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Characterization of the Lassa virus matrix protein Z: electron microscopic study of virus-like particles and interaction with the nucleoprotein (NP).

Lassa virus is the causative agent of a hemorrhagic fever endemic in west Africa. The RNA genome of Lassa virus encodes the glycoprotein precursor GP-C, a nucleoprotein (NP), the viral polymerase L and a small protein Z (11 kDa). Here, we analyze the role of Z protein for virus maturation. We have recently shown that expression of Z protein in the absence of other viral proteins is sufficient for the release of enveloped Z-containing particles. In this study, we examined particles secreted into the supernatant of a stably Z protein-expressing CHO cell line by electron microscopy. The observed Z-induced virus-like particles did not significantly differ in their morphology and size from Lassa virus particles. Mutation of two proline-rich domains within Z which are known to drastically reduce the release of virus-like particles, had no effect on the cellular localization of the protein nor on its membrane-association. Furthermore, we present evidence that Z interacts with the NP. We assume that Z recruits NP to cellular membranes where virus assembly takes place. We conclude from our data that Lassa virus Z protein plays an essential role in Lassa virus maturation.

Amino Acid Sequence↗

[Current serologic data on viral hemorrhagic fevers in the Central African Republic].

During the years 1984-1985, 1,528 serum samples were taken through out the CAR. Of these sera, 319 (20.8%) contained anti-Filoviridae antibodies (Ebola, Marburg). This figure is higher than those found in Cameroon, Sudan, Gabon and Zaïre. Three zones of the country are particularly exposed, the North-East where the population is in the contact with Sudan Ebola, the South-East where it is in contact with Zaïre Ebola, and the South-West where it is in contact with Sudan Ebola. The authors believe that there could exist either a Central African Ebola strain or an Ebola-Like less pathogenic virus which is responsible for cross reactions. Results concerning Rift Valley Fever virus, Congo virus and Lassa virus seem less interesting. However RVF and Congo strains were isolated.

Arenaviridae↗

Phylogenetic analysis reveals a low rate of homologous recombination in negative-sense RNA viruses.

Recombination is increasingly seen as an important means of shaping genetic diversity in RNA viruses. However, observed recombination frequencies vary widely among those viruses studied to date, with only sporadic occurrences reported in RNA viruses with negative-sense genomes. To determine the extent of homologous recombination in negative-sense RNA viruses, phylogenetic analyses of 79 gene sequence alignments from 35 negative-sense RNA viruses (a total of 2154 sequences) were carried out. Powerful evidence was found for recombination, in the form of incongruent phylogenetic trees between different gene regions, in only five sequences from Hantaan virus, Mumps virus and Newcastle disease virus. This is the first report of recombination in these viruses. More tentative evidence for recombination, where conflicting phylogenetic trees were observed (but were without strong bootstrap support) and/or where putative recombinant regions were very short, was found in three alignments from La Crosse virus and Puumala virus. Finally, patterns of sequence variation compatible with the action of recombination, but not definitive evidence for this process, were observed in a further ten viruses: Canine distemper virus, Crimean-Congo haemorrhagic fever virus, Influenza A virus, Influenza B virus, Influenza C virus, Lassa virus, Pirital virus, Rabies virus, Rift Valley Fever virus and Vesicular stomatitis virus. The possibility of recombination in these viruses should be investigated further. Overall, this study reveals that rates of homologous recombination in negative-sense RNA viruses are very much lower than those of mutation, with many viruses seemingly clonal on current data. Consequently, recombination rate is unlikely to be a trait that is set by natural selection to create advantageous or purge deleterious mutations.

Animals↗

Individual and bivalent vaccines based on alphavirus replicons protect guinea pigs against infection with Lassa and Ebola viruses.

Lassa and Ebola viruses cause acute, often fatal, hemorrhagic fever diseases, for which no effective vaccines are currently available. Although lethal human disease outbreaks have been confined so far to sub-Saharan Africa, they also pose significant epidemiological concern worldwide as demonstrated by several instances of accidental importation of the viruses into North America and Europe. In the present study, we developed experimental individual vaccines for Lassa virus and bivalent vaccines for Lassa and Ebola viruses that are based on an RNA replicon vector derived from an attenuated strain of Venezuelan equine encephalitis virus. The Lassa and Ebola virus genes were expressed from recombinant replicon RNAs that also encoded the replicase function and were capable of efficient intracellular self-amplification. For vaccinations, the recombinant replicons were incorporated into virus-like replicon particles. Guinea pigs vaccinated with particles expressing Lassa virus nucleoprotein or glycoprotein genes were protected from lethal challenge with Lassa virus. Vaccination with particles expressing Ebola virus glycoprotein gene also protected the animals from lethal challenge with Ebola virus. In order to evaluate a single vaccine protecting against both Lassa and Ebola viruses, we developed dual-expression particles that expressed glycoprotein genes of both Ebola and Lassa viruses. Vaccination of guinea pigs with either dual-expression particles or with a mixture of particles expressing Ebola and Lassa virus glycoprotein genes protected the animals against challenges with Ebola and Lassa viruses. The results showed that immune responses can be induced against multiple vaccine antigens coexpressed from an alphavirus replicon and suggested the possibility of engineering multivalent vaccines based upon alphavirus vectors for arenaviruses, filoviruses, and possibly other emerging pathogens.

Alphavirus↗

Tropical myeloneuropathies revisited.

An interesting neurological syndrome, characterized by recurrent optic neuritis, cervical myelopathy from syringomyelia, paraparesis, amenorrhea-galactorrhea, and other endocrine problems, has been described among young black women in the French West Indies. The etiology remains unknown, but possible links with Devic's disease, acute disseminated encephalomyelitis, and neurotoxicity from quinolines in Annona muricata teas have been postulated. The largest epidemic of neuropathy in this century occurred in Cuba in 1991-1994. Clinical features and etiologic studies are reviewed. Its primary cause was nutritional. A similar epidemic was recently described in Tanzania. A number of infectious neuropathies and myopathies are reviewed, including leprosy, tuberculosis, hemorrhagic fevers (Ebola and Marburg filoviruses, Lassa, Argentinean and Bolivian arenaviruses), the human retrovirus human T-cell lymphotropic virus type I, Lyme disease and postimmunization neuropathies. The tropics continue to contribute interesting and important clinical conditions that may illuminate the etiopathiogenesis of other common disorders.

Cuba↗

Pathology of Lassa virus infection in the rhesus monkey.

The clinical signs and gross and microscopic lesions of Lassa virus infection in the rhesus monkey are described. Of 17 monkeys infected with Lassa virus, nine died or were killed when moribund. The clinical signs were lethargy, aphagia, constipation, fever, conjunctivitis, and skin rash. Pulmonary congestion, pleural effusion, pericardial edema, hydropericardium, and a few visceral hemorrhages were present grossly. Major microscopic lesions were necrotizing hepatitis and interstitial pneumonia. Other microscopic changes were present in the heart, small intestine, spleen, lymph nodes, kidney, urinary bladder, adrenal glands, and central nervous system; however, most of these lesions were mild. In fact, death could not always be attributed to the morphologic changes; therefore, function alterations must be examined.

Animals↗

Update: management of patients with suspected viral hemorrhagic fever--United States.

In 1988, CDC published guidelines for managing patients with suspected viral hemorrhagic fever (VHF) (1). Pending a comprehensive review of the 1988 guidelines, this notice provides interim recommendations that update the 1988 guidelines for healthcare settings in the United States. This update applies to four viruses that cause syndromes of VHF: Lassa, Marburg, Ebola, and Congo-Crimean hemorrhagic fever viruses; although the risk and/or mode of nosocomial transmission differs for each of these viruses, the limited data do not permit clear distinctions.

Ebolavirus↗

[Diagnosis of fever in a patient returning from black Africa (author's transl)].

The diagnostic problems which arise when fever occurs in a patient returning from black Africa are more and more frequently encountered because of the multiplication of rapid connections with this continent. Analysis of the main etiologies leads the author to review most of the specifically tropical diseases. However, cosmopolitan diseases should not be underrated. The author emphasizes the high incidence of pernicious malaria, liver amebiasis, and typho-paratyphoid fevers, along with the necessity of keeping in mind the new viral diseases (Lassa, Marburg, Ebola).

Africa↗

Exotic emerging viral diseases: progress and challenges.

The agents causing viral hemorrhagic fever (VHF) are a taxonomically diverse group of viruses that may share commonalities in the process whereby they produce systemic and frequently fatal disease. Significant progress has been made in understanding the biology of the Ebola virus, one of the best known examples. This knowledge has guided our thinking about other VHF agents, including Marburg, Lassa, the South American arenaviruses, yellow fever, Crimean-Congo and Rift Valley fever viruses. Comparisons among VHFs show that a common pathogenic feature is their ability to disable the host immune response by attacking and manipulating the cells that initiate the antiviral response. Of equal importance, these comparisons highlight critical gaps in our knowledge of these pathogens.

Communicable Diseases, Emerging↗

Arenaviruses other than Lassa virus.

The family Arenaviridae includes 23 viral species, of which 5 can cause viral hemorrhagic fevers with a case fatality rate of about 20%. These five viruses are Junin, Machupo, Guanarito, Sabia and Lassa virus, the manipulation of which requires biosafety level 4 facilities. They are included in the Category A Pathogen List established by the Center for Disease Control and Prevention that groups agents with the greatest potential for adverse public health impact and mass casualties whether a situation characterized by a ill-intentioned abuse of natural or engineered arenavirus would be encountered. The aims of this article are to (i) summarize the current situation; (ii) provide information to help anticipating the effects to be expected in such a situation; and to (iii) emphasize the need for fundamental research to allow the development of diagnostic, prevention and therapeutic tools as countermeasures to weaponized arenaviruses.

Animals↗

Antibody prevalence against haemorrhagic fever viruses in randomized representative Central African populations.

Between 1985 and 1987, 5,070 randomly selected persons living in 6 central African countries (Cameroon, Central African Republic, Chad, Congo, Equatorial Guinea and Gabon) were checked for serological evidence of haemorrhagic fever. Rural and urban areas were studied, including ecoclimatic zones ranging from dry savana to tropical rain forest. Virus-reactive antibodies were found with all antigens tested, and the global prevalence of positive sera was distributed as follows: Crimean-Congo haemorrhagic fever virus, 0.22%; Rift Valley fever virus, 0.18%; Ebola virus, 12.40%; Marburg virus, 0.39%; Lassa virus, 0.06%; and Hantaan virus, 6.15%. A significant variation in antibody prevalence was observed within the study regions. Association between the viruses was not observed.

Africa, Central↗

[Microbiological surveillance: viral hemorrhagic fever in Central African Republic: current serological data in man].

An investigation was conducted between 1994 and 1997 in forested areas of the Central African Republic (CAR) to determine the seroprevalence of IgG antibodies against several haemorrhagic fever viruses present in the region. Sera were obtained from 1762 individuals in two groups (Pygmy and Bantu locuted populations) living in 4 forested areas in the south of the country. Sera were tested for IgG antibodies against Ebola, Marburg, Rift Valley fever (RVF), Yellow fever (YF) and Hantaviruses by enzyme immunoassay (EIA), and against Lassa virus by immunofluorescent assay. The prevalence of IgG antibodies was 5.9% for Ebola, 2% for Marburg, 6.9% pour RVF, 6.5% for YF, 2% for Hantaan. No antibodies were detected against Lassa, Seoul, Puumala and Thottapalayam viruses. No IgM antibodies were detected against RVF and YF viruses. The distribution of antibodies appears to be related to tropical rain forest areas. This study indicates that several haemorrhagic fever viruses are endemic in forested areas of the CAR and could emerge due to environmental modification.

Antibodies, Viral↗

Arenaviruses.

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Animals↗

[Viral haemorrhagic fever].

Two outbreaks of haemorrhagic fever caused by a Marburg-like virus occurred in the Sudan and Zaire from August to November 1976. The inital epidemiological investigations and emergency control measures were carried out by Sudanese and Zairian health personnel and several of them unfortunately died in the course of their duties. In view of the unusual gravity of the outbreaks and the unknown nature of the agent, assistance was provided by a WHO team in the Sudan and a multinational team in Zaire. A consultation arranged by WHO was held at the London School of Hygiene and Tropical Medicine in January 1977 to review the experience acquired during these outbreaks and to make recommendations which, to a large extent, may be applicable to other outbreaks of suspected viral haemorrhagic fever. Because it is felt that this information would be of value to many health administrations, large abstracts of the report of this consultation are given here.

Democratic Republic of the Congo↗