS AND MAIN RESULTS: Thirty-eight anemic patients (hemoglobin, median [interquartile range] = 8.4 g/dL [7.7-9.2]) (men, 25 [66%]; aged 68 yr [48-77]; Simplified Acute Physiology Score II, 48.5 [39-59]) and 39 healthy volunteers (men, 18 [46%]; aged 42.1 yr [29-50]) were included. Blood samples were drawn before (H0) and 2, 6, and 24 hours (H2, H6, and H24) after a 60-minute iron infusion for the determination of nontransferrin bound iron, markers of lipid peroxidation-8α-isoprostanes, protein oxidation-advanced oxidized protein product, and glutathione reduced/oxidized. Iron infusion had no effect on hemodynamic parameter in patients and volunteers. At baseline, patients had much higher interleukin-6, C-reactive protein, and hepcidin levels. 8α-isoprostanes was also higher in patients at baseline (8.5 pmol/L [6.5-12.9] vs 4.6 pmol/L [3.5-5.5]), but the area under the curve above baseline from H0 to H6 was not different (p = 0.38). Neither was it for advanced oxidized protein product and nontransferrin bound iron. The area under the curve above baseline from H0 to H6 (glutathione reduced/oxidized) was lower in volunteers (p = 0.009). Eight patients had a second set of dosages (after the fourth iron infusion), showing higher increase in 8α-isoprostanes. CONCLUSIONS: In our observation, IV iron infusion does not induce more nontransferrin bound iron, lipid, or protein oxidation in patients compared with volunteers, despite higher inflammation, oxidative stress, and hepcidin levels and lower antioxidant at baseline. In contrary, iron induces a greater decrease in antioxidant, compatible with higher oxidative stress in volunteers than in critically ill patients.
Asunto(s)
Enfermedad Crítica , Compuestos Férricos/uso terapéutico , Ácido Glucárico/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Adulto , Anciano , Anemia/tratamiento farmacológico , Antioxidantes/uso terapéutico , Área Bajo la Curva , Proteína C-Reactiva , Estudios de Casos y Controles , Femenino , Compuestos Férricos/sangre , Sacarato de Óxido Férrico , Ácido Glucárico/sangre , Voluntarios Sanos , Humanos , Infusiones Intravenosas , Interleucina-6 , Peroxidación de Lípido/efectos de los fármacos , Masculino , Persona de Mediana EdadRESUMEN
The host response to Chikungunya virus is dependent on the direct action of type I IFN on infected nonhematopoietic cells. Prior studies have demonstrated that multiple host sensors coordinate an antiviral response; however, the tissue source(s) and signaling pathways for IFN production remain unknown. In this study, we demonstrate that IRF-3 and IRF-7 are functionally redundant, but lack of both factors results in lethal infection in adult mice. Reciprocal bone marrow chimeras indicated that IRF-3 or IRF-7 expression in either hematopoietic or nonhemotopoietic cell compartments was capable of inducing an antiviral response. Interestingly, redundancy of IRF-3 and IRF-7 was age dependent, as neonatal animals lacking either factor succumbed to infection. We further demonstrate that IPS-1 is essential in nonhematopoietic cells and preferentially required during early life. These results highlight the interplay between nonimmune and immune cells during Chikungunya virus infection and suggest an important role for nonhematopoietic cells as a critical source of IFN-α/ß.
Asunto(s)
Infecciones por Alphavirus/inmunología , Fibroblastos/virología , Células Madre Hematopoyéticas/virología , Factor 3 Regulador del Interferón/fisiología , Factor 7 Regulador del Interferón/fisiología , Proteínas Adaptadoras Transductoras de Señales/fisiología , Factores de Edad , Animales , Animales Recién Nacidos , Trasplante de Médula Ósea , Células Cultivadas , Fiebre Chikungunya , Virus Chikungunya/crecimiento & desarrollo , Virus Chikungunya/inmunología , Fibroblastos/metabolismo , Células Madre Hematopoyéticas/metabolismo , Interacciones Huésped-Patógeno , Factor 3 Regulador del Interferón/deficiencia , Factor 3 Regulador del Interferón/genética , Factor 7 Regulador del Interferón/deficiencia , Factor 7 Regulador del Interferón/genética , Interferón-alfa/biosíntesis , Interferón-alfa/genética , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/deficiencia , Factor 88 de Diferenciación Mieloide/genética , Quimera por Radiación , Receptor Toll-Like 7/deficiencia , Receptor Toll-Like 7/genéticaRESUMEN
Chikungunya virus (CHIKV) is a re-emerging alphavirus that has caused significant disease in the Indian Ocean region since 2005. During this outbreak, in addition to fever, rash and arthritis, severe cases of CHIKV infection have been observed in infants. Challenging the notion that the innate immune response in infants is immature or defective, we demonstrate that both human infants and neonatal mice generate a robust type I interferon (IFN) response during CHIKV infection that contributes to, but is insufficient for, the complete control of infection. To characterize the mechanism by which type I IFNs control CHIKV infection, we evaluated the role of ISG15 and defined it as a central player in the host response, as neonatal mice lacking ISG15 were profoundly susceptible to CHIKV infection. Surprisingly, UbE1Lâ»/â» mice, which lack the ISG15 E1 enzyme and therefore are unable to form ISG15 conjugates, displayed no increase in lethality following CHIKV infection, thus pointing to a non-classical role for ISG15. No differences in viral loads were observed between wild-type (WT) and ISG15â»/â» mice, however, a dramatic increase in proinflammatory cytokines and chemokines was observed in ISG15â»/â» mice, suggesting that the innate immune response to CHIKV contributes to their lethality. This study provides new insight into the control of CHIKV infection, and establishes a new model for how ISG15 functions as an immunomodulatory molecule in the blunting of potentially pathologic levels of innate effector molecules during the host response to viral infection.
Asunto(s)
Infecciones por Alphavirus/inmunología , Virus Chikungunya/fisiología , Citocinas/inmunología , Interferón Tipo I/inmunología , Enzimas Activadoras de Ubiquitina/inmunología , Ubiquitinas/inmunología , Infecciones por Alphavirus/diagnóstico , Infecciones por Alphavirus/metabolismo , Animales , Animales Recién Nacidos , Fiebre Chikungunya , Virus Chikungunya/patogenicidad , Citocinas/metabolismo , Modelos Animales de Enfermedad , Humanos , Interferón Tipo I/metabolismo , Ratones , Ratones Endogámicos C57BL , Unión Proteica , Recombinación Genética , Estudios Retrospectivos , Enzimas Activadoras de Ubiquitina/metabolismo , Ubiquitinas/metabolismoRESUMEN
Cell-free HIV-1 virions are poor stimulators of type I interferon (IFN) production. We examined here how HIV-infected cells are recognized by plasmacytoid dendritic cells (pDCs) and by other cells. We show that infected lymphocytes are more potent inducers of IFN than virions. There are target cell-type differences in the recognition of infected lymphocytes. In primary pDCs and pDC-like cells, recognition occurs in large part through TLR7, as demonstrated by the use of inhibitors and by TLR7 silencing. Donor cells expressing replication-defective viruses, carrying mutated reverse transcriptase, integrase or nucleocapsid proteins induced IFN production by target cells as potently as wild-type virus. In contrast, Env-deleted or fusion defective HIV-1 mutants were less efficient, suggesting that in addition to TLR7, cytoplasmic cellular sensors may also mediate sensing of infected cells. Furthermore, in a model of TLR7-negative cells, we demonstrate that the IRF3 pathway, through a process requiring access of incoming viral material to the cytoplasm, allows sensing of HIV-infected lymphocytes. Therefore, detection of HIV-infected lymphocytes occurs through both endosomal and cytoplasmic pathways. Characterization of the mechanisms of innate recognition of HIV-infected cells allows a better understanding of the pathogenic and exacerbated immunologic events associated with HIV infection.
Asunto(s)
Células Dendríticas/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Linfocitos/metabolismo , Linfocitos/virología , Western Blotting , Células Cultivadas , Células Dendríticas/metabolismo , Células Dendríticas/virología , Glicoproteínas/genética , Glicoproteínas/metabolismo , VIH , Infecciones por VIH/metabolismo , Seropositividad para VIH , Células Madre Hematopoyéticas/metabolismo , Humanos , Factor 3 Regulador del Interferón/genética , Factor 3 Regulador del Interferón/metabolismo , Interferón-alfa/metabolismo , Linfocitos/inmunología , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/metabolismo , Virión/patogenicidad , Replicación ViralRESUMEN
Interleukin-7 (IL-7), the principal cytokine implicated in thymopoiesis and peripheral T-cell homeostasis, is presently under evaluation in human diseases characterized by persistent lymphopenia. Unexpectedly, before the eventual IL-7-driven T-cell expansion, all treated patients showed a profound T-cell depletion 24 hours after injection. The current study uses the rhesus macaque model to investigate the mechanisms involved in this IL-7-induced T-cell depletion. We identify a new critical function of IL-7 that induces massive and rapid T-cell migration from the blood into various organs, including lymph nodes, parts of the intestine, and the skin. This homing process was initiated after the induction of chemokine receptor expression by circulating T cells and the production of corresponding chemokines in target organs. Finally, we demonstrate that the IL-7-induced cell cycling is initiated within these organs before T cells migrate back into the bloodstream, indicating that T-cell homing is required for in vivo IL-7 function.
Asunto(s)
Quimiotaxis de Leucocito/efectos de los fármacos , Interleucina-7/farmacología , Linfocitos T/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Proliferación Celular/efectos de los fármacos , Glicosilación , Inyecciones , Interleucina-7/administración & dosificación , Interleucina-7/metabolismo , Interleucina-7/fisiología , Recuento de Linfocitos , Macaca mulatta , Receptores de Quimiocina/metabolismo , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacología , Linfocitos T/fisiología , Factores de TiempoRESUMEN
Chikungunya virus (CHIKV) is a re-emerging arbovirus responsible for a massive outbreak currently afflicting the Indian Ocean region and India. Infection from CHIKV typically induces a mild disease in humans, characterized by fever, myalgia, arthralgia, and rash. Cases of severe CHIKV infection involving the central nervous system (CNS) have recently been described in neonates as well as in adults with underlying conditions. The pathophysiology of CHIKV infection and the basis for disease severity are unknown. To address these critical issues, we have developed an animal model of CHIKV infection. We show here that whereas wild type (WT) adult mice are resistant to CHIKV infection, WT mouse neonates are susceptible and neonatal disease severity is age-dependent. Adult mice with a partially (IFN-alpha/betaR(+/-)) or totally (IFN-alpha/betaR(-/-)) abrogated type-I IFN pathway develop a mild or severe infection, respectively. In mice with a mild infection, after a burst of viral replication in the liver, CHIKV primarily targets muscle, joint, and skin fibroblasts, a cell and tissue tropism similar to that observed in biopsy samples of CHIKV-infected humans. In case of severe infections, CHIKV also disseminates to other tissues including the CNS, where it specifically targets the choroid plexuses and the leptomeninges. Together, these data indicate that CHIKV-associated symptoms match viral tissue and cell tropisms, and demonstrate that the fibroblast is a predominant target cell of CHIKV. These data also identify the neonatal phase and inefficient type-I IFN signaling as risk factors for severe CHIKV-associated disease. The development of a permissive small animal model will expedite the testing of future vaccines and therapeutic candidates.
Asunto(s)
Infecciones por Alphavirus/metabolismo , Virus Chikungunya/fisiología , Modelos Animales de Enfermedad , Interferón Tipo I/metabolismo , Adulto , Factores de Edad , Infecciones por Alphavirus/patología , Infecciones por Alphavirus/fisiopatología , Animales , Animales Recién Nacidos , Animales no Consanguíneos , Línea Celular Tumoral , Virus Chikungunya/patogenicidad , Chlorocebus aethiops , Femenino , Humanos , Recién Nacido , Interferón Tipo I/deficiencia , Interferón Tipo I/genética , Hígado/metabolismo , Hígado/patología , Hígado/virología , Longevidad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal , Células Vero , Carga Viral , Replicación ViralRESUMEN
An unprecedented epidemic of chikungunya virus (CHIKV) infection recently started in countries of the Indian Ocean area, causing an acute and painful syndrome with strong fever, asthenia, skin rash, polyarthritis, and lethal cases of encephalitis. The basis for chikungunya disease and the tropism of CHIKV remain unknown. Here, we describe the replication characteristics of recent clinical CHIKV strains. Human epithelial and endothelial cells, primary fibroblasts and, to a lesser extent, monocyte-derived macrophages, were susceptible to infection and allowed viral production. In contrast, CHIKV did not replicate in lymphoid and monocytoid cell lines, primary lymphocytes and monocytes, or monocyte-derived dendritic cells. CHIKV replication was cytopathic and associated with an induction of apoptosis in infected cells. Chloroquine, bafilomycin-A1, and short hairpin RNAs against dynamin-2 inhibited viral production, indicating that viral entry occurs through pH-dependent endocytosis. CHIKV was highly sensitive to the antiviral activity of type I and II interferons. These results provide a general insight into the interaction between CHIKV and its mammalian host.
Asunto(s)
Infecciones por Alphavirus/virología , Virus Chikungunya/patogenicidad , Enfermedades Transmisibles Emergentes/virología , Replicación Viral , Infecciones por Alphavirus/epidemiología , Virus Chikungunya/ultraestructura , Enfermedades Transmisibles Emergentes/epidemiología , Efecto Citopatogénico Viral , Células Endoteliales/patología , Células Endoteliales/virología , Células Epiteliales/patología , Células Epiteliales/virología , Humanos , Islas del Oceano ÍndicoRESUMEN
BACKGROUND: Bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx) results from bronchial epithelial cell (BECs) damages, thought to be orchestrated by T cells primed by antigen-presenting cell presenting alloantigens. In this cell cross-talk, BECs are also suspected to play a pivotal immunosuppressive role in T cell alloreactivity. We studied the immunomodulating role of BECs in a human ex vivo model of allogeneic T cell response, both in healthy subjects and LTx recipients. METHODS: BECs from 35 LTx recipients (n = 22 stable, n = 13 BOS) and healthy controls (n = 25) were cultured as primary cell cultures. Their inhibitory capacities through the involvement of tolerogenic molecules (HLA-G, TGF-ß, and IL-10) were tested on a mixed lymphocyte reaction between antigen-presenting cells and recipient T cells. RESULTS: Control BECs inhibited T cell alloproliferation by a mean of 53 ± 7%. This inhibitory effect of BECs was significantly reduced in the stable LTx group (24 ± 8%, P = 0.009), but not in the BOS TxP group (53 ± 10%, P = 0.97). Neutralization of HLA-G, TGF-ß, and IL-10 partially restored T cell alloproliferation, arguing for their involvement in the immunosuppressive effect of BECs. BECs culture supernatant from stable LTx patients with impaired BEC properties showed a skewed Th2-type secretion profile (high IL-4/IFN-γ ratio). CONCLUSIONS: The inhibitory properties of BECs are dysregulated in stable LTx recipients, which could suggest their instrumental role in the initiation of BOS process and potential targeted therapies.
Asunto(s)
Bronquiolitis Obliterante/etiología , Células Epiteliales/metabolismo , Antígenos HLA-G/metabolismo , Inmunidad Mucosa , Interleucina-10/metabolismo , Trasplante de Pulmón/efectos adversos , Mucosa Respiratoria/metabolismo , Linfocitos T/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Bronquiolitis Obliterante/inmunología , Bronquiolitis Obliterante/metabolismo , Bronquiolitis Obliterante/patología , Estudios de Casos y Controles , Proliferación Celular , Células Cultivadas , Técnicas de Cocultivo , Células Epiteliales/inmunología , Células Epiteliales/patología , Femenino , Antígenos HLA-G/inmunología , Humanos , Interleucina-10/inmunología , Activación de Linfocitos , Prueba de Cultivo Mixto de Linfocitos , Masculino , Persona de Mediana Edad , Cultivo Primario de Células , Estudios Prospectivos , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/patología , Transducción de Señal , Linfocitos T/inmunología , Linfocitos T/patología , Factor de Crecimiento Transformador beta/inmunología , Resultado del TratamientoRESUMEN
BACKGROUND: Arthritogenic alphaviruses, including Chikungunya virus (CHIKV), are responsible for acute fever and arthralgia, but can also lead to chronic symptoms. In 2006, a Chikungunya outbreak occurred in La Réunion Island, during which we constituted a prospective cohort of viremic patients (nâ=â180) and defined the clinical and biological features of acute infection. Individuals were followed as part of a longitudinal study to investigate in details the long-term outcome of Chikungunya. METHODOLOGY/PRINCIPAL FINDINGS: Patients were submitted to clinical investigations 4, 6, 14 and 36 months after presentation with acute CHIKV infection. At 36 months, 22 patients with arthralgia and 20 patients without arthralgia were randomly selected from the cohort and consented for blood sampling. During the 3 years following acute infection, 60% of patients had experienced symptoms of arthralgia, with most reporting episodic relapse and recovery periods. Long-term arthralgias were typically polyarthralgia (70%), that were usually symmetrical (90%) and highly incapacitating (77%). They were often associated with local swelling (63%), asthenia (77%) or depression (56%). The age over 35 years and the presence of arthralgia 4 months after the disease onset are risk factors of long-term arthralgia. Patients with long-term arthralgia did not display biological markers typically found in autoimmune or rheumatoid diseases. These data helped define the features of CHIKV-associated chronic arthralgia and permitted an estimation of the economic burden associated with arthralgia. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that chronic arthralgia is a frequent complication of acute Chikungunya disease and suggests that it results from a local rather than systemic inflammation.
Asunto(s)
Infecciones por Alphavirus/complicaciones , Artralgia/patología , Adulto , Anciano , Anciano de 80 o más Años , Infecciones por Alphavirus/epidemiología , Artralgia/epidemiología , Fiebre Chikungunya , Estudios de Cohortes , Brotes de Enfermedades , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Reunión/epidemiología , Factores de RiesgoRESUMEN
OBJECTIVE: Skeletal muscle may be the site of a variety of poorly understood immune reactions, particularly after myofiber injury, which is typically observed in inflammatory myopathies. This study was undertaken to explore both the cell dynamics and functions of resident macrophages and dendritic cells (DCs) in damaged muscle, using a mouse model of notexin-induced myoinjury to study innate immune cell reactions. METHODS: The myeloid cell reaction to notexin-induced myoinjury was analyzed by microscopy and flow cytometry. Bone marrow (BM) transplantation studies were used to discriminate resident from exudate monocyte/macrophages. Functional tests included cytokine screening and an alloantigenic mixed leukocyte reaction to assess the antigen-presenting cell (APC) function. Selective resident macrophage depletion was obtained by injection of diphtheria toxin (DT) into CD11b-DT receptor-transgenic mice transplanted with DT-insensitive BM. RESULTS: The connective tissue surrounding mouse muscle/fascicle tissue (the epimysium/perimysium) after deep muscle injury displayed a resident macrophage population of CD11b+F4/80+CD11c-Ly-6C-CX3CR1- cells, which concentrated first in the epimysium. These resident macrophages were being used by leukocytes as a centripetal migration pathway, and were found to selectively release 2 chemokines, cytokine-induced neutrophil chemoattractant and monocyte chemoattractant protein 1, and to crucially contribute to massive recruitment of neutrophils and monocytes from the blood. Early epimysial inflammation consisted of a predominance of Ly-6C(high)CX3CR1(low)CD11c- cells that were progressively substituted by Ly-6C(low)CX3CR1(high) cells displaying an intermediate, rather than high, level of CD11c expression. These CD11c(intermediate) cells were derived from circulating CCR2+ monocytes, functionally behaved as immature APCs in the absence of alloantigenic challenge, and migrated to draining lymph nodes while acquiring the phenotype of mature DCs (CD11c+Ia+CD80+ cells, corresponding to an inflammatory DC phenotype). CONCLUSION: The results in this mouse model show that resident macrophages in the muscle epimysium/perimysium orchestrate the innate immune response to myoinjury, which is linked to adaptive immunity through the formation of inflammatory DCs.
Asunto(s)
Tejido Conectivo/efectos de los fármacos , Venenos Elapídicos/toxicidad , Macrófagos/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Neurotoxinas/toxicidad , Animales , Trasplante de Médula Ósea , Antígeno CD11c/metabolismo , Receptor 1 de Quimiocinas CX3C , Quimiocina CCL2/metabolismo , Quimiocina CXCL1/metabolismo , Tejido Conectivo/inmunología , Tejido Conectivo/patología , Modelos Animales de Enfermedad , Citometría de Flujo , Técnica del Anticuerpo Fluorescente Indirecta , Técnicas para Inmunoenzimas , Macrófagos/inmunología , Macrófagos/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Desnudos , Ratones Transgénicos , Músculo Esquelético/inmunología , Músculo Esquelético/patología , Infiltración Neutrófila/inmunología , Receptores de Quimiocina/metabolismoRESUMEN
Chikungunya virus (CHIKV) is the causative agent of an outbreak that began in La Réunion in 2005 and remains a major public health concern in India, Southeast Asia, and southern Europe. CHIKV is transmitted to humans by mosquitoes and the associated disease is characterized by fever, myalgia, arthralgia, and rash. As viral load in infected patients declines before the appearance of neutralizing antibodies, we studied the role of type I interferon (IFN) in CHIKV pathogenesis. Based on human studies and mouse experimentation, we show that CHIKV does not directly stimulate type I IFN production in immune cells. Instead, infected nonhematopoietic cells sense viral RNA in a Cardif-dependent manner and participate in the control of infection through their production of type I IFNs. Although the Cardif signaling pathway contributes to the immune response, we also find evidence for a MyD88-dependent sensor that is critical for preventing viral dissemination. Moreover, we demonstrate that IFN-alpha/beta receptor (IFNAR) expression is required in the periphery but not on immune cells, as IFNAR(-/-)-->WT bone marrow chimeras are capable of clearing the infection, whereas WT-->IFNAR(-/-) chimeras succumb. This study defines an essential role for type I IFN, produced via cooperation between multiple host sensors and acting directly on nonhematopoietic cells, in the control of CHIKV.