RNA interference inhibits yellow fever virus replication in vitro and in vivo

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Hepatocyte lesions and cellular immune response in yellow fever infection

The study of the in-situ cellular immune response is very important for the understanding of different liver infections. In the present study, 53 liver samples obtained by viscerotomy from patients who died during the course of jungle yellow fever were analyzed. The diagnosis was confirmed by serology, viral isolation and virus-specific immunohistochemistry. The specimens were analyzed by immunohistochemistry using specific antibodies for apoptosis, CD45RO, CD4, CD8, CD20, S100, CD57 and CD68. Quantitative analysis of the labeling pattern showed a clear predominance of the different phenotypes in the portal tract and midzone region of the acini. There was a predominance of T CD4+ lymphocytes, accompanied by the presence of T CD8+ lymphocytes, natural killer cells (CD57), macrophages and antigen-presenting cells (S100). The disproportion between the intensity of inflammation and the degree of hepatic injury was probably due to the intense apoptotic component, which classically does not induce an inflammatory response. The present study demonstrates that, despite the disproportion between injury and inflammation, the cellular immune response plays an important role in the pathogenesis of the hepatocytic injury observed in yellow fever, probably as a result of cytolytic actions through mechanisms involving MHC II and the activation of Fas receptors and granzymes/perforins. (C) 2006 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.

The eukaryotic translation initiation factor 3 subunit L protein interacts with Flavivirus NS5 and may modulate yellow fever virus replication

Background: Yellow fever virus (YFV) belongs to the Flavivirus genus and causes an important disease. An alarming resurgence of viral circulation and the expansion of YFV-endemic zones have been detected in Africa and South America in recent years. NS5 is a viral protein that contains methyltransferase and RNA-dependent RNA polymerase (RdRp) domains, which are essential for viral replication, and the interactions between NS5 and cellular proteins have been studied to better understand viral replication. The aim of this study was to characterize the interaction of the NS5 protein with eukaryotic translation initiation factor 3 subunit L (eIF3L) and to evaluate the role of eIF3L in yellow fever replication. Methods. To identify interactions of YFV NS5 with cellular proteins, we performed a two-hybrid screen using the YFV NS5 RdRp domain as bait with a human cDNA library, and RNApol deletion mutants were generated and analyzed using the two-hybrid system for mapping the interactions. The RNApol region involved was segmented into three fragments and analyzed using an eIF3L-expressing yeast strain. To map the NS5 residues that are critical for the interactions, we performed site-direct mutagenesis in segment 3 of the interaction domain (ID) and confirmed the interaction using in vitro assays and in vivo coimmunoprecipitation. The significance of eIF3L for YFV replication was investigated using eIF3L overexpression and RNA interference. Results: In this work, we describe and characterize the interaction of NS5 with the translation factor eIF3L. The interaction between NS5 and eIF3L was confirmed using in vitro binding and in vivo coimmunoprecipitation assays. This interaction occurs at a region (the interaction domain of the RNApol domain) that is conserved in several flaviviruses and that is, therefore, likely to be relevant to the genus. eIF3L overexpression and plaque reduction assays showed a slight effect on YFV replication, indicating that the interaction of eIF3L with YFV NS5 may play a role in YFV replication. Conclusions: Although the precise function of eIF3L on interactions with viral proteins is not entirely understood, these results indicate an interaction of eIF3L with YF NS5 and that eIF3L overexpression facilitates translation, which has potential implications for virus replication. © 2013 Morais et al.; licensee BioMed Central Ltd.

Yellow fever: reemerging in the state of Sao Paulo, Brazil, 2009

OBJECTIVE: To describe the investigation of a sylvatic yellow fever outbreak in the state of Sao Paulo and the main control measures undertaken.METHODS: This is a descriptive study of a sylvatic yellow fever outbreak in the Southwestern region of the state from February to April 2009. Suspected and confirmed cases in humans and in non-human primates were evaluated. Entomological investigation in sylvatic environment involved capture at ground level and in the tree canopy to identify species and detect natural infections. Control measures were performed in urban areas to control Aedes aegypti. Vaccination was directed at residents living in areas with confirmed viral circulation and also at nearby cities according to national recommendation.RESULTS: Twenty-eight human cases were confirmed (39.3% case fatality rate) in rural areas of Sarutaia, Piraju, Tejupa, Avare, and Buri. The deaths of 56 non-human primates were also reported, 91.4% were Allouatta sp. Epizootics was confirmed in two non-human primates in the cities of Itapetininga and Buri. A total of 1,782 mosquitoes were collected, including Haemagogus leucocelaenus, Hg. janthinomys/capricornii, and Sabethes chloropterus, Sa. purpureus and Sa. undosus. Yellow fever virus was isolated from a group of Hg. Leucocelaenus from Buri. Vaccination was carried out in 49 cities, with a total of 1,018,705 doses. Nine serious post-vaccination adverse events were reported.CONCLUSIONS: The cases occurred between February and April 2009 in areas with no recorded yellow fever virus circulation in over 60 years. The outbreak region occurred outside the original recommended vaccination area with a high percentage of susceptible population. The fast adoption of control measures interrupted the human transmission within a month and the confirmation of viral circulation in humans, monkeys and mosquitoes. The results allowed the identification of new areas of viral circulation but further studies are required to clarify the dynamics of the spread of this disease.

Reconsideration of histopathology and ultrastructural aspects of the human liver in yellow fever

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. (c) 2005 Elsevier B.V. All rights reserved.

Crotoxin and phospholipases A(2) from Crotalus durissus terrificus showed antiviral activity against dengue and yellow fever viruses

Dengue is the most important arbovirus in the world with an estimated of 50 million dengue infections occurring annually and approximately 2.5 billion people living in dengue endemic countries. Yellow fever is a viral hemorrhagic fever with high mortality that is transmitted by mosquitoes. Effective vaccines against yellow fever have been available for almost 70 years and are responsible for a significant reduction of occurrences of the disease worldwide; however, approximately 200,000 cases of yellow fever still occur annually, principally in Africa. Therefore, it is a public health priority to develop antiviral agents for treatment of these virus infections. Crotalus durissus terrificus snake, a South American rattlesnake, presents venom with several biologically actives molecules. In this study, we evaluated the antiviral activity of crude venom and isolated toxins from Crotalus durissus terrificus and found that phospholipases A(2) showed a high inhibition of Yellow fever and dengue viruses in VERO E6 cells. (C) 2011 Elsevier Ltd. All rights reserved.

Dr. William Gorgas and his style of management against yellow fever during the construction of the Panama Canal: A historical case study

This study describes the style of management of Dr. William Gorgas as he led the public health effort to reduce diseases to a level that permitted the completion of the Panama Canal construction. Initially, Gorgas was skeptical of the mosquito vector theory. He fully accepted this theory after participating in Walter Reed’s massive cleanup of Havana, Cuba during the Spanish American War of 1898. During 1905 to 1914, Gorgas was selected to lead the sanitary effort during the construction of the Panama Canal. The lessons learned from this historical case study provide public health administrators with guidance to effectively lead current and future infectious diseases threats. Understanding styles of management within the context of disease control is essential in tackling epidemics like yellow fever and other infectious diseases. ^

TRANSOVARIAL TRANSMISSION OF YELLOW FEVER VIRUS BY A SYLVATIC VECTOR, HAEMAGOGUS EQUINUS (THEOBALD)

The potential of a sylvatic vector to act as reservoir of yellow fever virus was assessed in Haemagogus equinus (Theobald). Mosquitoes from the Maje'75 laboratory colony and a Panamanian human isolated strain of yellow fever virus were used. Female mosquitoes infected with yellow fever virus had a minimum transovarial transmission rate of 1:5745. This is the first time transovarial transmission of yellow fever virus has been demonstrated in a New World sylvatic vector. Transovarial transmission of yellow fever virus in this sylvatic mosquito species may be an alternative mechanism for biological survival of the virus during adverse periods or in the absence of susceptible vertebrate hosts. ^

Three novel families of miniature inverted-repeat transposable elements are associated with genes of the yellow fever mosquito, Aedes aegypti

Three novel families of transposable elements, Wukong, Wujin, and Wuneng, are described in the yellow fever mosquito, Aedes aegypti. Their copy numbers range from 2,100 to 3,000 per haploid genome. There are high degrees of sequence similarity within each family, and many structural but not sequence similarities between families. The common structural characteristics include small size, no coding potential, terminal inverted repeats, potential to form a stable secondary structure, A+T richness, and putative 2- to 4-bp A+T-biased specific target sites. Evidence of previous mobility is presented for the Wukong elements. Elements of these three families are associated with 7 of 16 fully or partially sequenced Ae. aegypti genes. Characteristics of these mosquito elements indicate strong similarities to the miniature inverted-repeat transposable elements (MITEs) recently found to be associated with plant genes. MITE-like elements have also been reported in two species of Xenopus and in Homo sapiens. This characterization of multiple families of highly repetitive MITE-like elements in an invertebrate extends the range of these elements in eukaryotic genomes. A hypothesis is presented relating genome size and organization to the presence of highly reiterated MITE families. The association of MITE-like elements with Ae. aegypti genes shows the same bias toward noncoding regions as in plants. This association has potentially important implications for the evolution of gene regulation.

Ioannis Moultrie ... Dissertatio medica de febre maligna biliosa Americae : anglice the Yellow Fever, habita olim die X martii 1749 in Academia Edinburgensi pro gradu doctoris /

Mode of access: Internet.

The Seaman's medical advocate, or, An attempt to shew that five thousand seamen are ... through the yellow fever and other diseases and means ... /

Mode of access: Internet.

Observations on the changes of the air and the concomitant epidemical diseases in the island of Barbadoes : to which is added a treatise on the putrid bilious fever commonly called the yellow fever and such other diseases as are indigenous or endemial in the West India islands or in the torrid zone /

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Observations on the changes of the air and the concomitant epidemical diseases in the island of Barbados : to which is added a treatise on the putrid bilious fever, commonly called the yellow fever /

Mode of access: Internet.

An essay on the disease called yellow fever, with observations concerning febrile contagion, typhus fever, dysentery, and the plague, partly delivered as the Gulstonian lectures, before the college of physicians, in the years 1806 and 1807 /

Mode of access: Internet.