RESUMEN
Although master transcription factors (TFs) are key to the development of specific T cell subsets, whether additional transcriptional regulators are induced by the same stimuli that dominantly repress the development of other, non-specific T cell lineages has not been fully elucidated. Through the use of regulatory T cells (Treg cells) induced by transforming growth factor-ß (TGF-ß), we identified the TF musculin (MSC) as being critical for the development of induced Treg cells (iTreg cells) by repression of the T helper type 2 (TH2) transcriptional program. Loss of MSC reduced expression of the Treg cell master TF Foxp3 and induced TH2 differentiation even under iTreg-cell-differentiation conditions. MSC interrupted binding of the TF GATA-3 to the locus encoding TH2-cell-related cytokines and diminished intrachromosomal interactions within that locus. MSC-deficient (Msc-/-) iTreg cells were unable to suppress TH2 responses, and Msc-/- mice spontaneously developed gut and lung inflammation with age. MSC therefore enforced Foxp3 expression and promoted the unidirectional induction of iTreg cells by repressing the TH2 developmental program.
Asunto(s)
Diferenciación Celular , Inflamación , Mucosa Intestinal/inmunología , Neumonía/inmunología , Linfocitos T Reguladores/fisiología , Células Th2/fisiología , Factores de Transcripción/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Células Cultivadas , Factores de Transcripción Forkhead/metabolismo , Factor de Transcripción GATA3/metabolismo , Regulación de la Expresión Génica , Inflamación/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factores de Transcripción/genética , Transcripción Genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
The ß-galactoside-binding protein galectin-9 is critical in regulating the immune response, but the mechanism by which it functions remains unclear. We have demonstrated that galectin-9 is highly expressed by induced regulatory T cells (iTreg) and was crucial for the generation and function of iTreg cells, but not natural regulatory T (nTreg) cells. Galectin-9 expression within iTreg cells was driven by the transcription factor Smad3, forming a feed-forward loop, which further promoted Foxp3 expression. Galectin-9 increased iTreg cell stability and function by directly binding to its receptor CD44, which formed a complex with transforming growth factor-ß (TGF-ß) receptor I (TGF-ßRI), and activated Smad3. Galectin-9 signaling was further found to regulate iTreg cell induction by dominantly acting through the CNS1 region of the Foxp3 locus. Our data suggest that exogenous galectin-9, in addition to being an effector molecule for Treg cells, acts synergistically with TGF-ß to enforce iTreg cell differentiation and maintenance.
Asunto(s)
Factores de Transcripción Forkhead/biosíntesis , Galectinas/inmunología , Receptores de Hialuranos/inmunología , Linfocitos T Reguladores/inmunología , Animales , Diferenciación Celular/inmunología , Colitis/genética , Colitis/inmunología , Galectinas/genética , Receptor 2 Celular del Virus de la Hepatitis A , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Serina-Treonina Quinasas/inmunología , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/inmunología , Receptores Virales/inmunología , Transducción de Señal/inmunología , Proteína smad3/inmunología , Factor de Crecimiento Transformador beta/inmunologíaRESUMEN
One of the physiologic mechanisms responsible to maintain asymmetric phospholipid distribution (in particular phosphatidylserine, PS) in human erythrocyte membranes is orchestrated by the balance between enzymes responsible for active transport of PS from the outer to the inner leaflet (ATP11C) and those whose counteracts these activities (PLSCR1). Using quantitative real-time polymerase chain reaction and standard flow cytometry procedures, we hypothesized that the aberrant expression of either or both ATP11C and PLSCR1 transcripts may disrupt the PS internalization/externalization process and become clinically relevant for patients with sickle cell anemia (SCA). Overall, neither ATP11C/PLSCR1 ratio or ATP11C and PLSCR1 (if analyzed separately) had impact on risk to present acute or chronic organ damage in 178 patients with SCA. By collecting a new set of samples from SCA patients during a vaso-occlusive crisis (VOC, crisis state, 13 patients) and comparing with new samples of patients in steady state (15 patients), we noticed that patients in steady state exhibited mean values of ATP11C/PLSCR1 ratio significantly higher (mean value: 18.2, range, 0.3-53) than those who were in crisis (mean value: 3.7, range, 0.5-9) (P = 0.013). Most importantly, there was a strong inverse correlation between PS exposure and ATP11C/PLSCR1 ratio in sickle erythrocytes (Pearson correlation coefficient, r: - 0.78). Based on these findings, it is conceivable that the ATP11C/PLSCR1 ratio may switch from high to low during a VOC, although the underlying reasons require further investigations.
Asunto(s)
Adenosina Trifosfatasas/genética , Anemia de Células Falciformes/genética , Proteínas de Transporte de Membrana/genética , Proteínas de Transferencia de Fosfolípidos/genética , ARN Mensajero/genética , Adolescente , Adulto , Anciano , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Transcriptoma , Adulto JovenRESUMEN
BACKGROUND: Zika virus (ZIKV) is a recently emerged arbovirus, which infection during pregnancy is associated with a series of congenital malformations, collectively denominated Congenital Zika Syndrome (CZS). Following infection, ZIKV RNA has a median duration period of 10 days in plasma and up to 6 months in semen in immunocompetent adult individuals. Moreover, ZIKV is able to replicate and persist in fetal brains and placentas, consequently, infection is associated with pregnancy loss, albeit the pathogenic mechanisms are still unknown. CASE PRESENTATION: Here we report a CZS case of an infant born during the ZIKV outbreak in northeast Brazil, the child presented recurrent episodes of seizures with prolonged presence of ZIKV RNA on the central nervous system (CNS) and blood. ZIKV RNA was identified and partially sequenced from a sample of cerebrospinal fluid (CSF) obtained from the infant with 6 months of life, and later from another sample after the infant completed 17 months of life. Commonly congenital infections were discarded based on STORCH (syphilis, toxoplasmosis, rubella, cytomegalovirus and herpes simplex virus) negative laboratory results. Presence of specific ZIKV antibodies on both mother and children confirmed the association of severe microcephaly and ZIKV infection, diagnosed after birth. CONCLUSIONS: Altogether, our data raise the possibility that CZS cases may result in prolonged viral presence, these findings could be useful for therapy and diagnostic recommendations.
Asunto(s)
Microcefalia/virología , Infección por el Virus Zika/congénito , Infección por el Virus Zika/complicaciones , Adulto , Brasil , Epilepsia/etiología , Epilepsia/patología , Epilepsia/virología , Femenino , Humanos , Lactante , Recién Nacido , Microcefalia/patología , Embarazo , Complicaciones Infecciosas del Embarazo/virología , ARN Viral/aislamiento & purificación , Índice de Severidad de la Enfermedad , Virus Zika/genética , Virus Zika/aislamiento & purificación , Infección por el Virus Zika/diagnóstico , Infección por el Virus Zika/patologíaRESUMEN
Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by joint destruction and severe morbidity. Methotrexate (MTX) is the standard first-line therapy of RA. However, about 40% of RA patients are unresponsive to MTX treatment. Regulatory T cells (Tregs, CD4(+)CD25(+)FoxP3(+)) are thought to play an important role in attenuating RA. To investigate the role of Tregs in MTX resistance, we recruited 122 RA patients (53 responsive, R-MTX; 69 unresponsive, UR-MTX) and 33 healthy controls. Three months after MTX treatment, R-MTX but not UR-MTX showed higher frequency of peripheral blood CD39(+)CD4(+)CD25(+)FoxP3(+) Tregs than the healthy controls. Tregs produce adenosine (ADO) through ATP degradation by sequential actions of two cell surface ectonucleotidases: CD39 and CD73. Tregs from UR-MTX expressed a lower density of CD39, produced less ADO, and had reduced suppressive activity than Tregs from R-MTX. In a prospective study, before MTX treatment, UR-MTX expressed a lower density of CD39 on Tregs than those of R-MTX or control (P < 0.01). In a murine model of arthritis, CD39 blockade reversed the antiarthritic effects of MTX treatment. Our results demonstrate that MTX unresponsiveness in RA is associated with low expression of CD39 on Tregs and the decreased suppressive activity of these cells through reduced ADO production. Our findings thus provide hitherto unrecognized mechanism of immune regulation in RA and on mode of action of MTX. Furthermore, our data suggest that low expression of CD39 on Tregs could be a noninvasive biomarker for identifying MTX-resistant RA patients.
Asunto(s)
Antígenos CD/metabolismo , Apirasa/metabolismo , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Resistencia a Medicamentos/inmunología , Metotrexato/uso terapéutico , Linfocitos T Reguladores/inmunología , 5'-Nucleotidasa/metabolismo , Adenosina/metabolismo , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/inmunología , Artritis Experimental/patología , Artritis Reumatoide/patología , Biomarcadores/metabolismo , Resistencia a Medicamentos/efectos de los fármacos , Humanos , Recuento de Linfocitos , Metotrexato/farmacología , Ratones Endogámicos C57BL , Linfocitos T Reguladores/efectos de los fármacos , Células TH1/inmunología , Células Th17/inmunologíaRESUMEN
Anti-Flavivirus antibodies are highly cross-reactive and may facilitate Zika virus (ZIKV) infection through the antibody-dependent enhancement (ADE) mechanism. We demonstrate that dengue-specific antibodies enhance the infection of a primary Brazilian ZIKV isolate in a FcγRII-expressing K562 cell line. In addition, we demonstrate that serum samples from dengue-immune pregnant women enhanced ZIKV infection. These findings highlight the need for epidemiological studies and animal models to further confirm the role of ADE in the development of congenital and neurological complications associated with ZIKV infections.
Asunto(s)
Anticuerpos Antivirales/sangre , Acrecentamiento Dependiente de Anticuerpo , Virus del Dengue , Infección por el Virus Zika/inmunología , Virus Zika/patogenicidad , Anticuerpos Antivirales/inmunología , Antivirales/farmacología , Brasil , Reacciones Cruzadas , Femenino , Humanos , Células K562 , Embarazo , Receptores de IgG/inmunología , Infección por el Virus Zika/sangreRESUMEN
BACKGROUND: Viral encephalitis is a common cause of lethal infections in humans, and several different viruses are documented to be responsible. Rocio virus is a flavivirus that causes a severe lethal encephalitis syndrome in humans and also mice, providing an interesting model to study the CNS compartmentalized immune response. Interleukin 33 (IL-33), a member of the IL-1 family, is an immunomodulatory cytokine that is highly expressed in the CNS. However, the role of IL-33 on viral encephalitis remains unclear. Therefore, we aimed to explore how the IL-33/ST2 axis regulates the local immune response during Rocio virus infection. METHODS: Wild-type (WT), ST2 (ST2(-/-)), and nitric oxide synthase-deficient mice (iNOS(-/-)) and Stat6 (Stat6(-/-))-deficient mice were infected with different concentrations of the Rocio virus by intraperitoneal route, the cytokine mRNA level in CNS was analyzed by qPCR, and cellular immunophenotyping was performed on infected mice by the flow cytometry of isolated CNS mononuclear cells. RESULTS: We have shown that the mRNA expression of IL-33 and ST2 receptors is increased in the CNS of Rocio virus-infected WT mice and that ST2(-/-) mice showed increased susceptibility to infection. ST2 deficiency was correlated with increased tissue pathology, cellular infiltration, and tumor necrosis factor alpha (TNF-α) and interferon-gamma (IFN-γ) mRNA levels and higher viral load in the CNS, compared with wild-type mice. The increased Th1 cytokine levels released in the CNS acted on infiltrating macrophages, as evidenced by flow cytometry characterization of cellular infiltrates, inducing the expression of iNOS, contributing to brain injury. Moreover, iNOS(-/-) mice were more resistant to Rocio virus encephalitis, presenting a lower clinical score and reduced mortality rate, despite the increased tissue pathology. CONCLUSIONS: We provide evidences of a specific role for IL-33 receptor signaling in nitric oxide induction through local IFN-γ modulation, suggesting that nitric oxide overproduction might have an important role in the progression of experimental viral encephalitis.
Asunto(s)
Sistema Nervioso Central , Encefalitis Viral/patología , Interleucina-33/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Animales , Antígenos de Diferenciación/metabolismo , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/patología , Sistema Nervioso Central/virología , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo/genética , Femenino , Infecciones por Flaviviridae/patología , Citometría de Flujo , Proteína 1 Similar al Receptor de Interleucina-1/deficiencia , Proteína 1 Similar al Receptor de Interleucina-1/genética , Interleucina-33/genética , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/patología , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Óxido Nítrico Sintasa de Tipo II/genética , ARN Mensajero/metabolismo , Factor de Transcripción STAT6/deficiencia , Factor de Transcripción STAT6/genética , Transducción de Señal/fisiologíaRESUMEN
Intracellular pattern recognition receptors such as the nucleotide-binding oligomerization domain (NOD)-like receptors family members are key for innate immune recognition of microbial infection and may play important roles in the development of inflammatory diseases, including rheumatic diseases. In this study, we evaluated the role of NOD1 and NOD2 on development of experimental arthritis. Ag-induced arthritis was generated in wild-type, NOD1(-/-), NOD2(-/-), or receptor-interacting serine-threonine kinase 2(-/-) (RIPK2(-/-)) immunized mice challenged intra-articularly with methylated BSA. Nociception was determined by electronic Von Frey test. Neutrophil recruitment and histopathological analysis of proteoglycan lost was evaluated in inflamed joints. Joint levels of inflammatory cytokine/chemokine were measured by ELISA. Cytokine (IL-6 and IL-23) and NOD2 expressions were determined in mice synovial tissue by RT-PCR. The NOD2(-/-) and RIPK2(-/-), but not NOD1(-/-), mice are protected from Ag-induced arthritis, which was characterized by a reduction in neutrophil recruitment, nociception, and cartilage degradation. NOD2/RIPK2 signaling impairment was associated with a reduction in proinflammatory cytokines and chemokines (TNF, IL-1ß, and CXCL1/KC). IL-17 and IL-17 triggering cytokines (IL-6 and IL-23) were also reduced in the joint, but there is no difference in the percentage of CD4(+) IL-17(+) cells in the lymph node between arthritic wild-type and NOD2(-/-) mice. Altogether, these findings point to a pivotal role of the NOD2/RIPK2 signaling in the onset of experimental arthritis by triggering an IL-17-dependent joint immune response. Therefore, we could propose that NOD2 signaling is a target for the development of new therapies for the control of rheumatoid arthritis.
Asunto(s)
Artritis Experimental/inmunología , Interleucina-17/metabolismo , Articulación de la Rodilla/inmunología , Proteína Adaptadora de Señalización NOD2/fisiología , Proteína Serina-Treonina Quinasas de Interacción con Receptores/fisiología , Transducción de Señal/inmunología , Animales , Artritis Experimental/metabolismo , Artritis Experimental/patología , Bovinos , Células Cultivadas , Interleucina-17/fisiología , Articulación de la Rodilla/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína Adaptadora de Señalización NOD1/deficiencia , Proteína Adaptadora de Señalización NOD2/deficiencia , Proteína Serina-Treonina Quinasa 2 de Interacción con Receptor , Proteína Serina-Treonina Quinasas de Interacción con Receptores/deficiencia , Albúmina Sérica Bovina/inmunología , Albúmina Sérica Bovina/toxicidad , Transducción de Señal/genéticaRESUMEN
Chikungunya virus (CHIKV), an alphavirus transmitted by mosquitoes, has experienced a recent re-emergence in various regions of the world, leading to large-scale outbreaks [...].
Asunto(s)
Virus Chikungunya , Culicidae , Animales , Brotes de EnfermedadesRESUMEN
SARS-CoV-2 serologic surveys estimate the proportion of the population with antibodies against historical variants, which nears 100% in many settings. New approaches are required to fully exploit serosurvey data. Using a SARS-CoV-2 anti-Spike (S) protein chemiluminescent microparticle assay, we attained a semi-quantitative measurement of population IgG titers in serial cross-sectional monthly samples of blood donations across seven Brazilian state capitals (March 2021−November 2021). Using an ecological analysis, we assessed the contributions of prior attack rate and vaccination to antibody titer. We compared anti-S titer across the seven cities during the growth phase of the Delta variant and used this to predict the resulting age-standardized incidence of severe COVID-19 cases. We tested ~780 samples per month, per location. Seroprevalence rose to >95% across all seven capitals by November 2021. Driven by vaccination, mean antibody titer increased 16-fold over the study, with the greatest increases occurring in cities with the highest prior attack rates. Mean anti-S IgG was strongly correlated (adjusted R2 = 0.89) with the number of severe cases caused by Delta. Semi-quantitative anti-S antibody titers are informative about prior exposure and vaccination coverage and may also indicate the potential impact of future SARS-CoV-2 variants.
RESUMEN
Background: The COVID-19 situation in Brazil is complex due to large differences in the shape and size of regional epidemics. Understanding these patterns is crucial to understand future outbreaks of SARS-CoV-2 or other respiratory pathogens in the country. Methods: We tested 97,950 blood donation samples for IgG antibodies from March 2020 to March 2021 in 8 of Brazil's most populous cities. Residential postal codes were used to obtain representative samples. Weekly age- and sex-specific seroprevalence were estimated by correcting the crude seroprevalence by test sensitivity, specificity, and antibody waning. Results: The inferred attack rate of SARS-CoV-2 in December 2020, before the Gamma variant of concern (VOC) was dominant, ranged from 19.3% (95% credible interval [CrI] 17.5-21.2%) in Curitiba to 75.0% (95% CrI 70.8-80.3%) in Manaus. Seroprevalence was consistently smaller in women and donors older than 55 years. The age-specific infection fatality rate (IFR) differed between cities and consistently increased with age. The infection hospitalisation rate increased significantly during the Gamma-dominated second wave in Manaus, suggesting increased morbidity of the Gamma VOC compared to previous variants circulating in Manaus. The higher disease penetrance associated with the health system's collapse increased the overall IFR by a minimum factor of 2.91 (95% CrI 2.43-3.53). Conclusions: These results highlight the utility of blood donor serosurveillance to track epidemic maturity and demonstrate demographic and spatial heterogeneity in SARS-CoV-2 spread. Funding: This work was supported by Itaú Unibanco 'Todos pela Saude' program; FAPESP (grants 18/14389-0, 2019/21585-0); Wellcome Trust and Royal Society Sir Henry Dale Fellowship 204311/Z/16/Z; the Gates Foundation (INV- 034540 and INV-034652); REDS-IV-P (grant HHSN268201100007I); the UK Medical Research Council (MR/S0195/1, MR/V038109/1); CAPES; CNPq (304714/2018-6); Fundação Faculdade de Medicina; Programa Inova Fiocruz-CE/Funcap - Edital 01/2020 Number: FIO-0167-00065.01.00/20 SPU N°06531047/2020; JBS - Fazer o bem faz bem.
Asunto(s)
COVID-19 , Anticuerpos Antivirales , Donantes de Sangre , Brasil/epidemiología , COVID-19/epidemiología , Estudios Transversales , Femenino , Humanos , Inmunoglobulina G , Masculino , SARS-CoV-2 , Estudios SeroepidemiológicosRESUMEN
BACKGROUND: Zika virus is an emerging arbovirus of global importance. ZIKV infection is associated with a range of neurological complications such as the Congenital Zika Syndrome and Guillain Barré Syndrome. Despite the magnitude of recent outbreaks, there is no specific therapy to prevent or to alleviate disease pathology. OBJECTIVE: To investigate the role of P-MAPA immunomodulator in Zika-infected THP-1 cells. METHODS: THP-1 cells were subjected to Zika virus infection (Multiplicity of Infection = 0.5) followed by treatment with P-MAPA for until 96 hours post-infection. After that, the cell death was analyzed by annexin+/ PI+ and caspase 3/ 7+ staining by flow cytometry. In addition, virus replication and cell proliferation were accessed by RT-qPCR and Ki67 staining, respectively. RESULTS: We demonstrate that P-MAPA in vitro treatment significantly reduces Zika virus-induced cell death and caspase-3/7 activation on THP-1 infected cells, albeit it has no role in virus replication and cell proliferation. CONCLUSION: Our study reveals that P-MAPA seems to be a satisfactory alternative to inhibit the effects of Zika virus infection in mammalian cells.
Asunto(s)
Apoptosis/efectos de los fármacos , Factores Inmunológicos/farmacología , Ácidos Linoleicos/farmacología , Ácidos Oléicos/farmacología , Infección por el Virus Zika/patología , Antivirales/farmacología , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Proliferación Celular , Activación Enzimática/efectos de los fármacos , Citometría de Flujo , Humanos , Antígeno Ki-67 , Reacción en Cadena en Tiempo Real de la Polimerasa , Células THP-1 , Replicación Viral/efectos de los fármacos , Virus ZikaRESUMEN
Although the mixed lineage leukemia 5 (MLL5) gene has prognostic implications in acute promyelocyte leukemia (APL), the underlying mechanism remains to be elucidated. Here, we demonstrate the critical role exerted by MLL5 in APL regarding cell proliferation and resistance to drug-induced apoptosis, through mtROS regulation. Additionally, MLL5 overexpression increased the responsiveness of APL leukemic cells to all-trans retinoic acid (ATRA)-induced differentiation, via regulation of the epigenetic modifiers SETD7 and LSD1. In silico analysis indicated that APL blasts with MLL5high transcript levels were associated with retinoic acid binding and downstream signaling, while MLL5low blasts displayed decreased expression of epigenetic modifiers (such as KMT2C, PHF8 and ARID4A). Finally, APL xenograft transplants demonstrated improved engraftment of MLL5-expressing cells and increased myeloid differentiation over time. Concordantly, evaluation of engrafted blasts revealed increased responsiveness of MLL5-expressing cells to ATRA-induced granulocytic differentiation. Together, we describe the epigenetic changes triggered by the interaction of MLL5 and ATRA resulting in enhanced granulocytic differentiation.
Asunto(s)
Antineoplásicos/farmacología , Diferenciación Celular/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Xenoinjertos/inmunología , Leucemia Promielocítica Aguda/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Xenoinjertos/metabolismo , Histona Demetilasas/efectos de los fármacos , Histona Demetilasas/metabolismo , Humanos , Factores de Transcripción/efectos de los fármacos , Factores de Transcripción/metabolismoRESUMEN
The diagnostic of arbovirus-related obstetric complications in high-risk pregnancy and childbirth care is challenging, especially in endemic areas. We conducted a prospective study to track active or recent Zika (ZIKV), dengue (DENV), or chikungunya (CHIKV) virus infection among hospitalized pregnant women (PW) with obstetric complications in a hospital at the epicenter of Zika outbreak and ZIKV-related microcephaly in Brazil. Clinical data and blood samples were collected at enrollment and 10 days after the admission of study participants, between October 2018 and May 2019. Further clinical data were extracted from medical records. Samples were screened by molecular and serological tests. Out of 780 participants, 93.1% (95% CI: 91.1-94.7%) presented previous DENV exposure (IgG). ZIKV, CHIKV, and/or DENV laboratory markers of recent or active infection were detected in 130 PW, yielding a prevalence of 16.6% (95% CI: 14.2-19.5%); 9.4% (95% CI: 7.4-11.7%), 7.4% (95% CI: 5.7-9.7%), and 0.38% (95% CI: 0.1-1.2%) of CHIKV, ZIKV, and DENV infections, respectively. Most ZIKV infections were detected by molecular assays (89.6%), while CHIKV infections were detected by serology (95.9%). Our findings highlight the need for arbovirus infections screening in PW with obstetrical complications, potentially associated to these infections in endemic areas regardless of the signs or symptoms suggestive of arboviral disease.
Asunto(s)
Fiebre Chikungunya/epidemiología , Virus Chikungunya , Infección Hospitalaria/epidemiología , Complicaciones Infecciosas del Embarazo/epidemiología , Infección por el Virus Zika/epidemiología , Virus Zika , Adolescente , Adulto , Brasil/epidemiología , Infección Hospitalaria/virología , Susceptibilidad a Enfermedades , Femenino , Humanos , Incidencia , Persona de Mediana Edad , Embarazo , Complicaciones Infecciosas del Embarazo/virología , Estudios Prospectivos , Vigilancia en Salud Pública , Factores de Riesgo , Adulto JovenRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread rapidly in Manaus, the capital of Amazonas state in northern Brazil. The attack rate there is an estimate of the final size of the largely unmitigated epidemic that occurred in Manaus. We use a convenience sample of blood donors to show that by June 2020, 1 month after the epidemic peak in Manaus, 44% of the population had detectable immunoglobulin G (IgG) antibodies. Correcting for cases without a detectable antibody response and for antibody waning, we estimate a 66% attack rate in June, rising to 76% in October. This is higher than in São Paulo, in southeastern Brazil, where the estimated attack rate in October was 29%. These results confirm that when poorly controlled, COVID-19 can infect a large proportion of the population, causing high mortality.
Asunto(s)
Anticuerpos Antivirales/sangre , COVID-19/epidemiología , Epidemias , Inmunoglobulina G/sangre , SARS-CoV-2/aislamiento & purificación , Adolescente , Adulto , Anciano , Donantes de Sangre , Brasil/epidemiología , COVID-19/sangre , COVID-19/mortalidad , Monitoreo Epidemiológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , SARS-CoV-2/inmunología , Estudios Seroepidemiológicos , Adulto JovenRESUMEN
Chikungunya fever (CHIK) has caused important epidemic outbreaks in the Americas, with musculoskeletal involvement being the main manifestation, causing chronic symptoms in half of the affected patients. This study was performed to evaluate the clinical course of the infection in 168 patients with autoimmune inflammatory disease using biological disease-modifying antirheumatic drugs (bDMARDs), comparing this group with 56 household controls. Anti-CHIKV IgG serology was positive in 42 (25%) of the patients in the bDMARD group and in 15 (27%) of the controls (p=0.79). Of those with positive serology, 32 (76%) and 14 (93%) were symptomatic among subjects in the bDMARD and control groups, respectively (p=0.87). Persistence of musculoskeletal symptoms for more than three months occurred in 64% of the patients in the control group and only in 28% in the bDMARD group (p=0.021), maintaining a statistically significant difference only for users of anti-TNF. This study found that patients affected by chikungunya fever using bDMARDs did not present severe forms or complications in the acute phase of the disease, and patients using anti-TNF biologicals had a lower frequency of chronic joint symptoms than the household controls. This favorable outcome may be related to the cytokine blockade, with a reduction in the inflammatory response and joint damage.
RESUMEN
The Chikungunya virus (CHIKV) is a re-emerging arbovirus, in which its infection causes a febrile illness also commonly associated with severe joint pain and myalgia. Although the immune response to CHIKV has been studied, a better understanding of the virus-host interaction mechanisms may lead to more effective therapeutic interventions. In this context, neutrophil extracellular traps (NETs) have been described as a key mediator involved in the control of many pathogens, including several bacteria and viruses, but no reports of this important protective mechanism were documented during CHIKV infection. Here we demonstrate that the experimental infection of mouse-isolated neutrophils with CHIKV resulted in NETosis (NETs release) through a mechanism dependent on TLR7 activation and reactive oxygen species generation. In vitro, mouse-isolated neutrophils stimulated with phorbol 12-myristate 13-acetate release NETs that once incubated with CHIKV, resulting in further virus capture and neutralization. In vivo, NETs inhibition by the treatment of the mice with DNase resulted in the enhanced susceptibility of IFNAR-/- mice to CHIKV experimental acute infection. Lastly, by accessing the levels of MPO-DNA complex on the acutely CHIKV-infected patients, we found a correlation between the levels of NETs and the viral load in the blood, suggesting that NETs are also released in natural human infection cases. Altogether our findings characterize NETosis as a contributing natural process to control CHIKV acute infection, presenting an antiviral effect that helps to control systemic virus levels.
Asunto(s)
Fiebre Chikungunya/inmunología , Fiebre Chikungunya/virología , Virus Chikungunya/inmunología , Trampas Extracelulares/inmunología , Interacciones Huésped-Patógeno/inmunología , Neutrófilos/inmunología , Animales , Biomarcadores , Línea Celular , Fiebre Chikungunya/genética , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Trampas Extracelulares/genética , Interacciones Huésped-Patógeno/genética , Inmunidad Innata , Glicoproteínas de Membrana , Ratones , Ratones Noqueados , Pruebas de Neutralización , Neutrófilos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptor Toll-Like 7 , Carga Viral , Replicación Viral , Virus Zika/inmunologíaRESUMEN
Defining cases of Zika virus (ZIKV) infection is a critical challenge for epidemiological research. Due to ZIKV's overlapping clinical features and potential immunologic cross-reactivity with other flaviviruses and the current lack of an optimal ZIKV-specific diagnostic assay, varying approaches for identifying ZIKV infections have been employed to date. This paper presents the laboratory results and diagnostic criteria developed by the Microcephaly Epidemic Research Group for defining cases of maternal ZIKV infection in a cohort of pregnant women with rash (N = 694) recruited during the declining 2015-2017 epidemic in northeast Brazil. For this investigation, we tested maternal sera for ZIKV by quantitative reverse transcription polymerase chain reaction (qRT-PCR), Immunoglobulin (Ig) M and IgG3 enzyme-linked immunosorbent assays (ELISAs), and Plaque Reduction Neutralization Test (PRNT50). Overall, 23.8% of participants tested positive by qRT-PCR during pregnancy (range of detection: 0-72 days after rash onset). However, the inter-assay concordance was lower than expected. Among women with qRT-PCR-confirmed ZIKV and further testing, only 10.1% had positive IgM tests within 90 days of rash, and only 48.5% had ZIKV-specific PRNT50 titers ≥20 within 1 year of rash. Given the complexity of these data, we convened a panel of experts to propose an algorithm for identifying ZIKV infections in pregnancy based on all available lines of evidence. When the diagnostic algorithm was applied to the cohort, 26.9% of participants were classified as having robust evidence of a ZIKV infection during pregnancy, 4.0% as having moderate evidence, 13.3% as having limited evidence of a ZIKV infection but with uncertain timing, and 19.5% as having evidence of an unspecified flavivirus infection before or during pregnancy. Our findings suggest that integrating longitudinal data from nucleic acid and serologic testing may enhance diagnostic sensitivity and underscore the need for an on-going dialogue regarding the optimization of strategies for defining cases of ZIKV in research.