Early events in arenavirus replication are sensitive to lysosomotropic compounds

Glushakova, Svetlana; Lukashevich, Igor S.

doi:10.1007/bf01313817

Cited by 33 publications

(29 citation statements)

References 8 publications

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“…Following receptor binding, pH-dependent viruses are routed into endosomal vesicles, where fusion between viral and cellular membranes is activated by acidification. Lysosomotropic agents, which inhibit the drop of pH in endocytic particles, were previously shown to inhibit the cell entry of several arenaviruses, including LCMV and LV, suggesting that the fusion process is triggered by low pH (6,13,20,21,48,49). We confirmed that treatment of Vero cells with bafilomycin A1 prior to and during infection inhibited infection with wt LV (data not shown).…”

Section: Biochemical and Electron Microscopic Characterization Ofsupporting

confidence: 74%

“…The interaction of the LV GPs with their cellular receptor ␣-dystroglycan and the dependence of LV cell entry on lyso- somotropic agents are well described in the literature (6,10,21). However, in comparison to its close relative LCMV and other New World arenaviruses, characterization of the route of LV cell entry has only recently been described and seems to depend on an as-yet-uncharacterized endocytic pathway (49,61), and the only report on the pH dependence of fusion activation of the LV GP complex has only recently become public in the form of a cell-cell fusion assay (28).…”

Section: Discussionmentioning

confidence: 96%

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Characterization of Lassa Virus Cell Entry and Neutralization with Lassa Virus Pseudoparticles

Cosset

Marianneau

Verney

et al. 2009

J Virol

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The cell entry and humoral immune response of the human pathogen Lassa virus (LV), a biosafety level 4 (BSL4) Old World arenavirus, are not well characterized. LV pseudoparticles (LVpp) are a surrogate model system that has been used to decipher factors and routes involved in LV cell entry under BSL2 conditions. Here, we describe LVpp, which are highly infectious, with titers approaching those obtained with pseudoparticles displaying G protein of vesicular stomatitis virus and their the use for the characterization of LV cell entry and neutralization. Upon cell attachment, LVpp utilize endocytic vesicles for cell entry as described for many pH-dependent viruses. However, the fusion of the LV glycoproteins is activated at unusually low pH values, with optimal fusion occurring between pH 4.5 and 3, a pH range at which fusion characteristics of viral glycoproteins have so far remained largely unexplored. Consistent with a shifted pH optimum for fusion activation, we found wild-type LV and LVpp to display a remarkable resistance to exposure to low pH. Finally, LVpp allow the fast and quantifiable detection of neutralizing antibodies in human and animal sera and will thus facilitate the study of the humoral immune response in LV infections.Lassa virus (LV) is a negative-strand RNA virus and belongs to the family Arenaviridae, which comprises many important human pathogens such as Junin virus, Machupo virus, and the prototype arenavirus lymphocytic choriomeningitis virus (LCMV). LV virions are pleiomorphic enveloped particles ranging from 50 to 300 nm in diameter and encapsidate two segments of single-stranded RNA, both containing two genes encoded in an ambisense orientation. The glycoprotein (GP) precursor (GPC) is encoded by the smaller RNA, is posttranslationally cleaved into two subunits (GP1, which is responsible for cell attachment, and GP2, harboring transmembrane and fusogenicity determinants), and is essential for ␣-dystroglycan receptor recognition, cell entry, and the induction of neutralizing antibodies (7,8,22,30,41).The natural hosts of LV are rodents, and the transmission of the virus from its reservoir to humans causes approximately 150,000 cases of Lassa fever annually in West Africa, which vary in severity from mild influenza-like illness to lethal hemorrhagic fever (39). For Lassa fever, mortality is associated with a high viral load, and humoral immune responses are thought not to contribute to disease resolution, because neutralizing antibodies are generally detected in LV-infected patients only late in convalescence, and recombinant Lassa fever vaccines provide protection from lethal challenge in the absence of neutralizing antibodies (19,26). During acute infection, rapid viral dissemination critically depends on the efficient attachment of the viruses to receptor molecules on target cells and subsequent entry and replication (31). Investigations of cell entry of LV have so far been a difficult area of research due to the high pathogenicity and biosafety level 4 (BSL4) classification of the vir...

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Section: Biochemical and Electron Microscopic Characterization Ofsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 96%

Characterization of Lassa Virus Cell Entry and Neutralization with Lassa Virus Pseudoparticles

Cosset

Marianneau

Verney

et al. 2009

J Virol

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“…Two different cellular receptors have been described, ␣-dystroglycan for the Old World and New World clade C viruses (10,30,38) and transferrin receptor type 1 (TfR1) for the New World clade B viruses (35). Binding of GP1 to a receptor results in endocytosis of the viral particle, where exposure to low pH triggers a series of conformational changes in GP2 that lead to fusion (7,11,25).…”

mentioning

confidence: 99%

Substitutions in the Glycoprotein (GP) of the Candid#1 Vaccine Strain of Junin Virus Increase Dependence on Human Transferrin Receptor 1 for Entry and Destabilize the Metastable Conformation of GP

Droniou-Bonzom

Reignier

Oldenburg

et al. 2011

J Virol

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Candid#1 (Cd1) is an attenuated vaccine strain of Junin virus, the causative agent of Argentine hemorrhagic fever. Although several substitutions are present in Cd1, their importance for attenuation has not been established. We functionally characterized the substitutions present in the Cd1 glycoprotein (GP) and identified F427I in the transmembrane domain of the GP2 subunit as reducing infectivity in a reconstituted viral system. We further showed that this phenotype derives from the destabilization of the GP metastable conformation. Lastly, we identified an increased dependence of Cd1 GP on human transferrin receptor type 1 (hTfR-1) for entry, which may affect the tropism of the attenuated strain in vivo.

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“…Using lysosomotropic agents (NH4Cl, chloroquine, monensin) we [225], and others [213] documented that LASV infection was more resistant to pH increase in comparison to non-pathogenic MOPV. This is in line with findings that demonstrated a very low pH requirement for LASV fusion [218].…”

Section: Probing Lcmv-arm Versus Lcmv-we Infection With Inhibitor Drugsmentioning

confidence: 87%

“…The fusion of arenavirus proteins with cell-derived membranes is the last step of intracellular trafficking of the virus-containing vesicles. The low pHmediated fusion occurs in late endosomes/lysosomes and can be blocked by drugs raising pH in this sub-cellular compartment [225]. To assess LCMV strainspecific sensitivity to inhibitors blocking fusion with cell membrane, an established protocol was used to treat Vero cells with bafilomycin A1 to prevent acidification of the late endosomes [218].…”

Section: Probing Lcmv-arm Versus Lcmv-we Infection With Inhibitor Drugsmentioning

confidence: 99%

The involvement of epithelial cells in arenavirus-induced pathogenesis.

Warner¹

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Early events in arenavirus replication are sensitive to lysosomotropic compounds

Cited by 33 publications

References 8 publications

Characterization of Lassa Virus Cell Entry and Neutralization with Lassa Virus Pseudoparticles

Characterization of Lassa Virus Cell Entry and Neutralization with Lassa Virus Pseudoparticles

Substitutions in the Glycoprotein (GP) of the Candid#1 Vaccine Strain of Junin Virus Increase Dependence on Human Transferrin Receptor 1 for Entry and Destabilize the Metastable Conformation of GP

The involvement of epithelial cells in arenavirus-induced pathogenesis.

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