摘要 :
Yellow fever, a mosquito-borne viral hemorrhagic fever, is one of the most lethal diseases of humankind. The etiologic agent is the prototype member of the genus Flavivirus, family Flaviviridae, a group of small, enveloped, positi...
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Yellow fever, a mosquito-borne viral hemorrhagic fever, is one of the most lethal diseases of humankind. The etiologic agent is the prototype member of the genus Flavivirus, family Flaviviridae, a group of small, enveloped, positive-sense, single-strand RNA viruses. Approximately one in seven people who become infected develop a rapidly progressive illness, with hepatitis, renal failure, hemorrhage and cardiovascular shock, with a case fatality rate of 20-50%. Yellow fever occurs in sub-Saharan Africa and tropical South America, where it remains a continuing public health problem of varying magnitude, depending on the level of vaccination coverage in the human population and cyclical, ecologic and climatic factors that influence virus transmission.
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摘要 :
Yellow fever (YF) was one of the most dangerous infectious diseases of the 18th and 19th centuries, resulting in mass casualties in Africa and the Americas. The etiologic agent is yellow fever virus (YFV), and its live-attenuated ...
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Yellow fever (YF) was one of the most dangerous infectious diseases of the 18th and 19th centuries, resulting in mass casualties in Africa and the Americas. The etiologic agent is yellow fever virus (YFV), and its live-attenuated form, YFV-17D, remains one of the most potent vaccines ever developed. During the first half of the 20th century, vaccination combined with mosquito control eradicated YFV transmission in urban areas. However, the recent 2016–2018 outbreaks in areas with historically low or no YFV activity have raised serious concerns for an estimated 400–500 million unvaccinated people who now live in at-risk areas. Once a forgotten disease, we highlight here that YF still represents a very real threat to human health and economies. As many gaps remain in our understanding of how YFV interacts with the human host and causes disease, there is an urgent need to address these knowledge gaps and propel YFV research forward.
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摘要 :
Yellow fever (YF) was one of the most dangerous infectious diseases of the 18th and 19th centuries, resulting in mass casualties in Africa and the Americas. The etiologic agent is yellow fever virus (YFV), and its live-attenuated ...
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Yellow fever (YF) was one of the most dangerous infectious diseases of the 18th and 19th centuries, resulting in mass casualties in Africa and the Americas. The etiologic agent is yellow fever virus (YFV), and its live-attenuated form, YFV-17D, remains one of the most potent vaccines ever developed. During the first half of the 20th century, vaccination combined with mosquito control eradicated YFV transmission in urban areas. However, the recent 2016–2018 outbreaks in areas with historically low or no YFV activity have raised serious concerns for an estimated 400–500 million unvaccinated people who now live in at-risk areas. Once a forgotten disease, we highlight here that YF still represents a very real threat to human health and economies. As many gaps remain in our understanding of how YFV interacts with the human host and causes disease, there is an urgent need to address these knowledge gaps and propel YFV research forward.
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摘要 :
The yellow fever 17D virus (YF17D) has several characteristics that are desirable for the development of new, live attenuated vaccines. We approached its development as a vector for heterologous antigens by studying the expression...
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The yellow fever 17D virus (YF17D) has several characteristics that are desirable for the development of new, live attenuated vaccines. We approached its development as a vector for heterologous antigens by studying the expression of a humoral epitope at the surface of the E protein based on the results of modelling its three-dimensional structure. This model indicated that the most promising insertion site is between beta-strands f and g, a site that is exposed at the external surface of the virus. The large deletion of six residues from the fg loop of the E protein from yellow fever virus, compared to tick-born encephalitis virus, leaves space at the dimer interface for a large insertion without creating steric hindrance. We have tested this hypothesis by inserting a model humoral epitope from the circumsporozoite protein of Plasmodium falciparum consisting of triple NANP repeats. Recombinant virus (17D/8) expressing this insertion flanked by two glycine residues at each end, is specifically neutralized by a monoclonal antibody to the model epitope. Furthermore, mouse antibodies raised to the recombinant virus recognize the parasite protein in an ELISA assay. Serial passage analysis confirmed the genetic stability of the insertion made in the viral genome and the resulting 17D/8 virus is significantly more attenuated in mouse neurovirulence tests than the 17DD vaccine. The fg loop belongs to the dimerization domain of the E protein and lies at the interface between monomers. This domain undergoes a low pH transition, which is related to the fusion of the viral envelope to the endosome membrane. It is conceivable that a slower rate of fusion, resulting from the insertion close to the dimer interface, may delay the onset of virus production and thereby lead to a milder infection of the host. This would account for the more attenuated phenotype of the recombinant virus in the mouse model and lower extent of replication in cultured cells. The vectorial capacity of the yellow fever virus is being further explored for the expression and presentation of other epitopes, including those mediating T-cell responses.
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Viscerotropic yellow fever virus (YFV) infection occurs primarily in humans and non-human primates. Lack of an appropriate small animal model of viscerotropic YFV infection has been a major deterrent to molecular studies of viscer...
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Viscerotropic yellow fever virus (YFV) infection occurs primarily in humans and non-human primates. Lack of an appropriate small animal model of viscerotropic YFV infection has been a major deterrent to molecular studies of viscerotropism. A hamster model of viscerotropic YFV infection has recently been described; however, these studies have focused on hamster-viscerotropic strains of YFV (including Asibi hamster P7 virus) that caused outward clinical signs of infection and mortality. In order to map more closely the molecular determinants of viscerotropism in the hamster model, a second sequential series of seven liver-to-liver passages of Asibi virus was undertaken through hamsters to generate Asibi P7b virus. Asibi hamster P7b virus did not cause clinically detectable signs of YFV infection; however, high quantities of circulating virus were isolated from the serum, and microscopic evaluation of the liver and spleen demonstrated histopathological lesions consistent with YFV infection. The genomic sequence of Asibi P7b virus was determined and compared to wild-type Asibi virus and the lethal, hamster-viscerotropic Asibi P7 virus and found to differ by only two amino acids in the envelope protein, E-98 and E-331.
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The clinical syndrome referred to as viral hemorrhagic fever (VHF) can be caused by several different families of RNA viruses, including select members of the arenaviruses, bunyaviruses, filoviruses, and flaviviruses. VHF is chara...
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The clinical syndrome referred to as viral hemorrhagic fever (VHF) can be caused by several different families of RNA viruses, including select members of the arenaviruses, bunyaviruses, filoviruses, and flaviviruses. VHF is characterized by malaise, fever, vascular permeability, decreased plasma volume, coagulation abnormalities, and varying degrees of hemorrhage. Study of the filovirus Ebola virus has demonstrated a critical role for suppression of innate antiviral defenses in viral pathogenesis. Additionally, antigen-presenting cells are targets of productive infection and immune dysregulation. Among these cell populations, monocytes and macrophages are proposed to produce damaging inflammatory cytokines, while infected dendritic cells fail to undergo proper maturation, potentially impairing adaptive immunity. Uncontrolled virus replication and accompanying inflammatory responses are thought to promote vascular leakage and coagulopathy. However, the specific molecular pathways that underlie these features of VHF remain poorly understood. The arenavirus Lassa virus and the flavivirus yellow fever virus exhibit similar molecular pathogenesis suggesting common underlying mechanisms. Because non-human primate models that closely mimic VHF are available for Ebola, Lassa, and yellow fever viruses, we propose that comparative molecular studies using these models will yield new insights into the molecular underpinnings of VHF and suggest new therapeutic approaches.
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Non-human primates contribute to the spread of yellow fever virus (YFV) and the establishment of transmission cycles in endemic areas, such as Brazil. This study aims to investigate virological, histopathological and immunohistoch...
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Non-human primates contribute to the spread of yellow fever virus (YFV) and the establishment of transmission cycles in endemic areas, such as Brazil. This study aims to investigate virological, histopathological and immunohistochemical findings in livers of squirrel monkeys (Saimiri spp.) infected with the YFV. Viremia occurred 1-30 days post infection (dpi) and the virus showed a predilection for the middle zone (Z2). The livers were jaundiced with subcapsular and hemorrhagic multifocal petechiae. Apoptosis, lytic and coagulative necrosis, steatosis and cellular edema were also observed. The immune response was characterized by the expression of S100, CD11b, CD57, CD4 and CD20; endothelial markers; stress and cell death; pro and anti-inflammatory cytokines, as well as Treg (IL-35) and IL-17 throughout the experimental period. Lesions during the severe phase of the disease were associated with excessive production of apoptotic pro-inflammatory cytokines, such as IFN-γ and TNF-α, released by inflammatory response cells (CD4+ and CD8+ T lymphocytes) and associated with high expression of molecules of adhesion in the inflammatory foci observed in Z2. Immunostaining of the local endothelium in vascular cells and the bile duct was intense, suggesting a fundamental role in liver damage and in the pathogenesis of the disease.
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Abstract Despite the availability of a safe and efficacious yellow fever vaccine since 1937, yellow fever remains a public health threat as a re-emerging disease in Africa and South America. We reviewed the trend of reported yello...
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Abstract Despite the availability of a safe and efficacious yellow fever vaccine since 1937, yellow fever remains a public health threat as a re-emerging disease in Africa and South America. We reviewed the trend of reported yellow fever outbreaks in eastern African countries, identified the risk epidemiological factors associated with the outbreaks and assessed the current situation of Yellow Fever vaccination in Africa. Surveillance and case finding for yellow fever in Africa are insufficient primarily due to lack of appropriate diagnostic capabilities, poor health infrastructure resulting in under-recognition, underreporting and underestimation of the disease. Despite these challenges, Ethiopia reported 302,614 cases (30,505 deaths) in 1943–2015, Kenya had 207 cases (38 deaths) in 1992–2016, Sudan experienced 31,750 suspected cases (1855 deaths) from 1940 to 2012 and Uganda had 452 cases (65 deaths) in 1941–2016. Major risk factors associated with past yellow fever outbreaks include climate, human practices and virus genetics. Comparisons between isolates from different outbreaks after 45 years have revealed the genetic stability of the structural proteins of YFV which are the primary targets of the host immune cells. This probably explains why yellow fever 17D vaccine is considered as outstandingly efficacious and safe after being used for 75 years. However, the 14 amino-acid changes among these isolates may have a greater impact on the changing disease epidemiology, virulence and transmission rate. Low population immunity against YF influences outbreak frequency especially in countries where the incorporation of YF vaccination is not combined with mass vaccination campaigns or vaccination is limited to international travellers. Understanding Yellow fever virus epidemiology as determined by its evolution underscores appropriate disease mitigation strategies and immunization policies. Mobilizing scarce resources to enhance population immunity through sufficient vaccination, promoting environmental sanitation/hygienic practices, driving behavioral change and community-based vector control are significant to preventing future epidemics. Highlights ? YF led to 1843, 30,505, 65 and 38 deaths in Sudan, Ethiopia, Uganda and Kenya. ? Genetic evolution of the Yellow Fever virus does not affect its immunogenicity. ? YF outbreaks occur due to low population immunity in the affected countries. ? Mass YF vaccination campaigns for all ages will boost population immunity. ? Mass YF vaccination is more cost effective than reactive vaccination during outbreaks.
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The growth of air travel has diminished the barriers to the spread of yellow fever, posing a threat to regions that have not previously been reached by the disease but are considered receptive, including the Middle East, coastal E...
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The growth of air travel has diminished the barriers to the spread of yellow fever, posing a threat to regions that have not previously been reached by the disease but are considered receptive, including the Middle East, coastal East Africa, the Indian subcontinent, Asia and Australia. For many decades, vaccination against yellow fever has been required for travelers entering many countries with receptive mosquito vectors in order to prevent the importation of yellow fever virus from a country that had ongoing transmission. Each year, approximately 9 million tourists travel to countries where yellow fever is endemic; the number of tourists who visit yellow fever-endemic regions within these countries may exceed 3 million. Risk estimates of yellow fever to travelers are extremely difficult to ascertain due to fluctuation of the disease by year and season, incomplete surveillance data, and lack of accurate data regarding vaccine coverage of the local population. The 17D live yellow fever vaccine has been widely acknowledged as one of the most effective and safe vaccines in use. Recently, however, reports of severe and previously unrecognized significant adverse events linked to the 17D vaccine have caused major concern. Some have called for the development of new inactivated yellow fever vaccines for travelers. A new approach for manufacturing the live 17D vaccine involves using a full-length cDNA clone of 17D-204 virus. This new method allows production in a cell culture system and potentially reduces the risk of adventitious viruses and selection of a subpopulation during replication, thereby increasing safety.
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Yellow fever is a re-emerging infectious disease that currently is at risk of urbanization due to the advance of the Aedes aegypti vector. The disease affects about 200,000 individuals annually, mainly in tropical Africa and South...
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Yellow fever is a re-emerging infectious disease that currently is at risk of urbanization due to the advance of the Aedes aegypti vector. The disease affects about 200,000 individuals annually, mainly in tropical Africa and South America. It causes severe disease involving especially the liver, with lesions characterized by midzonal steatosis, apoptosis and lytic necrosis of the hepatocytes. Quantitative histological and immunohistochemical analysis of 53 human hepatic samples demonstrated apoptosis, steatosis and lytic necrosis of hepatocytes with midzonal pattern. No substantial alterations and reticular network were observed. The inflammatory infiltrate consisted of mononuclear cells and intensity was minimal or moderate, disproportionate to the intense death of the hepatocytes. Hepatic damage in yellow fever resulted mainly from a massive death of hepatocytes due to apoptosis and to a lesser extent due to lytic necrosis. It is recommended that therapeutic regimens for serious cases should include measures to protect against apoptosis.
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