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PubMedDate not supplied

[Immunogenic and protective characteristics of recombinant Lassa virus NP protein].

Recombinant fragment of Lassa virus (strain Josiah) nucleocapsid protein (corresponding to amino acid residues 141 + 569) constructed by Dr. Jan ter Meulen (Tropenmedizine, Hamburg) was used for immunizing CBA/calac mice. The preparation was injected intraperitoneally twice with 2-week interval in a dose of 10 micrograms. The parameters of the resultant specific humoral and cell-mediated immunity were comparable to those in reference animals immunized with inactivated Lassa virus. Challenge with Lassa virus (10,000 PFU) resulted in 100% death of the reference animals, while of 15 animals immunized with the recombinant NP protein 8 survived.

Animals↗
PubMed2001

Antibodies to Lassa virus Z protein and nucleoprotein co-occur in human sera from Lassa fever endemic regions.

It is not known whether the small 11-kDa Z protein of Lassa virus is immunogenic during human Lassa virus infection. To obtain evidence for the existence of an antibody response and to test the suitability of these antibodies for serosurveys, sera from Lassa fever endemic regions (Guinea and Nigeria, n = 75) were tested for co-reactivity to Z protein and nucleoprotein (NP). Sera from a non-endemic region (Uganda, n = 50) served as a specificity control. Z protein and NP were expressed in Escherichia coli, affinity-purified, and used as antigen in Western blot. Indirect immunofluorescence (IIF) with Lassa virus-infected cells was performed for comparison. Due to high unspecific reactivity of the African sera, Western blot testing was performed with a 1:1,000 serum dilution. Under these conditions, none of the control sera but 12% of the sera from endemic regions co-reacted with both Z protein and NP. Reactivity to Z protein was significantly associated with NP reactivity (P < 10(-6)). NP and Z protein-specific antibodies were co-detected in 33% of the IIF-positive sera and in 5% of the IIF-negative sera (P = 0.001). These data provide evidence for appearance of antibodies to Z protein and NP following Lassa virus infection. A recombinant blot for detection of both antibody specificities seems to be specific but less sensitive than IIF.

Antibodies, Viral↗
PubMed2004

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↗
PubMed2004

Sequence analysis of L RNA of Lassa virus.

The L RNA of three Lassa virus strains originating from Nigeria, Ghana/Ivory Coast, and Sierra Leone was sequenced and the data subjected to structure predictions and phylogenetic analyses. The L gene products had 2218-2221 residues, diverged by 18% at the amino acid level, and contained several conserved regions. Only one region of 504 residues (positions 1043-1546) could be assigned a function, namely that of an RNA polymerase. Secondary structure predictions suggest that this domain is very similar to RNA-dependent RNA polymerases of known structure encoded by plus-strand RNA viruses, permitting a model to be built. Outside the polymerase region, there is little structural data, except for regions of strong alpha-helical content and probably a coiled-coil domain at the N terminus. No evidence for reassortment or recombination during Lassa virus evolution was found. The secondary structure-assisted alignment of the RNA polymerase region permitted a reliable reconstruction of the phylogeny of all negative-strand RNA viruses, indicating that Arenaviridae are most closely related to Nairoviruses. In conclusion, the data provide a basis for structural and functional characterization of the Lassa virus L protein and reveal new insights into the phylogeny of negative-strand RNA viruses.

Amino Acid Sequence↗
PubMed1986

Nucleotide sequence of the glycoprotein gene and intergenic region of the Lassa virus S genome RNA.

Two overlapping cDNA clones corresponding to the 5' region of the Lassa virus S genome RNA were isolated and their nucleotide sequences determined. Similar to Pichinde and lymphocytic choriomeningitis viruses (LCMV), Lassa virus has an ambisense S RNA. The precursor to the viral glycoproteins (GPC) is encoded in viral RNA sequence originating at position 56 and terminating at position 1529 from the 5' terminus of the S RNA. A short, noncoding, intergenic region capable of forming a hairpin structure separates the termination codons of the nucleoprotein (N) and GPC genes. Hydropathic analysis of the GPC gene product of Lassa virus indicates the presence of hydrophobic domains near the amino and carboxy termini as previously noted in the corresponding proteins of Pichinde and LCM viruses. A comparison of the nucleotide sequences on the 3' termini of the viral and viral-complimentary S RNA species of Lassa, LCM, and Pichinde viruses reveals slight sequence differences that may possibly be involved in the regulation of RNA synthesis and gene expression.

Amino Acid Sequence↗
PubMed1990

Detection of Lassa virus RNA in specimens from patients with Lassa fever by using the polymerase chain reaction.

Suitable oligonucleotide primers and probes were synthesized to amplify Lassa virus (Josiah strain)-specific nucleoprotein and glycoprotein gene fragments by using reverse transcription combined with the polymerase chain reaction (PCR). Our primers did not amplify the related lymphocytic choriomeningitis virus. By using PCR, about 50 50% tissue culture infective doses could be detected in the supernatant of infected cells. Furthermore, in all five serum specimens and four of five urine specimens of patients with acute Lassa fever, viral RNA could be demonstrated. Negative results were obtained with all serum and urine specimens of healthy subjects. Our data suggest that PCR may be applied as an alternative to virus isolation in the rapid diagnosis of Lassa fever.

Base Sequence↗
PubMed2001

Lassa fever encephalopathy: Lassa virus in cerebrospinal fluid but not in serum.

The pathogenesis of neurologic complications of Lassa fever is poorly understood. A Nigerian patient had fever, disorientation, seizures, and blood-brain barrier dysfunction, and Lassa virus was found in cerebrospinal fluid (CSF) but not in serum. The concentration of Lassa virus RNA in CSF corresponded to 1 x 10(3) pfu/mL, as determined by a quantitative real-time polymerase chain reaction assay. To characterize the Lassa virus in CSF, the 3.5-kb S RNA was sequenced. In the S RNA coding sequences, the CSF strain differed between 20% and 24.6% from all known prototype strains. These data suggest that Lassa virus or specific Lassa virus strains can persist in the central nervous system and thus contribute to neuropathogenesis. Lassa virus infection should be considered in West African patients or in travelers returning from this area who present only with fever and neurologic signs.

Amino Acid Sequence↗
PubMed2004

Inhibition of different Lassa virus strains by alpha and gamma interferons and comparison with a less pathogenic arenavirus.

The high pathogenicity of Lassa virus is assumed to involve resistance to the effects of interferon (IFN). We have analyzed the effects of alpha IFN (IFN-alpha), IFN-gamma, and tumor necrosis factor alpha (TNF-alpha) on replication of Lassa virus compared to the related, but less pathogenic, lymphocytic choriomeningitis virus (LCMV). Three low-passage Lassa virus strains (AV, NL, and CSF), isolated from humans with mild to fulminant Lassa fever, were tested. Lassa virus replication was inhibited by IFN-alpha and IFN-gamma, but not TNF-alpha, in Huh7 and Vero cells. The degree of IFN sensitivity of a Lassa virus isolate did not correlate with disease severity in human patients. Furthermore, cytokine effects observed for Lassa virus and LCMV (strains CH-5692, Armstrong, and WE) were similar. To address the mechanisms involved in the IFN effect, we used cell lines in which overexpression of IFN-stimulated proteins promyelocytic leukemia protein (PML) and Sp100 could be induced. Both proteins reside in PML bodies, a cellular target of the LCMV and Lassa virus Z proteins. Overexpression of PML or Sp100 did not affect replication of either virus. This, together with the previous finding that PML knockout facilitates LCMV replication in vitro and in vivo (M. Djavani, J. Rodas, I. S. Lukashevich, D. Horejsh, P. P. Pandolfi, K. L. Borden, and M. S. Salvato, J. Virol. 75:6204-6208, 2001; W. V. Bonilla, D. D. Pinschewer, P. Klenerman, V. Rousson, M. Gaboli, P. P. Pandolfi, R. M. Zinkernagel, M. S. Salvato, and H. Hengartner, J. Virol. 76:3810-3818, 2002), describes PML as a mediator within the antiviral pathway rather than as a direct effector protein. In conclusion, the high pathogenicity of Lassa virus compared to LCMV is probably not due to increased resistance to the effects of IFN-alpha or IFN-gamma. Both cytokines inhibit replication which is relevant for the design of antiviral strategies against Lassa fever with the aim of enhancing the IFN response.

Animals↗
PubMedDate not supplied

[Effect of immunosuppression on the development and outcome of an acute infection in mice caused by administration of the Lassa virus].

In experimental infection of mice with Lassa virus, the infectious virus could be detected in all the organs and brain tissues tested. Histopathological lesions were demonstrated in cerebral and spinal cord tissues only. Roentgen irradiation in a dose of 500 R and cyclophosphamide protected mice against a lethal Lassa virus dose. Cyclosporin A in various doses exerted no effect on the outcome of the acute infection. The adoptive transfer of splenocytes from mouse donors inoculated intraperitoneally prevented the development of lethal disease symptoms and death of mice-recipients. It is suggested that immunocompetent cells are involved in the development and outcome of experimental infection of mice with Lassa virus.

Acute Disease↗
PubMed1980

Effect of storage temperature on the stability of Lassa virus complement-fixing antigen.

Inactivated Lassa virus complement-fixing antigen is normally prepared as a wet frozen antigen, and shipped in dry ice from the Center for Disease Control, Atlanta, Georgia, USA, to other laboratories not equipped for handling live Lassa virus. However, with this antigen there is a considerable loss of potency during shipping. In the search for a more stable antigen, inactivated Lassa antigen was lyophilized and subjected to different storage temperatures. Lyophilization did not significantly affect the CF titre, and the lyophilized antigen remained stable for 15 and 28 days at 25 degrees C and 4 degrees C, respectively.

Animals↗
PubMed1989

Preparation and biochemical characterization of Lassa virus subvirion fractions.

14C-labelled Lassa virus was purified by isopycnic centrifugation and split to subvirion fractions. The purified virus was treated with nonionic detergents Nonidet P-40 (NP-40) and with octylglycoside. After ultracentrifugation in urographin density gradient, two subvirion fractions with buoyant density of 1.24-1.26 and 1.08-1.10 g/cm3 were obtained. The first fraction corresponded to the nucleocapsid of Lassa virus: it contained a protein with molecular mass of 60 kDa, the L and S segments of the genomic RNA. The second one contained a protein with molecular mass of 48 kDa and represented, apparently, envelope fraction of virus particles.

Arenaviridae↗
PubMed1987

Vaccinia recombinant expressing Lassa-virus internal nucleocapsid protein protects guineapigs against Lassa fever.

The Lister strain of vaccinia virus was used to construct a recombinant that expressed the nucleocapsid gene of Lassa virus. Guineapigs immunised with the recombinant virus were protected against challenge with Lassa virus, whereas control animals showed the usual disease course, including pyrexia, anorexia, viraemia, and death. These data indicate not only that protective immunity to Lassa fever can be evoked by an experimental vaccine, but also that this response can be mediated by an internal protein component of the virus.

Animals↗
PubMed1984

Effect of environmental factors on aerosol-induced Lassa virus infection.

Previous studies suggested that the most frequent means of transmission of Lassa virus was by either direct or indirect contact with infectious material. Aerosol stability and respiratory infectivity of the Josiah strain of Lassa virus were assessed to determine the effect of environmental factors on aerosol-induced infection. The stability of the virus in aerosol, particularly at low relative humidity (30% RH), plus the ability of the virus to infect guinea pigs and monkeys via the respiratory route emphasize the potential for aerosol transmission of Lassa virus. Biological half-lives at both 24 and 32 degrees C ranged from 10.1 to 54.6 min, and were sufficient for aerosol dispersion of virus to considerable distances in natural situations. Infectivity of Lassa virus in small particle aerosol was demonstrated in outbred guinea pigs and cynomolgus monkeys using dynamic aerosol equipment. Monkeys exposed to inhaled doses to 465 PFU were infected and died. The median infectious dose (ID50) for guinea pigs was 15 PFU, yet a definitive median lethal aerosol dose (LD50) could not be established. Organ tropism of aerosol-induced Lassa virus infections in outbred guinea pigs was similar to that previously reported for inbred guinea pigs infected by subcutaneous inoculation.

Aerosols↗
PubMed2003

Cutting edge: impairment of dendritic cells and adaptive immunity by Ebola and Lassa viruses.

Acute infection of humans with Ebola and Lassa viruses, two principal etiologic agents of hemorrhagic fevers, often results in a paradoxical pattern of immune responses: early infection, characterized by an outpouring of inflammatory mediators such as TNF-alpha, IL-1 beta, and IL-6, vs late stage infections, which are associated with poor immune responses. The mechanisms underlying these diverse outcomes are poorly understood. In particular, the role played by cells of the innate immune system, such as dendritic cells (DC), is not known. In this study, we show that Ebola and Lassa viruses infect human monocyte-derived DC and impair their function. Monocyte-derived DC exposed to either virus fail to secrete proinflammatory cytokines, do not up-regulate costimulatory molecules, and are poor stimulators of T cells. These data represent the first evidence for a mechanism by which Ebola and Lassa viruses target DC to impair adaptive immunity.

Antigen Presentation↗
PubMed1982

Experimental infection of rhesus monkeys with Lassa virus and a closely related arenavirus, Mozambique virus.

As a model for the pathogenesis of Lassa fever in humans, nine rhesus monkeys were inoculated with Lassa virus. Three monkeys had had a previous asymptomatic experimental infection with Mozambique virus, a closely related arenavirus; these monkeys were protected from illness and viremia and manifested only mild pathologic lesions. The other animals developed severe disease and viremia. At necropsy, hepatocellular necrosis, interstitial pneumonia, a unique pulmonary arteritis, adrenal gland necrosis, encephalitis, and uveitis were prominent pathologic lesions which correlated with the organ titers of virus. One animal infected with Lassa virus developed prolonged viremia, a typical immune response, and sudden onset of lower limb paralysis after recovery; at necropsy chronic proliferative arteritis of the spinal cord, brain, and heart was evident. Similarities and differences in the pathologic lesions in this model and Lassa fever in humans indicate that care must be taken in interpreting the results of experiments concerning immune prophylaxis, pathogenesis, and treatment in rhesus monkeys.

Animals↗
PubMedDate not supplied

[The immunogenic activity of the Lassa virus structural proteins].

The immunogenic properties of Lassa virus GP1, GP2, and NP polypeptides were studied in rabbits. Lassa virus NP polypeptide, in contrast to GP1 and GP2 polypeptides, was shown to induce the highest titres of antibodies determined by IFA and ELISA tests. Moreover, the antibody relative avidity experiment showed that the anti-NP antibodies has ELISA index of 0.63 whereas anti-GP1 and anti-GP2 antisera had those of 0.49 and 0.28, respectively.

Animals↗
PubMed2006

Reverse ELISA for IgG and IgM antibodies to detect Lassa virus infections in Africa.

BACKGROUND: Anti-Lassa antibodies are detected by indirect immunofluorescence assay (IFA) or by enzyme-immunoassay (ELISA). Both methods have problems to detect low amounts of specific antibodies. OBJECTIVES: We report here highly sensitive and specific reverse ELISAs to detect Lassa virus IgG and IgM antibodies. Due to the reverse techniques, serum samples could be applied at dilutions of 1:10 without increasing non-specific background reactions. STUDY DESIGN: For IgM antibody detection microtiter plates were coated with anti-IgM antibodies and for IgG antibody detection with rheumatoid factor (RF) (Sachers M, Emmerich P, Mohr H, Schmitz H. Simple detection of antibodies to different viruses using rheumatoid factor and enzyme-labelled antigen (ELA). J Virol Methods 1985;10:99-110). In both assays a tissue culture antigen was used in combination with a labeled anti-Lassa monoclonal antibody (Hufert FT, Ludke W, Schmitz H. Epitope mapping of the Lassa virus nucleoprotein using monoclonal anti-nucleocapsid antibodies. Arch Virol 1989;106(3-4):201-12). RESULTS: The reverse ELISA turned out to detect virus-specific IgG and IgM antibody in all 20 samples of West African patients collected 2-8 weeks after onset of Lassa fever. Moreover, both IFA and reverse ELISA found IgG antibodies in 53 out of 643 samples of healthy West Africans (sensitivity of 100%). Six of the 643 samples were positive by reverse IgG ELISA only. Thus, the specificity compared to IIF was 99.0%, but it may be even higher, because compared to IFA the IgG ELISA was clearly more sensitive in detecting low antibody titers. CONCLUSIONS: In Ghana 3% seropositives were found by IFA, but 4% by the reverse ELISA. The reverse ELISAs can be performed with high sensitivity and specificity under field conditions in Africa.

Africa↗
PubMed2003

Signal peptide of Lassa virus glycoprotein GP-C exhibits an unusual length.

Lassa virus glycoprotein is synthesized as precursor GP-C into the lumen of the endoplasmic reticulum and cleaved posttranslationally into the N-terminal subunit GP-1 and the C-terminal subunit GP-2 by subtilase SKI-1/S1P. The N-terminal portion of the primary translation product preGP-C contains a signal peptide of unknown length. In order to demonstrate the signal peptide cleavage site, purified viral GP-1 isolated from Lassa virus particles was N-terminally sequenced as TSLYKGV, identical to amino acids 59-65 of GP-C. Mutational analysis of the amino acid residues flanking the putative cleavage site led to non-cleavable preGP-C indicating that no other signal peptide cleavage site exists. Interestingly, GP-C mutants with a non-cleavable signal peptide were not further processed by SKI-1/S1P. This observation suggests that the signal peptide cleavage is necessary for GP-C maturation and hence for Lassa virus replication.

Animals↗