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1.
PLoS One ; 16(1): e0244937, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33406122

RESUMO

BACKGROUND: The impact of SARS-CoV-2 in regions endemic for both Dengue and Chikungunya is still not fully understood. Considering that symptoms/clinical features displayed during Dengue, Chikungunya and SARS-CoV-2 acute infections are similar, undiagnosed cases of SARS-CoV-2 in co-endemic areas may be more prevalent than expected. This study was conducted to assess the prevalence of covert cases of SARS-CoV-2 among samples from patients with clinical symptoms compatible with either Dengue or Chikungunya viral infection in the state of Espírito Santo, Brazil. METHODS: Presence of immunoglobulin G (IgG) antibody specific to SARS-CoV-2 nucleoprotein was detected using a chemiluminescent microparticle immunoassay in samples from 7,370 patients, without previous history of COVID-19 diagnosis, suspected of having either Dengue (n = 1,700) or Chikungunya (n = 7,349) from December 1st, 2019 to June 30th, 2020. FINDINGS: Covert cases of SARS-CoV-2 were detected in 210 (2.85%) out of the 7,370 serum samples tested. The earliest undiagnosed missed case of COVID-19 dated back to a sample collected on December 18, 2019, also positive for Dengue Virus. Cross-reactivity with either Dengue virus or other common coronaviruses were not observed. INTERPRETATION: Our findings demonstrate that concomitant Dengue or Chikungunya outbreaks may difficult the diagnosis of SARS-CoV-2 infections. To our knowledge, this is the first study to demonstrate, with a robust sample size (n = 7,370) and using highly specific and sensitive chemiluminescent microparticle immunoassay method, that covert SARS-CoV-2 infections are more frequent than previously expected in Dengue and Chikungunya hyperendemic regions. Moreover, our results suggest that SAR-CoV-2 cases were occurring prior to February, 2020, and that these undiagnosed missed cases may have contributed to the fast expansion of SARS-CoV-2 outbreak in Brazil. Data presented here demonstrate that in arboviral endemic regions, SARS-CoV-2 infection must be always considered, regardless of the existence of a previous positive diagnosis for Dengue or Chikungunya.


Assuntos
/epidemiologia , Febre de Chikungunya/epidemiologia , Dengue/epidemiologia , Adulto , Anticorpos Antivirais/sangue , Brasil/epidemiologia , Vírus Chikungunya/patogenicidade , Coinfecção/epidemiologia , Vírus da Dengue/patogenicidade , Erros de Diagnóstico/tendências , Surtos de Doenças , Feminino , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Prevalência , /patogenicidade
2.
Molecules ; 25(22)2020 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-33202656

RESUMO

The rapid spread of the new Coronavirus Disease 2019 (COVID-19) has actually become the newest challenge for the healthcare system since, to date, there is not an effective treatment. Among all drugs tested, Hydroxychloroquine (HCQ) has attracted significant attention. This systematic review aims to analyze preclinical and clinical studies on HCQ potential use in viral infection and chronic diseases. A systematic search of Scopus and PubMed databases was performed to identify clinical and preclinical studies on this argument; 2463 papers were identified and 133 studies were included. Regarding HCQ activity against COVID-19, it was noticed that despite the first data were promising, the latest outcomes highlighted the ineffectiveness of HCQ in the treatment of viral infection. Several trials have seen that HCQ administration did not improve severe illness and did not prevent the infection outbreak after virus exposure. By contrast, HCQ arises as a first-line treatment in managing autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, and Sjögren syndrome. It also improves glucose and lipid homeostasis and reveals significant antibacterial activity.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Síndrome de Sjogren/tratamento farmacológico , Artrite Reumatoide/imunologia , Artrite Reumatoide/fisiopatologia , Betacoronavirus/patogenicidade , Febre de Chikungunya/tratamento farmacológico , Febre de Chikungunya/epidemiologia , Febre de Chikungunya/fisiopatologia , Febre de Chikungunya/virologia , Vírus Chikungunya/patogenicidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/virologia , Esquema de Medicação , HIV/patogenicidade , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por HIV/fisiopatologia , Infecções por HIV/virologia , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/fisiopatologia , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Pneumonia Viral/virologia , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/epidemiologia , Síndrome Respiratória Aguda Grave/fisiopatologia , Síndrome Respiratória Aguda Grave/virologia , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/fisiopatologia , Zika virus/patogenicidade , Infecção por Zika virus/tratamento farmacológico , Infecção por Zika virus/epidemiologia , Infecção por Zika virus/fisiopatologia , Infecção por Zika virus/virologia
3.
PLoS One ; 15(8): e0238254, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32841293

RESUMO

The identification of host / pathogen interactions is essential to both understanding the molecular biology of infection and developing rational intervention strategies to overcome disease. Alphaviruses, such as Sindbis virus, Chikungunya virus, and Venezuelan Equine Encephalitis virus are medically relevant positive-sense RNA viruses. As such, they must interface with the host machinery to complete their infectious lifecycles. Nonetheless, exhaustive RNA:Protein interaction discovery approaches have not been reported for any alphavirus species. Thus, the breadth and evolutionary conservation of host interactions on alphaviral RNA function remains a critical gap in the field. Herein we describe the application of the Cross-Link Assisted mRNP Purification (CLAMP) strategy to identify conserved alphaviral interactions. Through comparative analyses, conserved alphaviral host / pathogen interactions were identified. Approximately 100 unique host proteins were identified as a result of these analyses. Ontological assessments reveal enriched Molecular Functions and Biological Processes relevant to alphaviral infection. Specifically, as anticipated, Poly(A) RNA Binding proteins are significantly enriched in virus specific CLAMP data sets. Moreover, host proteins involved in the regulation of mRNA stability, proteasome mediated degradation, and a number of 14-3-3 proteins were identified. Importantly, these data expand the understanding of alphaviral host / pathogen interactions by identifying conserved interactants.


Assuntos
Alphavirus/genética , Alphavirus/patogenicidade , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/fisiologia , Proteínas de Ligação a Poli(A)/genética , Proteínas de Ligação a Poli(A)/metabolismo , RNA Viral/genética , RNA Viral/metabolismo , Alphavirus/fisiologia , Animais , Linhagem Celular , Vírus Chikungunya/genética , Vírus Chikungunya/patogenicidade , Vírus Chikungunya/fisiologia , Vírus da Encefalite Equina Venezuelana/genética , Vírus da Encefalite Equina Venezuelana/patogenicidade , Vírus da Encefalite Equina Venezuelana/fisiologia , Evolução Molecular , Células HEK293 , Humanos , Mapas de Interação de Proteínas , Ribonucleoproteínas/genética , Ribonucleoproteínas/isolamento & purificação , Ribonucleoproteínas/metabolismo , Vírus Sindbis/genética , Vírus Sindbis/patogenicidade , Vírus Sindbis/fisiologia , Especificidade da Espécie
5.
Am J Trop Med Hyg ; 103(1): 149-156, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32342853

RESUMO

Dengue fever and other febrile mosquito-borne diseases place considerable health and economic burdens on small island nations in the Caribbean. Here, we used two methods of cluster detection to find potential hotspots of transmission of dengue and chikungunya in Barbados, and to assess the impact of input surveillance data and methodology on observed patterns of risk. Using Moran's I and spatial scan statistics, we analyzed the geospatial and temporal distribution of disease cases and rates across Barbados for dengue fever in 2013-2016, and a chikungunya outbreak in 2014. During years with high numbers of dengue cases, hotspots for cases were found with Moran's I in the south and central regions in 2013 and 2016, respectively. Using smoothed disease rates, clustering was detected in all years for dengue. Hotspots suggesting higher rates were not detected via spatial scan statistics, but coldspots suggesting lower than expected rates of disease activity were found in southwestern Barbados during high case years of dengue. No significant spatiotemporal structure was found in cases during the chikungunya outbreak. Spatial analysis of surveillance data is useful in identifying outbreak hotspots, potentially complementing existing early warning systems. We caution that these methods should be used in a manner appropriate to available data and reflecting explicit public health goals-managing for overall case numbers or targeting anomalous rates for further investigation.


Assuntos
Febre de Chikungunya/epidemiologia , Vírus Chikungunya/patogenicidade , Vírus da Dengue/patogenicidade , Dengue/epidemiologia , Surtos de Doenças , Análise Espaço-Temporal , Aedes/virologia , Animais , Barbados/epidemiologia , Febre de Chikungunya/transmissão , Febre de Chikungunya/virologia , Vírus Chikungunya/fisiologia , Análise por Conglomerados , Dengue/transmissão , Dengue/virologia , Vírus da Dengue/fisiologia , Doenças Endêmicas/estatística & dados numéricos , Monitoramento Epidemiológico , Humanos , Incidência , Mosquitos Vetores/virologia , Saúde Pública , Risco
6.
Sci Rep ; 10(1): 6364, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286447

RESUMO

In recent decades, chikungunya virus (CHIKV) has re-emerged, leading to outbreaks of chikungunya fever in Africa, Asia and Central and South America. The disease is characterized by a rapid onset febrile illness with (poly)arthralgia, myalgia, rashes, headaches and nausea. In 30 to 40% of the cases, CHIKV infection causes persistent (poly)arthralgia, lasting for months or even years after initial infection. Despite the drastic re-emergence and clinical impact there is no vaccine nor antiviral compound available to prevent or control CHIKV infection. Here, we evaluated the antiviral potential of tomatidine towards CHIKV infection. We demonstrate that tomatidine potently inhibits virus particle production of multiple CHIKV strains. Time-of -addition experiments in Huh7 cells revealed that tomatidine acts at a post-entry step of the virus replication cycle. Furthermore, a marked decrease in the number of CHIKV-infected cells was seen, suggesting that tomatidine predominantly acts early in infection yet after virus attachment and cell entry. Antiviral activity was still detected at 24 hours post-infection, indicating that tomatidine controls multiple rounds of CHIKV replication. Solasodine and sarsasapogenin, two structural derivatives of tomatidine, also showed strong albeit less potent antiviral activity towards CHIKV. In conclusion, this study identifies tomatidine as a novel compound to combat CHIKV infection in vitro.


Assuntos
Alcaloides/farmacologia , Febre de Chikungunya/tratamento farmacológico , Vírus Chikungunya/efeitos dos fármacos , Tomatina/análogos & derivados , Animais , Febre de Chikungunya/virologia , Vírus Chikungunya/patogenicidade , Chlorocebus aethiops , Humanos , Esteroides/farmacologia , Tomatina/farmacologia , Células Vero/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
7.
PLoS One ; 15(2): e0220753, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32027652

RESUMO

BACKGROUND: Three arthropod-borne viruses (arboviruses) causing human disease have been the focus of a large number of studies in the Americas since 2013 due to their global spread and epidemiological impacts: Zika, dengue, and chikungunya viruses. A large proportion of infections by these viruses are asymptomatic. However, all three viruses are associated with moderate to severe health consequences in a small proportion of cases. Two mosquito species, Aedes aegypti and Aedes albopictus, are among the world's most prominent arboviral vectors, and are known vectors for all three viruses in the Americas. OBJECTIVES: This review summarizes the state of the entomological literature surrounding the mosquito vectors of Zika, dengue and chikungunya viruses and factors affecting virus transmission. The rationale of the review was to identify and characterize entomological studies that have been conducted in the Americas since the introduction of chikungunya virus in 2013, encompassing a period of arbovirus co-circulation, and guide future research based on identified knowledge gaps. METHODS: The preliminary search for this review was conducted on PubMed (National Library of Health, Bethesda, MD, United States). The search included the terms 'zika' OR 'dengue' OR 'chikungunya' AND 'vector' OR 'Aedes aegypti' OR 'Aedes albopictus'. The search was conducted on March 1st of 2018, and included all studies since January 1st of 2013. RESULTS: A total of 96 studies were included in the scoping review after initial screening and subsequent exclusion of out-of-scope studies, secondary data publications, and studies unavailable in English language. KEY FINDINGS: We observed a steady increase in number of publications, from 2013 to 2018, with half of all studies published from January 2017 to March 2018. Interestingly, information on Zika virus vector species composition was abundant, but sparse on Zika virus transmission dynamics. Few studies examined natural infection rates of Zika virus, vertical transmission, or co-infection with other viruses. This is in contrast to the wealth of research available on natural infection and co-infection for dengue and chikungunya viruses, although vertical transmission research was sparse for all three viruses.


Assuntos
Infecções por Arbovirus/transmissão , Arbovirus/patogenicidade , Mosquitos Vetores/virologia , América/epidemiologia , Vírus Chikungunya/patogenicidade , Vírus da Dengue/patogenicidade , Humanos , Zika virus/patogenicidade
8.
J Virol ; 94(9)2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32102875

RESUMO

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes explosive epidemics of a febrile illness characterized by debilitating arthralgia and arthritis that can endure for months to years following infection. In mouse models, CHIKV persists in joint tissues for weeks to months and is associated with chronic synovitis. Using a recombinant CHIKV strain encoding a CD8+ T cell receptor epitope from ovalbumin, as well as a viral peptide-specific major histocompatibility complex class I tetramer, we interrogated CD8+ T cell responses during CHIKV infection. Epitope-specific CD8+ T cells, which were reduced in Batf3 -/- and Wdfy4 -/- mice with known defects in antigen cross-presentation, accumulated in joint tissue and the spleen. Antigen-specific ex vivo restimulation assays and in vivo killing assays demonstrated that CD8+ T cells produce cytokine and have cytolytic activity. Despite the induction of a virus-specific CD8+ T cell response, the CHIKV burden in joint-associated tissues and the spleen were equivalent in wild-type (WT) and CD8α-/- mice during both the acute and the chronic phases of infection. In comparison, CD8+ T cells were essential for the control of acute and chronic lymphocytic choriomeningitis virus infection in the joint and spleen. Moreover, adoptive transfer of virus-specific effector CD8+ T cells or immunization with a vaccine that induces virus-specific effector CD8+ T cells prior to infection enhanced the clearance of CHIKV infection in the spleen but had a minimal impact on CHIKV infection in the joint. Collectively, these data suggest that CHIKV establishes and maintains a persistent infection in joint-associated tissue in part by evading CD8+ T cell immunity.IMPORTANCE CHIKV is a reemerging mosquito-transmitted virus that in the last decade has spread into Europe, Asia, the Pacific Region, and the Americas. Joint pain, swelling, and stiffness can endure for months to years after CHIKV infection, and epidemics have a severe economic impact. Elucidating the mechanisms by which CHIKV subverts antiviral immunity to establish and maintain a persistent infection may lead to the development of new therapeutic strategies against chronic CHIKV disease. In this study, we found that CHIKV establishes and maintains a persistent infection in joint-associated tissue in part by evading antiviral CD8+ T cell immunity. Thus, immunomodulatory therapies that improve CD8+ T cell immune surveillance and clearance of CHIKV infection could be a strategy for mitigating chronic CHIKV disease.


Assuntos
Febre de Chikungunya/imunologia , Vírus Chikungunya/metabolismo , Articulações/virologia , Imunidade Adaptativa/imunologia , Transferência Adotiva/métodos , Animais , Anticorpos Antivirais/imunologia , Antivirais/uso terapêutico , Artrite/virologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Febre de Chikungunya/metabolismo , Vírus Chikungunya/patogenicidade , Vírus Chikungunya/fisiologia , Modelos Animais de Doenças , Epitopos de Linfócito T/imunologia , Feminino , Imunização , Articulações/imunologia , Lectinas Tipo C , Masculino , Camundongos , Receptores Mitogênicos
9.
PLoS One ; 15(1): e0222900, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31990920

RESUMO

Mosquito-borne diseases have become a significant health issue in many regions around the world. For tropical countries, diseases such as Dengue, Zika, and Chikungunya, became epidemic in the last decades. Health surveillance reports during this period were crucial in providing scientific-based information to guide decision making and resources allocation to control outbreaks. In this work, we perform data analysis of the last Chikungunya epidemics in the city of Rio de Janeiro by applying a compartmental mathematical model. Sensitivity analyses were performed in order to describe the contribution of each parameter to the outbreak incidence. We estimate the "basic reproduction number" for those outbreaks and predict the potential epidemic outbreak of the Mayaro virus. We also simulated several scenarios with different public interventions to decrease the number of infected people. Such scenarios should provide insights about possible strategies to control future outbreaks.


Assuntos
Febre de Chikungunya/epidemiologia , Vírus Chikungunya/patogenicidade , Modelos Teóricos , Animais , Número Básico de Reprodução , Brasil/epidemiologia , Febre de Chikungunya/virologia , Surtos de Doenças , Epidemias/prevenção & controle , Humanos , Insetos Vetores/virologia , Mosquitos Vetores/virologia
10.
PLoS One ; 15(1): e0227058, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31910225

RESUMO

Nanotrap® (NT) particles are hydrogel microspheres developed for target analyte separation and discovery applications. NT particles consist of cross-linked N-isopropylacrylamide (NIPAm) copolymers that are functionalized with a variety of chemical affinity baits to enable broad-spectrum collection and retention of target proteins, nucleic acids, and pathogens. NT particles have been previously shown to capture and enrich arboviruses including Rift Valley fever and Venezuelan equine encephalitis viruses. Yet, there is still a need to enhance the detection ability for other re-emerging viruses such as Zika (ZIKV), chikungunya (CHIKV), and dengue (DENV) viruses. In this study, we exploited NT particles with different affinity baits, including cibacron blue, acrylic acid, and reactive red 120, to evaluate their capturing and enrichment capability for ZIKV, DENV and CHIKV in human fluids. Our results demonstrate that CN1030, a NT particle conjugated with reactive red 120, can recover between 8-16-fold greater genomic copies of ZIKV, CHIKV and DENV in virus spiked urine samples via RT-qPCR, superior to the other chemical baits. Also, we observed that CN1030 simultaneously enriched ZIKV, CHIKV and DENV in co-infection-based settings and could stabilize ZIKV, but not CHIKV infectivity in saliva spiked samples. CN1030 enriched viral detection at various viral concentrations, with significant enhancement observed at viral titers as low as 100 PFU/mL for ZIKV and 10 PFU/mL for CHIKV. The detection of ZIKV was further enhanced with NT particles by processing of larger volume urine samples. Furthermore, we developed a magnetic NT particle, CN3080, based on the same backbone of CN1030, and demonstrated that CN3080 could also capture and enrich ZIKV and CHIKV in a dose-dependent manner. Finally, in silico docking predictions support that the affinity between reactive red 120 and ZIKV or CHIKV envelope proteins appeared to be greater than acrylic acid. Overall, our data show that NT particles along with reactive red 120 can be utilized as a pre-processing technology for enhancement of detecting febrile-illness causing viruses.


Assuntos
Infecções por Arbovirus/urina , Vírus Chikungunya/isolamento & purificação , Vírus da Dengue/isolamento & purificação , Técnicas de Diagnóstico Molecular/métodos , Nanopartículas/química , Zika virus/isolamento & purificação , Infecções por Arbovirus/diagnóstico , Infecções por Arbovirus/virologia , Vírus Chikungunya/genética , Vírus Chikungunya/patogenicidade , Corantes/química , Vírus da Dengue/genética , Vírus da Dengue/patogenicidade , Humanos , Hidrogéis/química , Nanopartículas/metabolismo , Reação em Cadeia da Polimerase/métodos , Ligação Proteica , Saliva/virologia , Urina/virologia , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/metabolismo , Zika virus/genética , Zika virus/patogenicidade
11.
Antiviral Res ; 174: 104670, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31812638

RESUMO

The GloPID-R (Global Research Collaboration for Infectious Disease Preparedness) chikungunya (CHIKV), o'nyong-nyong (ONNV) and Mayaro virus (MAYV) Working Group has been established to investigate natural history, epidemiology and clinical aspects of infection by these viruses. Here, we present a report dedicated to entomological aspects of CHIKV, ONNV and MAYV. Recent global expansion of chikungunya virus has been possible because CHIKV established a transmission cycle in urban settings using anthropophilic vectors such as Aedes albopictus and Aedes aegypti. MAYV and ONNV have a more limited geographic distribution, being confined to Africa (ONNV) and central-southern America (MAYV). ONNV is probably maintained through an enzootic cycle that has not been characterized yet, with Anopheles species as main vectors and humans as amplification hosts during epidemics. MAYV is transmitted by Haemagogus species in an enzootic cycle using non-human primates as the main amplification and maintenance hosts, and humans becoming sporadically infected when venturing in or nearby forest habitats. Here, we focused on the transmission cycle and natural vectors that sustain circulation of these viruses in their respective locations. The knowledge of the natural ecology of transmission and the capacity of different vectors to transmit these viruses is crucial to understand CHIKV emergence, and to assess the risk that MAYV and ONNV will expand on wide scale using anthropophilic mosquito species not normally considered primary vectors. Finally, the experts identified knowledge gaps and provided adapted recommendations, in order to address future entomological investigations in the right direction.


Assuntos
Infecções por Alphavirus/transmissão , Febre de Chikungunya/transmissão , Mosquitos Vetores/virologia , Aedes/virologia , África , Animais , Anopheles/virologia , América Central , Vírus Chikungunya/patogenicidade , Humanos , Vírus O'nyong-nyong/patogenicidade , Primatas/virologia , Relatório de Pesquisa
12.
Emerg Microbes Infect ; 8(1): 1574-1583, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31682177

RESUMO

Chikungunya virus (CHIKV), a mosquito-borne alphavirus, has become an important re-emerging pathogen with its rapid spread to many non-endemic areas. The lack of effective vaccines and antiviral agents is largely attributed to the elusive infection and dissemination dynamics in vivo. In this study, we designed and developed a novel, replication-competent, CHIKV reporter virus (CHIKV-iRFP) encoding a near infrared fluorescent protein (iRFP). In vitro and in vivo characterization demonstrated that CHIKV-iRFP retained similar replication and virulence phenotypes to its parental virus. Neonatal BABL/c mice and IFNAR-/- A129 mice were highly susceptible to CHIKV-iRFP infection. Following intracranial (i.c.) inoculation, CHIKV-iRFP efficiently replicated and disseminated into whole body, resulting in rapid death in an age-dependent manner. Remarkably, upon footpad injection, CHIKV-iRFP readily disseminated from footpad to head and whole skeleton, with a specific tropism for bone marrow. Taken together, this novel reporter virus provides a powerful tool to track real time CHIKV replication and to test the in vivo efficacy of vaccines and antiviral therapeutics.


Assuntos
Febre de Chikungunya/virologia , Vírus Chikungunya/fisiologia , Animais , Vírus Chikungunya/genética , Vírus Chikungunya/patogenicidade , Feminino , Fluorescência , Genes Reporter , Humanos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Virulência , Replicação Viral
13.
Sci Rep ; 9(1): 17852, 2019 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-31780744

RESUMO

Arboviral diseases such as chikungunya, dengue, and Zika viruses have been threatening the European countries since the introduction in 1979 of the major vector Aedes albopictus. In 2017, more than three hundred of CHIKV autochthonous cases were reported in Italy, highlighting the urgent need for a risk assessment of arboviral diseases in European countries. In this study, the vector competence for three major arboviruses were analyzed in eight Ae. albopictus populations from Europe. Here we show that Southern European Ae. albopictus were susceptible to CHIKV, DENV-1 and ZIKV with the highest vector competence for CHIKV. Based on vector competence data and vector distribution, a prediction risk map for CHIKV was generated stressing the fear of CHIKV and to a lesser extent, of other arboviruses for Europe, calling us for new public health strategies.


Assuntos
Aedes/virologia , Febre de Chikungunya/transmissão , Dengue/transmissão , Mosquitos Vetores/virologia , Infecção por Zika virus/transmissão , Animais , Vírus Chikungunya/patogenicidade , Vírus da Dengue/patogenicidade , Europa (Continente) , Humanos , Zika virus/patogenicidade
14.
J Virol ; 94(1)2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31619554

RESUMO

Type I interferons (IFNs) are key mediators of the innate immune response. Although members of this family of cytokines signal through a single shared receptor, biochemical and functional variation exists in response to different IFN subtypes. While previous work has demonstrated that type I IFNs are essential to control infection by chikungunya virus (CHIKV), a globally emerging alphavirus, the contributions of individual IFN subtypes remain undefined. To address this question, we evaluated CHIKV pathogenesis in mice lacking IFN-ß (IFN-ß knockout [IFN-ß-KO] mice or mice treated with an IFN-ß-blocking antibody) or IFN-α (IFN regulatory factor 7 knockout [IRF7-KO] mice or mice treated with a pan-IFN-α-blocking antibody). Mice lacking either IFN-α or IFN-ß developed severe clinical disease following infection with CHIKV, with a marked increase in foot swelling compared to wild-type mice. Virological analysis revealed that mice lacking IFN-α sustained elevated infection in the infected ankle and in distant tissues. In contrast, IFN-ß-KO mice displayed minimal differences in viral burdens within the ankle or at distal sites and instead had an altered cellular immune response. Mice lacking IFN-ß had increased neutrophil infiltration into musculoskeletal tissues, and depletion of neutrophils in IFN-ß-KO but not IRF7-KO mice mitigated musculoskeletal disease caused by CHIKV. Our findings suggest disparate roles for the IFN subtypes during CHIKV infection, with IFN-α limiting early viral replication and dissemination and IFN-ß modulating neutrophil-mediated inflammation.IMPORTANCE Type I interferons (IFNs) possess a range of biological activity and protect against a number of viruses, including alphaviruses. Despite signaling through a shared receptor, there are established biochemical and functional differences among the IFN subtypes. The significance of our research is in demonstrating that IFN-α and IFN-ß both have protective roles during acute chikungunya virus (CHIKV) infection but do so by distinct mechanisms. IFN-α limits CHIKV replication and dissemination, whereas IFN-ß protects from CHIKV pathogenesis by limiting inflammation mediated by neutrophils. Our findings support the premise that the IFN subtypes have distinct biological activities in the antiviral response.


Assuntos
Febre de Chikungunya/genética , Vírus Chikungunya/patogenicidade , Fator Regulador 7 de Interferon/genética , Interferon-alfa/genética , Interferon beta/genética , Neutrófilos/imunologia , Animais , Anticorpos Neutralizantes/farmacologia , Osso e Ossos/imunologia , Osso e Ossos/patologia , Osso e Ossos/virologia , Febre de Chikungunya/imunologia , Febre de Chikungunya/patologia , Febre de Chikungunya/virologia , Vírus Chikungunya/imunologia , Feminino , Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Inflamação , Fator Regulador 7 de Interferon/deficiência , Fator Regulador 7 de Interferon/imunologia , Interferon-alfa/antagonistas & inibidores , Interferon-alfa/deficiência , Interferon-alfa/imunologia , Interferon beta/antagonistas & inibidores , Interferon beta/deficiência , Interferon beta/imunologia , Masculino , Camundongos , Camundongos Knockout , Músculo Esquelético/imunologia , Músculo Esquelético/patologia , Músculo Esquelético/virologia , Infiltração de Neutrófilos , Neutrófilos/patologia , Neutrófilos/virologia , Tarso Animal/imunologia , Tarso Animal/patologia , Tarso Animal/virologia , Replicação Viral
15.
Nature ; 574(7777): 259-263, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31554973

RESUMO

Chikungunya virus (CHIKV) is a re-emerging alphavirus that is transmitted to humans by mosquito bites and causes musculoskeletal and joint pain1,2. Despite intensive investigations, the human cellular factors that are critical for CHIKV infection remain unknown, hampering the understanding of viral pathogenesis and the development of anti-CHIKV therapies. Here we identified the four-and-a-half LIM domain protein 1 (FHL1)3 as a host factor that is required for CHIKV permissiveness and pathogenesis in humans and mice. Ablation of FHL1 expression results in the inhibition of infection by several CHIKV strains and o'nyong-nyong virus, but not by other alphaviruses and flaviviruses. Conversely, expression of FHL1 promotes CHIKV infection in cells that do not normally express it. FHL1 interacts directly with the hypervariable domain of the nsP3 protein of CHIKV and is essential for the replication of viral RNA. FHL1 is highly expressed in CHIKV-target cells and is particularly abundant in muscles3,4. Dermal fibroblasts and muscle cells derived from patients with Emery-Dreifuss muscular dystrophy that lack functional FHL15 are resistant to CHIKV infection. Furthermore,  CHIKV infection  is undetectable in Fhl1-knockout mice. Overall, this study shows that FHL1 is a key factor expressed by the host that enables CHIKV infection and identifies the interaction between nsP3 and FHL1 as a promising target for the development of anti-CHIKV therapies.


Assuntos
Febre de Chikungunya/virologia , Vírus Chikungunya/patogenicidade , Fatores Celulares Derivados do Hospedeiro/metabolismo , Interações Hospedeiro-Patógeno , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas com Domínio LIM/metabolismo , Proteínas Musculares/metabolismo , Animais , Células Cultivadas , Febre de Chikungunya/tratamento farmacológico , Vírus Chikungunya/efeitos dos fármacos , Vírus Chikungunya/genética , Vírus Chikungunya/crescimento & desenvolvimento , Feminino , Fibroblastos/virologia , Células HEK293 , Fatores Celulares Derivados do Hospedeiro/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas com Domínio LIM/deficiência , Proteínas com Domínio LIM/genética , Masculino , Camundongos , Proteínas Musculares/deficiência , Proteínas Musculares/genética , Mioblastos/virologia , Vírus O'nyong-nyong/crescimento & desenvolvimento , Vírus O'nyong-nyong/patogenicidade , Ligação Proteica , RNA Viral/biossíntese , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Replicação Viral
16.
Indian J Med Res ; 149(6): 771-777, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31496530

RESUMO

Background & objectives: Chikungunya virus (CHIKV), a mosquito-borne arthritogenic virus causes infections ranging from febrile illness to debilitating polyarthralgia in humans. Re-emergence of the virus has affected millions of people in Africa and Asia since 2004. During the outbreak, a new lineage of the virus has evolved as an adaptation for enhanced replication and transmission by Aedes albopictus mosquito. A study was designed to compare the susceptibility of four vertebrate cell lines, namely Vero E6 (African green monkey kidney), BHK-21 (Baby hamster kidney), RD (human rhabdomyosarcoma), A-549 (human alveolar basal epithelial cell) and C6/36 (Ae. albopictus) to Asian genotype and two lineages of East, Central and South African (E1:A226 and E1:A226V) of CHIKV. Methods: One-step growth kinetics of different CHIKV strains was carried out in the above five cell lines to determine the growth kinetics and virus yield. Virus titre was determined by 50 per cent tissue culture infectious dose assay and titres were calculated by the Reed and Muench formula. Growth and virus yield of the three strains in Ae. aegypti mosquitoes was studied by intrathoracic inoculation and virus titration in Vero E6 cell line. Results: Virus titration showed Vero E6, C6/36 and BHK-21 cell lines are high virus yielding with all the three lineages while RD and A-549 yielded low virus titres. C6/36 cell line was the most sensitive and yielded the maximum titre. Ae. aegypti mosquitoes, when inoculated with high titre virus, yielded an almost equal growth with the three strains while rapid growth of E1:A226V and Asian strain was observed with 1 log virus. Interpretation & conclusions: C6/36 cell line was found to be the most sensitive and high yielding for CHIKV irrespective of lineages while Vero E6 and BHK-21 cell lines yielded high titres and may find application for vaccine/diagnostic development. Infection of Ae. aegypti mosquitoes with the three CHIKV strains gave almost identical pattern of growth.


Assuntos
Aedes/virologia , Febre de Chikungunya/virologia , Vírus Chikungunya/crescimento & desenvolvimento , Culicidae/virologia , Células A549/virologia , África/epidemiologia , Animais , Ásia/epidemiologia , Febre de Chikungunya/epidemiologia , Febre de Chikungunya/genética , Vírus Chikungunya/genética , Vírus Chikungunya/patogenicidade , Chlorocebus aethiops , Surtos de Doenças , Genótipo , Humanos , Mosquitos Vetores/genética , Mosquitos Vetores/crescimento & desenvolvimento , Saliva/virologia , Células Vero/virologia
17.
Artigo em Inglês | MEDLINE | ID: mdl-31380302

RESUMO

The present study shows that the most prominent human arboviruses worldwide (dengue viruses 1, 2, 3, and 4, Chikungunya virus, and Zika virus) can infect wild animals and transfer from urban to sylvatic maintenance cycles in South America, as did the yellow fever virus (YFV) in the past. All these viruses are transmitted by the anthropophilic mosquito Aedes aegypti and cause epidemics throughout Brazil. The YFV is the oldest example of an urban arbovirus that became sylvatic in South America. Currently, the disease is a zoonosis of non-human primates that moves like a wave through the forests of the Brazilian countryside, traveling thousands of kilometers, killing many animals and eventually infecting man. However, since 2016, this zoonotic wave has reached the highly populated areas of Southeast Brazil, producing the largest human outbreak in the past 60 years. As with the YFV, sylvatic cycles may occur with dengue, Chikungunya, and Zika. In order to become sylvatic, arboviruses require an apparently unlikely conjunction of factors to unexpectedly take place. These arboviruses could start to infect sylvatic primates and be transmitted by Haemagogus mosquitoes that inhabit tree canopies. We mention here publications reporting evidence of sylvatic cycles of dengue, Chikungunya, and Zika virus in South America. Indeed, it is almost unfeasible to control these cycles of arboviruses since it is impossible to know where, when or why an arboviral spill-over would occur in wild animals. The sylvatic maintenance cycle could preclude the eradication of an arbovirus. Moreover, an arbovirus in a sylvatic cycle could re-emerge anytime, infecting humans and producing outbreaks. In case of the reemergence of an arbovirus, it is crucial to prevent the occurrence of an urban cycle as a spill-back from the sylvatic cycle.


Assuntos
Infecções por Arbovirus/epidemiologia , Febre de Chikungunya/epidemiologia , Dengue/epidemiologia , Primatas/virologia , Febre Amarela/epidemiologia , Infecção por Zika virus/epidemiologia , Zoonoses/epidemiologia , Aedes/virologia , Animais , Animais Selvagens/virologia , Infecções por Arbovirus/transmissão , Arbovirus/patogenicidade , Brasil/epidemiologia , Febre de Chikungunya/transmissão , Vírus Chikungunya/patogenicidade , Dengue/transmissão , Vírus da Dengue/patogenicidade , Humanos , Mosquitos Vetores/virologia , Febre Amarela/transmissão , Vírus da Febre Amarela/patogenicidade , Zika virus/patogenicidade , Infecção por Zika virus/transmissão , Zoonoses/transmissão
18.
PLoS Pathog ; 15(8): e1007993, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31465513

RESUMO

Chikungunya virus (CHIKV) is an arthritogenic alphavirus that acutely causes fever as well as severe joint and muscle pain. Chronic musculoskeletal pain persists in a substantial fraction of patients for months to years after the initial infection, yet we still have a poor understanding of what promotes chronic disease. While replicating virus has not been detected in joint-associated tissues of patients with persistent arthritis nor in various animal models at convalescent time points, viral RNA is detected months after acute infection. To identify the cells that might contribute to pathogenesis during this chronic phase, we developed a recombinant CHIKV that expresses Cre recombinase (CHIKV-3'-Cre). CHIKV-3'-Cre replicated in myoblasts and fibroblasts, and it induced arthritis during the acute phase in mice. Importantly, it also induced chronic disease, including persistent viral RNA and chronic myositis and synovitis similar to wild-type virus. CHIKV-3'-Cre infection of tdTomato reporter mice resulted in a population of tdTomato+ cells that persisted for at least 112 days. Immunofluorescence and flow cytometric profiling revealed that these tdTomato+ cells predominantly were myofibers and dermal and muscle fibroblasts. Treatment with an antibody against Mxra8, a recently defined host receptor for CHIKV, reduced the number of tdTomato+ cells in the chronic phase and diminished the levels of chronic viral RNA, implicating these tdTomato+ cells as the reservoir of chronic viral RNA. Finally, isolation and flow cytometry-based sorting of the tdTomato+ fibroblasts from the skin and ankle and analysis for viral RNA revealed that the tdTomato+ cells harbor most of the persistent CHIKV RNA at chronic time points. Therefore, this CHIKV-3'-Cre and tdTomato reporter mouse system identifies the cells that survive CHIKV infection in vivo and are enriched for persistent CHIKV RNA. This model represents a useful tool for studying CHIKV pathogenesis in the acute and chronic stages of disease.


Assuntos
Artrite Experimental/virologia , Febre de Chikungunya/virologia , Vírus Chikungunya/patogenicidade , Derme/patologia , Fibroblastos/patologia , Músculo Esquelético/patologia , RNA Viral/metabolismo , Animais , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Febre de Chikungunya/metabolismo , Vírus Chikungunya/genética , Derme/metabolismo , Derme/virologia , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibroblastos/virologia , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Fibras Musculares Esqueléticas/virologia , Músculo Esquelético/metabolismo , Músculo Esquelético/virologia , RNA Viral/genética , Replicação Viral
19.
Viruses ; 11(9)2019 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-31450552

RESUMO

Alphaviruses belong to a family of positive sense, single-stranded RNA viruses that are transmitted mainly by mosquitoes through a blood meal and cause arthritis and/or encephalitis in humans and animals [...].


Assuntos
Vírus Chikungunya , Animais , Artrite/virologia , Febre de Chikungunya/epidemiologia , Febre de Chikungunya/transmissão , Febre de Chikungunya/virologia , Vírus Chikungunya/genética , Vírus Chikungunya/isolamento & purificação , Vírus Chikungunya/patogenicidade , Doenças Transmissíveis Emergentes , Surtos de Doenças , Encefalite/virologia , Humanos , Mosquitos Vetores/virologia
20.
Nucleic Acids Res ; 47(17): 9296-9312, 2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31350895

RESUMO

Chikungunya virus (CHIKV) is a re-emerging, pathogenic Alphavirus transmitted to humans by Aedes spp. mosquitoes. We have mapped the RNA structure of the 5' region of the CHIKV genome using selective 2'-hydroxyl acylation analysed by primer extension (SHAPE) to investigate intramolecular base-pairing at single-nucleotide resolution. Taking a structure-led reverse genetic approach, in both infectious virus and sub-genomic replicon systems, we identified six RNA replication elements essential to efficient CHIKV genome replication - including novel elements, either not previously analysed in other alphaviruses or specific to CHIKV. Importantly, through a reverse genetic approach we demonstrate that the replication elements function within the positive-strand genomic copy of the virus genome, in predominantly structure-dependent mechanisms during efficient replication of the CHIKV genome. Comparative analysis in human and mosquito-derived cell lines reveal that a novel element within the 5'UTR is essential for efficient replication in both host systems, while those in the adjacent nsP1 encoding region are specific to either vertebrate or invertebrate host cells. In addition to furthering our knowledge of fundamental aspects of the molecular virology of this important human pathogen, we foresee that results from this study will be important for rational design of a genetically stable attenuated vaccine.


Assuntos
Febre de Chikungunya/genética , Vírus Chikungunya/genética , Proteínas não Estruturais Virais/genética , Replicação Viral/genética , Aedes/virologia , Animais , Febre de Chikungunya/virologia , Vírus Chikungunya/patogenicidade , Genoma Viral/genética , Humanos , RNA Viral/genética , Replicon/genética
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