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1.
PLoS Negl Trop Dis ; 14(8): e0008090, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32817670

RESUMO

BACKGROUND: Hantaan virus (HTNV; family Hantaviridae, order Bunyavirales) causes hemorrhagic fever with renal syndrome (HFRS), which has raised serious concerns in Eurasia, especially in China, Russia, and South Korea. Previous studies reported genetic diversity and phylogenetic features of HTNV in different parts of China, but the analyses from the holistic perspective are rare. METHODOLOGY AND PRINCIPAL FINDINGS: To better understand HTNV genetic diversity and gene evolution, we analyzed all available complete sequences derived from the small (S) and medium (M) segments with bioinformatic tools. Eleven phylogenetic groups were defined and showed geographic clustering; 42 significant amino acid variant sites were found, and 19 of them were located in immune epitopes; nine recombinant events and eight reassortments with highly divergent sequences were found and analyzed. We found that sequences from Guizhou showed high genetic divergence, contributing to multiple lineages of the phylogenetic tree and also to the recombination and reassortment events. Bayesian stochastic search variable selection analysis revealed that Heilongjiang, Shaanxi, and Guizhou played important roles in HTNV evolution and migration; the virus may originate from Zhejiang Province in the eastern part of China; and the virus population size expanded from the 1980s to 1990s. CONCLUSIONS/SIGNIFICANCE: These findings revealed the original and evolutionary features of HTNV, which will help to illustrate hantavirus epidemic trends, thus aiding in disease control and prevention.


Assuntos
Evolução Molecular , Variação Genética , Vírus Hantaan/genética , Animais , China/epidemiologia , Genoma Viral , Infecções por Hantavirus/epidemiologia , Humanos , Filogenia , RNA Viral/genética , Roedores , Análise de Sequência de Proteína , Musaranhos
2.
Medicine (Baltimore) ; 99(14): e19734, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32243412

RESUMO

RATIONALE: Bleeding in the anterior pituitary lobe leading to tissue necrosis occurs in the acute stage of severe clinical forms of hemorrhagic fever with renal syndrome (HFRS), while atrophy of the anterior pituitary lobe with diminution of the gland function occurs after the recovery stage. The relationship between Hantaan virus infection and empty Sella syndrome (ESS) has rarely been reported. PATIENT CONCERNS: This patient was a 54-year-old previously healthy Chinese male. He presented with fever, headache, and backache with dizziness and oliguria. Physical examination was notable for hypotension and the signs of conjunctival suffusion. His platelets decreased, and his urine protein was positive. Hantaan virus IgM and virus RNA were positive. DIAGNOSIS: He was diagnosed as having HFRS. In his diuretic phase, his 24-hour urine volume was maintained at 10,000 mL, and his blood pressure was higher for a week. Then, he was diagnosed as having ESS after a series of examinations. INTERVENTIONS: Hormone replacement therapy was given to this patient after the diagnosis "ESS" was made. OUTCOMES: The patient's symptoms improved, and he was discharged from the hospital soon after hormone replacement therapy. LESSONS: Pituitary function examination and brain magnetic resonance imaging (MRI) need to be considered to scan for ESS and panhypopituitarism in the patients with HFRS accompanied by diabetes insipidus.


Assuntos
Síndrome da Sela Vazia/virologia , Vírus Hantaan , Febre Hemorrágica com Síndrome Renal/complicações , Febre Hemorrágica com Síndrome Renal/virologia , Humanos , Masculino , Pessoa de Meia-Idade
3.
BMC Infect Dis ; 20(1): 103, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32019494

RESUMO

BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) is an endemic communicable disease in China, accounting for 90% of total reported cases worldwide. In this study, the authors want to investigate the risk factors for HFRS in recent years to provide the prevention and control advices. METHODS: A community-based, 1:2 matched case-control study was carried out to investigate the risk factors for HFRS. Cases were defined as laboratory-confirmed cases that tested positive for hantavirus-specific IgM antibodies. Two neighbourhood controls of each case were selected by sex, age and occupation. Standardized questionnaires were used to collect information and identify the risk factors for HFRS. RESULTS: Eighty-six matched pairs were investigated in the study. The median age of the cases was 55.0 years, 72.09% were male, and 73.26% were farmers. In the multivariate logistic regression analysis, cleaning spare room at home (OR = 3.310, 95%CI 1.335-8.210) was found to be risk factor for infection; storing food and crops properly (OR = 0.279 95%CI 0.097-0.804) provided protection from infection. CONCLUSION: Storing food and crops properly seemed to be protective factor, which was important for HFRS prevention and control. More attention should be paid to promote comprehensive health education and behaviour change among high-risk populations in the HFRS endemic area.


Assuntos
Febre Hemorrágica com Síndrome Renal/etiologia , Adolescente , Adulto , Idoso , Anticorpos Antivirais/sangue , Estudos de Casos e Controles , China , Fazendeiros , Feminino , Vírus Hantaan/imunologia , Vírus Hantaan/patogenicidade , Febre Hemorrágica com Síndrome Renal/transmissão , Humanos , Imunoglobulina M/sangue , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Controle de Roedores
4.
J Prev Med Public Health ; 52(5): 277-280, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31588696

RESUMO

The Ministry of Food and Drug Safety of Korea made an official announcement in March 2018 that the total number of inoculations of Hantaan virus vaccine (Hantavax®) would change from 3 to 4. Some aspects of this decision remain controversial. Based on the characteristics of Hantaan virus (HTNV) and its role in the pathogenesis of hemorrhagic fever with renal syndrome, it might be difficult to develop an effective and safe HTNV vaccine through the isolate-inactivate-inject paradigm. With the development of high-throughput 'omics' technologies in the 21st century, vaccinomics has been introduced. While the goal of vaccinomics is to develop equations to describe and predict the immune response, it could also serve as a tool for developing new vaccine candidates and individualized approaches to vaccinology. Thus, the possibility of applying the innovative field of vaccinomics to develop a more effective and safer HTNV vaccine should be considered.


Assuntos
Fidelidade a Diretrizes/normas , Medicina de Precisão , Vacinação , Vacinas , Vírus Hantaan/isolamento & purificação , Humanos , Imunogenética , República da Coreia
5.
Zhonghua Liu Xing Bing Xue Za Zhi ; 40(8): 930-935, 2019 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-31484256

RESUMO

Objective: To explore the spatial-temporal distribution and epidemic characteristics of hemorrhagic fever with renal syndrome (HFRS) in Hebei province from 2005 to 2016. Methods: Records of HFRS cases reported from each county in Hebei during January 2005 to December 2016 were collected from National Notifiable Disease Surveillance System (NNDSS). Global and local spatial association statistics were used to measure the spatial autocorrelation and software GeoDa 1.2.0. Software SaTScan 9.4.1 was used to analyze spatiotemporal clusters. Software ArcGIS 10.2 was used to visualize the yearly scan results. Results: In Hebei province, a total of 8 437 human HFRS cases reported from 170 counties with an annual incidence rate of 0.99/100 000 population during 2005-2016. The peak incidence season was spring. Global spatial autocorrelation analysis on the incidence of HFRS at county-level showed that the value of Moran's I were all above 0 (P<0.05), indicating that the significant spatial cluster. The result of local indicators on spatial association (LISA) analysis revealed that identified hot spots were mainly in northeastern area, while cold spots were found in some counties of central and southern areas. Spatial-temporal scan detected that the primary cluster of HFRS incidence was mainly distributed in Qinhuangdao city and Tangshan city, including 11 counties (city/district): Beidaihe district, Haigang district, Funing district, Shanhaiguan district, Changli county, Lulong county and Qinglong Manchu autonomous county in Qinhuangdao city, and Qian'an city, Laoting county, Luanzhou city and Luannan county in Tangshan city (RR=39.64, P<0.001), during January-July in 2005. Conclusions: There were significant spatial-temporal cluster of HFRS in Hebei from 2005 to 2016. The cluster areas of HFRS were mainly in northeastern Hebei, it is necessary to strengthen the prevention and control programs of HFRS in these areas.


Assuntos
Notificação de Doenças/estatística & dados numéricos , Vírus Hantaan , Febre Hemorrágica com Síndrome Renal/epidemiologia , Vigilância da População , China/epidemiologia , Cidades , Análise por Conglomerados , Humanos , Incidência , Estações do Ano , Análise Espacial , Análise Espaço-Temporal
6.
BMC Infect Dis ; 19(1): 492, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164087

RESUMO

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease characterized by an excessive systemic inflammatory response, which can be classified as primary HLH (pHLH) and secondary HLH (sHLH). Viruses are the primary pathogens causing sHLH. Hemorrhagic fever with renal syndrome (HFRS) is a rodent-borne disease caused by hantaviruses. Its main characteristics include fever, circulatory collapse with hypotension, hemorrhage, and acute kidney injury. The case of HFRS presented with sHLH is very rare in clinic. We reported the HFRS inducing by Hantaan virus (HTNV) presented with sHLH as the first case in Shaanxi province of west China. CASE PRESENTATION: A case of HFRS in 69-year-old Chinese woman, which had persistent fever, cytopenia, coagulopathy, ferritin significantly increased, hepatosplenomegaly and superficial lymphadenopathy. The hemophagocytosis was found in bone marrow, which was consistent with the characteristics of the HLH. The patient recovered completely after timely comprehensive treatments. CONCLUSIONS: HTNV should be considered as one of the underlying viruses resulting in hemophagocytosis, and if occurs, the early diagnosis and rapid therapeutic intervention are very important to the prognosis of sHLH.


Assuntos
Febre Hemorrágica com Síndrome Renal/complicações , Febre Hemorrágica com Síndrome Renal/diagnóstico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/etiologia , Idoso , China , Feminino , Vírus Hantaan/isolamento & purificação , Febre Hemorrágica com Síndrome Renal/virologia , Humanos , Linfo-Histiocitose Hemofagocítica/virologia
7.
Virus Res ; 267: 36-40, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31054291

RESUMO

Host reservoir specificity of pathogens is complex and may depend on receptor variability. For pathogenic orthohantaviruses, integrin ß3 had been previously identified as entry receptor and the presence of aspartic acid residue at position 39 (D39) in human integrin ß3 was described to be a prerequisite for infection of primate cells with Hantaan virus (HTNV). However, the role of integrin ß3 in orthohantavirus infection of host animals is not completely understood. Therefore, we analyzed the nucleotide sequence of the integrin ß3 gene of Myodes glareolus and Apodemus agrarius, the hosts of Puumala virus (PUUV) and HTNV, respectively. Sequence analysis in tissue samples demonstrated that the amino acid residue D39 is not present in integrin ß3 of these natural orthohantavirus hosts. Furthermore, we analyzed the transcription and protein expression levels of integrin ß3 in the renal cell line BVK168 generated from the PUUV host, bank vole. Transcription level of integrin ß3 was 100-fold lower in BVK168 cells than in Vero E6 cells and integrin ß3 expression was not detectable in BVK168 cells. However, despite the absence of amino acid residue D39 and no detectable integrin ß3 expression, BVK168 cells are susceptible to infection with both PUUV and HTNV. These results indicate that the mechanism of orthohantaviral entry in rodent species does not correspond to the requirements that were described for the entry in primate cells in vitro.


Assuntos
Arvicolinae/virologia , Reservatórios de Doenças/veterinária , Vírus Hantaan/genética , Febre Hemorrágica com Síndrome Renal/veterinária , Especificidade de Hospedeiro , Integrina beta3/genética , Animais , Linhagem Celular , Reservatórios de Doenças/virologia , Vírus Hantaan/patogenicidade , Febre Hemorrágica com Síndrome Renal/virologia , Murinae/virologia
8.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(2): 97-102, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-30975272

RESUMO

Objective To construct the plasmid expressing the fusion protein of Hantaan virus nucleocapsid protein (HTNV NP) with affinity tag, and isolate the host factors interacting with NP using the affinity purification. Methods The synthetic streptavidin-FLAG (SF) gene and HTNV NP gene were cloned into the mammalian eukaryotic expression vector to obtain the recombinant expression plasmid (pCAGGS-SF-NP). The plasmid pCAGGS-SF-NP was transfected into HEK293T cells, and the expression of SF-NP was detected by Western blotting. Next, cell lysates were mixed with StrepTrapTM HP agar beads. After incubating overnight at 4DegreesCelsius, the agar beads were transferred into affinity chromatography column and washed with elution buffer. Finally, the binding proteins that interacted with SF-NP were collected by competitive elution buffer with desthiobiotin, and then were subjected to SDS-PAGE. Results The recombinant SF-NP proteins were highly expressed in eukaryotic cells. The host factors interacting with SF-NP were successfully enriched by affinity purification, and confirmed by SDS-PAGE. Conclusion The host factors interacting with HTNV NP can be isolated by affinity purification.


Assuntos
Vírus Hantaan , Fatores Celulares Derivados do Hospedeiro/isolamento & purificação , Proteínas do Nucleocapsídeo/metabolismo , Animais , Cromatografia de Afinidade , Eletroforese em Gel de Poliacrilamida , Células HEK293 , Vírus Hantaan/metabolismo , Humanos , Proteínas do Nucleocapsídeo/genética , Plasmídeos/genética , Proteínas Recombinantes/metabolismo
9.
J Korean Med Sci ; 34(11): e87, 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30914905
10.
Am J Trop Med Hyg ; 100(5): 1236-1239, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30915955

RESUMO

Hemorrhagic fever with renal syndrome (HFRS) is a febrile disorder caused in Korea by the Hantaan and Seoul viruses. Its characteristic clinical manifestations include fever, hemorrhage, and renal failure, but a primary presentation with acute infectious diarrhea is rare. Owing to decreased urine output and renal function, a 54-year-old patient was transferred to our hospital from a local clinic, where he had been receiving treatment for diarrhea occurring more than 10 times a day. The patient was treated in the Gastroenterology Department at our hospital for acute renal failure secondary to inflammatory diarrhea based on the findings of stool leukocytes. An immunofluorescent antibody assay showed a 4-fold increase in the acute-phase antibody titer to Hantavirus during recovery. A nested reverse transcription polymerase chain reaction (RT-nPCR) assay of plasma yielded negative results, but Hantaan virus positivity was confirmed on an RT-nPCR assay of the buffy coat. Another 60-year-old patient with watery diarrhea was treated conservatively for suspected infectious diarrhea. However, an immunofluorescent antibody assay showed a 4-fold increase in the acute-phase HFRS antibody titer. RT-nPCR using plasma yielded negative results, but Seoul virus was detected on an RT-nPCR buffy coat assay, confirming the diagnosis of HFRS. Hemorrhagic fever with renal syndrome can present with gastrointestinal symptoms such as acute diarrhea alone. This report highlights the importance of considering HFRS in the differential diagnosis of patients with acute diarrhea and the need for additional research on the usefulness of the buffy coat in the PCR diagnosis of HFRS.


Assuntos
Anticorpos Antivirais/sangue , Diarreia/virologia , Febre Hemorrágica com Síndrome Renal/complicações , Febre Hemorrágica com Síndrome Renal/diagnóstico , Doença Aguda , Diagnóstico Diferencial , Diarreia/diagnóstico , Vírus Hantaan/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Vírus Seoul/isolamento & purificação
11.
Medicine (Baltimore) ; 98(9): e14640, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30817583

RESUMO

Hemorrhagic fever with renal syndrome (HFRS) is a rodent-borne disease caused by hantaviruses (HVs). Climate factors have a significant impact on the transmission of HFRS. Here, we characterized the dynamic temporal trend of HFRS and identified the roles of climate factors in its transmission in Changchun, China.Surveillance data of HFRS cases and data on related environmental variables from 2013 to 2017 were collected. A principal components regression (PCR) model was used to quantify the relationship between climate factors and transmission of HFRS.During 2013 to 2017, a distinctly declining temporal trend of annual HFRS incidence was identified. Four principal components were extracted, with a cumulative contribution rate of 89.282%. The association between HFRS epidemics and climate factors was better explained by the PCR model (F = 10.050, P <.001, adjusted R = 0.456) than by the general multiple regression model (F = 2.748, P <.005, adjusted R = 0.397).The monthly trends of HFRS were positively correlated with the mean wind velocity but negatively correlated with the mean temperature, relative humidity, sunshine duration, and accumulative precipitation of the different previous months. The study results may be useful for the development of HFRS preventive initiatives that are customized for Changchun regarding specific climate environments.


Assuntos
Clima , Epidemias/estatística & dados numéricos , Vírus Hantaan , Febre Hemorrágica com Síndrome Renal/epidemiologia , Vigilância da População , China/epidemiologia , Febre Hemorrágica com Síndrome Renal/etiologia , Febre Hemorrágica com Síndrome Renal/virologia , Humanos , Umidade , Incidência , Fatores de Risco , Temperatura , Vento
12.
J Med Microbiol ; 68(3): 480-492, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30657443

RESUMO

PURPOSE: Hantavirus infections cause severe haemorrhagic fever with renal syndrome (HFRS) in humans and are associated with high fatality rates. In 2017, numerous outbreaks were reported in China and Germany. This represents a significant public-healthcare issue with no effective HFRS vaccines that offer a long-term immune response. In this study, we investigated the long-term humoral and cellular immune responses and protective immunity of Hantaan virus (HTNV) granulocyte-macrophage colony stimulating factor (GM-CSF) and CD40 ligand (CD40L) virus-like particles (VLPs) in mice. METHODOLOGY: GM-CSF and CD40L VLPs were constructed via co-transfection of pCI-S and pCI-M-CD40L, and pCI-S and pCI-M-GM-CSF, into dihydrofolatereductase (dhfr)-deficient Chinese hamster ovary cells, respectively. Mice were immunized with HTNV VLPs 2 weeks apart. The animals were challenged 6 months after immunization. Specific and neutralizing antibodies were assessed by ELISA; IFN-γ was measured by enzyme-linked immunospot (ELISpot) assay and effectiveness by cytotoxic T lymphocyte (CTL) cytotoxicity assays. Nucleic acid loads of HTNV were tested by quantitative real-time PCR and viral antigen was detected via indirect ELISA. Pathological alterations were detected via haematoxylin-eosin staining. RESULTS: GM-CSF and CD40L VLPs provided stable, long-term protection with a high titre of neutralizing antibody in mice 6 months after immunization. Furthermore, VLPs increased HTNV-specific cellular immune responses via higher expression of IFN-γ and CTL responses. HTNV challenge assay results showed long-term protection against HFRS. No significant pathological alteration was observed in the organs of mice after immunization. CONCLUSION: This is, to the best of our knowledge, the first report demonstrating the long-term potency of HTNV VLP vaccines against HTNV infection and offers new insights into HTNV vaccine development.


Assuntos
Ligante de CD40/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Infecções por Hantavirus/prevenção & controle , Vacinas de Partículas Semelhantes a Vírus/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Antígenos Virais/imunologia , Ligante de CD40/administração & dosagem , Células CHO , Cricetulus , Ensaio de Imunoadsorção Enzimática , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Vírus Hantaan/genética , Infecções por Hantavirus/imunologia , Imunidade Celular , Imunidade Humoral , Camundongos , Camundongos Endogâmicos C57BL , Transfecção , Vacinas de Partículas Semelhantes a Vírus/genética
13.
Virus Res ; 260: 102-113, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30508604

RESUMO

Orthohantaviruses Hantaan (HTNV) and Puumala (PUUV) virus cause hemorrhagic fever with renal syndrome (HFRS), that is characterized by acute renal failure with often massive proteinuria and by morphological changes of the tubular and glomerular apparatus. Orthohantaviral N protein is found in renal cells and plays a key role in replication. However, the replication in human renal cells is not well characterized. Therefore, we examined the orthohantaviral infection in different human renal cells. Differences in localization of N protein, release of particles, and modulation of the actin cytoskeleton between both virus species are observed in human renal cells. A substantial portion of HTNV N protein demonstrates a filamentous pattern in addition to the typical punctate pattern. Release of HTNV depends on an intact actin and microtubule cytoskeleton. In contrast, PUUV N protein is generally localized in a punctate pattern and release of PUUV does not require an intact actin cytoskeleton. Infection of podocytes results in cytoskeletal rearrangements that are more pronounced for HTNV. Analyzing Vero E6 cells revealed differences compared to human renal cells. The pattern of N proteins is strictly punctate, release does not depend on an intact actin cytoskeleton and cytoskeletal rearrangements are not present. No virus-specific variations between HTNV and PUUV are observed in Vero E6 cells. Using human renal cells as cell culture model for orthohantavirus infection demonstrates virus-specific differences and orthohantavirus-induced cytoskeletal rearrangements that are not observed in Vero E6 cells. Therefore, the choice of an appropriate cell culture system is a prerequisite to study orthohantavirus pathogenicity.


Assuntos
Células Epiteliais/virologia , Vírus Hantaan/crescimento & desenvolvimento , Virus Puumala/crescimento & desenvolvimento , Replicação Viral , Animais , Variação Biológica da População , Proteínas do Capsídeo/análise , Linhagem Celular , Chlorocebus aethiops , Citoesqueleto/metabolismo , Humanos , Proteínas do Nucleocapsídeo/análise , Proteínas do Core Viral/análise , Liberação de Vírus
14.
Genes Immun ; 20(3): 234-244, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29765118

RESUMO

Hantaan virus (HTNV), member of the newly defined Hantaviridae family, within the order Bunyavirales, can cause a hemorrhagic fever with renal syndrome with high fatality rates in humans. However, no specific antiviral agents are currently available for HTNV infection approved by the US Food and Drug Administration. Although interferon lambdas (IFN-λs) have been shown to induce an antiviral state against HTNV, the molecular mechanisms remain to be determined. In this study, we found that IFN-λs exerted its anti-HTNV effect by activating Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway-mediated antiviral immunity in A549 cells. Simultaneously, IFN-λs downregulated suppressor of cytokine signaling proteins, which are the known negative feedback regulators of the JAK-STAT signaling pathway. Additionally, we demonstrated the role of IFN-λs-induced myxovirus resistance 2 (Mx2, also known as MxB) protein as a potential inhibitor for HTNV infection. These findings indicate that IFN-λs play an important role in cellular defenses against HTNV infection at an early stage and that human Mx2 may represent a potential therapeutic target for HTNV infection.


Assuntos
Antivirais/farmacologia , Vírus Hantaan/efeitos dos fármacos , Febre Hemorrágica com Síndrome Renal/imunologia , Interferons/farmacologia , Janus Quinases/metabolismo , Proteínas de Resistência a Myxovirus/metabolismo , Fatores de Transcrição STAT/metabolismo , Animais , Linhagem Celular Tumoral , Chlorocebus aethiops , Humanos , Proteínas de Resistência a Myxovirus/genética , Transdução de Sinais/efeitos dos fármacos , Células Vero
15.
Front Immunol ; 9: 2098, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30283445

RESUMO

Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) in humans. Both diseases are considered to be immunologically mediated but the exact pathological mechanisms are still poorly understood. Neutrophils are considered the first line of defense against invading microbes but little is still known of their role in virus infections. We wanted to study the role of neutrophils in HFRS using blood and tissue samples obtained from Puumala hantavirus (PUUV)-infected patients. We found that neutrophil activation products myeloperoxidase and neutrophil elastase, together with interleukin-8 (the major neutrophil chemotactic factor in humans), are strongly elevated in blood of acute PUUV-HFRS and positively correlate with kidney dysfunction, the hallmark clinical finding of HFRS. These markers localized mainly in the tubulointerstitial space in the kidneys of PUUV-HFRS patients suggesting neutrophil activation to be a likely component of the general immune response toward hantaviruses. We also observed increased levels of circulating extracellular histones at the acute stage of the disease supporting previous findings of neutrophil extracellular trap formation in PUUV-HFRS. Mechanistically, we did not find evidence for direct PUUV-mediated activation of neutrophils but instead primary blood microvascular endothelial cells acquired a pro-inflammatory phenotype and promoted neutrophil degranulation in response to PUUV infection in vitro. These results suggest that neutrophils are activated by hantavirus-infected endothelial cells and may contribute to the kidney pathology which determines the severity of HFRS.


Assuntos
Armadilhas Extracelulares/metabolismo , Vírus Hantaan/fisiologia , Febre Hemorrágica com Síndrome Renal/imunologia , Rim/fisiologia , Microvasos/patologia , Neutrófilos/patologia , Doença Aguda , Células Cultivadas , Humanos , Imunidade Inata , Interleucina-8/metabolismo , Rim/virologia , Elastase de Leucócito/metabolismo , Ativação de Neutrófilo , Neutrófilos/imunologia , Óxido Nítrico Sintase Tipo III , Peroxidase/metabolismo
16.
Dis Markers ; 2018: 9701619, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30018676

RESUMO

Thrombocytopenia is one of the main characteristics of hemorrhagic fever with renal syndrome (HFRS). This study aimed to evaluate the associations of platelet distribution width (PDW) with the disease severity and critical patients' survival of HFRS. The demographics, clinical data, and white blood cell and platelet parameters including PDW in 260 patients hospitalized for HFRS were analyzed. The results showed that PDW on the first day (PDW1) was positively associated with the disease severity (p = 0.005). Multiple regression analysis showed that in addition to age (odds ratio [OR], 1.091; 95% confidence interval [CI], 1.015-1.172) and occurrence of sepsis (OR, 22.283; 95% CI, 2.985-166.325), PDW1 (OR, 0.782; 95% CI, 0.617-0.992) was a risk factor of the mortality, having an area under the receiver operating characteristic curve of 0.709 (95% CI, 0.572-0.846, p = 0.013) for predicting mortality, with a sensitivity of 70% and a specificity of 67% at a cutoff of 16.5 fL, in patients with critical HFRS. These results suggest the potential of PDW at the first day of hospitalization as a valuable parameter for evaluating the severity of HFRS and a moderate parameter for predicting the prognosis of critical HFRS patients. A prospective study in large patient population is needed to validate these findings.


Assuntos
Febre Hemorrágica com Síndrome Renal/sangue , Adulto , Idoso , Biomarcadores/sangue , Feminino , Vírus Hantaan/patogenicidade , Febre Hemorrágica com Síndrome Renal/patologia , Febre Hemorrágica com Síndrome Renal/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Análise de Sobrevida
17.
Artigo em Inglês | MEDLINE | ID: mdl-29868489

RESUMO

Objective: This study analyzed the significance of procalcitonin (PCT) in patients with hemorrhagic fever with renal syndrome (HFRS) caused by Hantaan virus. Methods: The demographics and clinical and laboratory data including PCT at hospital admission in 146 adults with HFRS were retrospectively analyzed. Results: PCT level was significantly higher in severe patients (n = 72) than in mild patients (n = 74, p < 0.001) and independently associated with disease severity (OR 2.544, 95% CI 1.330-4.868, p = 0.005). PCT had an area under the receiver operating characteristic curve (AUC) value of 0.738 (95% CI 0.657-0.820, p < 0.001) for predicting severity. PCT level was significantly increased in patients with bacterial infection (n = 87) compared with those without (n = 59, p = 0.037) and associated with bacterial infection (OR 1.685, 95% CI 1.026-2.768, p = 0.039). The AUC value of PCT for predicting bacterial infection was 0.618 (95% CI 0.524-0.711, p = 0.016). PCT level was significantly elevated in non-survivors (n = 13) compared with survivors (n = 133, p < 0.001) and independently associated with mortality (OR 1.075, 95% CI 1.003-1.152, p = 0.041). The AUC value of PCT for predicting mortality was 0.819 (95% CI 0.724-0.914, p < 0.001). Conclusion: PCT concentrations at admission would be predictive of disease severity, secondary bacterial infection and mortality in patients with HFRS caused by Hantaan virus.


Assuntos
Infecções Bacterianas/sangue , Vírus Hantaan/patogenicidade , Febre Hemorrágica com Síndrome Renal/sangue , Pró-Calcitonina/sangue , Adulto , Área Sob a Curva , Infecções Bacterianas/complicações , Infecções Bacterianas/mortalidade , Biomarcadores/sangue , Feminino , Febre Hemorrágica com Síndrome Renal/complicações , Febre Hemorrágica com Síndrome Renal/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença
18.
PLoS Negl Trop Dis ; 12(6): e0006554, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29874263

RESUMO

BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) is a rodent-associated zoonosis caused by hantavirus. The HFRS was initially detected in northeast China in 1931, and since 1955 it has been detected in many regions of the country. Global climate dynamics influences HFRS spread in a complex nonlinear way. The quantitative assessment of the spatiotemporal variation of the "HFRS infections-global climate dynamics" association at a large geographical scale and during a long time period is still lacking. METHODS AND FINDINGS: This work is the first study of a recently completed dataset of monthly HFRS cases in Eastern China during the period 2005-2016. A methodological synthesis that involves a time-frequency technique, a composite space-time model, hotspot analysis, and machine learning is implemented in the study of (a) the association between HFRS incidence spread and climate dynamics and (b) the geographic factors impacting this association over Eastern China during the period 2005-2016. The results showed that by assimilating core and city-specific knowledge bases the synthesis was able to depict quantitatively the space-time variation of periodic climate-HFRS associations at a large geographic scale and to assess numerically the strength of this association in the area and period of interest. It was found that the HFRS infections in Eastern China has a strong association with global climate dynamics, in particular, the 12, 18 and 36 mos periods were detected as the three main synchronous periods of climate dynamics and HFRS distribution. For the 36 mos period (which is the period with the strongest association), the space-time correlation pattern of the association strength indicated strong temporal but rather weak spatial dependencies. The generated space-time maps of association strength and association hotspots provided a clear picture of the geographic variation of the association strength that often-exhibited cluster characteristics (e.g., the south part of the study area displays a strong climate-HFRS association with non-point effects, whereas the middle-north part displays a weak climate-HFRS association). Another finding of this work is the upward climate-HFRS coherency trend for the past few years (2013-2015) indicating that the climate impacts on HFRS were becoming increasingly sensitive with time. Lastly, another finding of this work is that geographic factors affect the climate-HFRS association in an interrelated manner through local climate or by means of HFRS infections. In particular, location (latitude, distance to coastline and longitude), grassland and woodland are the geographic factors exerting the most noticeable effects on the climate-HFRS association (e.g., low latitude has a strong effect, whereas distance to coastline has a wave-like effect). CONCLUSIONS: The proposed synthetic quantitative approach revealed important aspects of the spatiotemporal variation of the climate-HFRS association in Eastern China during a long time period, and identified the geographic factors having a major impact on this association. Both findings could improve public health policy in an HFRS-torn country like China. Furthermore, the synthetic approach developed in this work can be used to map the space-time variation of different climate-disease associations in other parts of China and the World.


Assuntos
Clima , Surtos de Doenças , Febre Hemorrágica com Síndrome Renal/epidemiologia , Animais , China/epidemiologia , Geografia , Vírus Hantaan/isolamento & purificação , Febre Hemorrágica com Síndrome Renal/transmissão , Febre Hemorrágica com Síndrome Renal/virologia , Humanos , Incidência , Saúde Pública , Estações do Ano , Análise Espaço-Temporal , Zoonoses
19.
Virus Res ; 253: 92-102, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29857122

RESUMO

BACKGROUND: Hantaan virus infection causes lethal hemorrhagic fever with renal syndrome (HFRS) in humans. Little is known about how monocytes contribute to HFRS pathogenesis. In this study, we aimed to investigate changes in various monocyte subsets in HFRS patients. METHODS: A total of 41 HFRS patients and 17 age-, sex-, and ethnicity-matched healthy control subjects were included in this study. Numbers/percentages of various monocyte subsets were quantitatively determined using flow cytometry. Serum levels of interleukin (IL)-10, IL-12, and tumor necrosis factor alpha (TNF-α) were detected using a cytometric bead array (CBA). RESULTS: CD14++CD16+ intermediate monocytes were significantly higher in HFRS patients compared to healthy controls (P < 0.01), especially during the acute phase. The expression of both CD163 and CD206 on CD14++CD16+ intermediate monocytes were increased during the acute phase of HFRS (P < 0.01 and P < 0.05, respectively) when comparing the convalescent phase and healthy controls. Furthermore, the numbers of CD14++CD16+ monocytes during the acute phase, and the percentages of CD14++CD16+CD163+ monocytes in patients with severe/critical HFRS were much higher compared to patients with mild/moderate HFRS. This also positively correlated with increased levels of white blood cells (WBC), blood urea nitrogen (BUN), and creatinine (Cr). However, the percentages of CD14++CD16+CD206+monocytes were higher in mild/moderate HFRS than in severe/critical HFRS, and they negatively correlated with platelets (PLT) and Cr. CONCLUSIONS: Higher frequency of the CD14++CD16+ intermediate monocytes and increased expression of CD163+ and CD206+ markers on CD14++CD16+ monocytes were detected in patients with HFRS. The changes in the frequency of CD14++CD16+ monocytes and expression of CD163 and CD206 markers on CD14++CD16+ monocytes positively correlated with the severity of HFRS.


Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Febre Hemorrágica com Síndrome Renal/metabolismo , Nefropatias/metabolismo , Lectinas Tipo C/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Lectinas de Ligação a Manose/metabolismo , Monócitos/metabolismo , Receptores de Superfície Celular/metabolismo , Receptores de IgG/metabolismo , Adulto , Antígenos CD/genética , Antígenos de Diferenciação Mielomonocítica/genética , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Vírus Hantaan/fisiologia , Febre Hemorrágica com Síndrome Renal/genética , Febre Hemorrágica com Síndrome Renal/patologia , Febre Hemorrágica com Síndrome Renal/virologia , Humanos , Interleucina-10/sangue , Interleucina-12/sangue , Nefropatias/genética , Nefropatias/patologia , Nefropatias/virologia , Lectinas Tipo C/genética , Receptores de Lipopolissacarídeos/genética , Masculino , Lectinas de Ligação a Manose/genética , Pessoa de Meia-Idade , Receptores de Superfície Celular/genética , Receptores de IgG/genética , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/sangue , Adulto Jovem
20.
Arch Virol ; 163(6): 1577-1584, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29488118

RESUMO

Hemorrhagic fever with renal syndrome (HFRS) is caused by hantavirus infection. Although host immunity is thought to be involved in the pathogenesis of HFRS, the mechanism remains to be elucidated. A mouse model of HFRS, which showed renal hemorrhage similar to that seen in patients, has been developed previously. In this study, we aimed to clarify whether CD4+ and CD8+ T cells are involved in the development of renal hemorrhage in the mouse model. At 2 days before virus inoculation, CD4+ or CD8+ T cells in 6-week-old BALB/c mice were depleted by administration of antibodies. The CD4+ T cell-depleted mice developed signs of disease such as transient weight loss, ruffled fur and renal hemorrhage as in non-depleted mice. In contrast, the CD8+ T cell-depleted mice showed no signs of disease. After determination of CTL epitopes on the viral glycoprotein in BALB/c mice, the quantity of virus-specific CTLs was analyzed using an MHC tetramer. The quantity of virus-specific CTLs markedly increased in spleens and kidneys of virus-infected mice. However, the quantity in high-pathogenic clone-infected mice was comparable to that in low-pathogenic clone-infected mice. We previously reported that the high-pathogenic clone propagated more efficiently than the low-pathogenic clone in kidneys of mice during the course of infection. Therefore, there is a possibility that the balance between quantities of the target and effector is important for disease outcome. In conclusion, this study showed that CD8+ T cells are involved in the development of renal hemorrhage in a mouse model of HFRS.


Assuntos
Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/virologia , Vírus Hantaan/patogenicidade , Febre Hemorrágica com Síndrome Renal/virologia , Rim/virologia , Linfócitos T Citotóxicos/virologia , Sequência de Aminoácidos , Animais , Anticorpos Neutralizantes/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Modelos Animais de Doenças , Epitopos de Linfócito T/química , Epitopos de Linfócito T/imunologia , Feminino , Vírus Hantaan/imunologia , Febre Hemorrágica com Síndrome Renal/imunologia , Febre Hemorrágica com Síndrome Renal/patologia , Febre Hemorrágica com Síndrome Renal/prevenção & controle , Humanos , Rim/irrigação sanguínea , Rim/imunologia , Rim/patologia , Contagem de Linfócitos , Depleção Linfocítica , Camundongos , Camundongos Endogâmicos BALB C , Peptídeos/química , Peptídeos/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia
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