scholarly journals Molecular Interaction and Inhibitory Activity of Dandelion’s Compounds on Nucleoprotein: A Therapeutic Intervention in Lassa Fever

2021 ◽  
Vol 11 (5) ◽  
pp. 12573-12583
Keyword(s):  
Hemorrhagic Fever ◽  
Inhibitory Effect ◽  
Lassa Fever ◽  
Vital Role ◽  
Lassa Virus ◽  
Induced Fit Docking ◽  
Reference Drug ◽  
Public Health Challenge ◽  
Hit Identification ◽  
Effective Drugs

Lassa fever (LF) is an acute and sometimes fatal viral hemorrhagic fever caused by the Lassa virus (LASV). It is a major public health challenge and endemic exclusively in West Africa. Despite the large toll of human morbidity and mortality, no vaccine or effective drugs are available to treat this disease. Therefore, there is an urgent need for the development of novel and effective treatments and therapeutics. LASV nucleoprotein plays a vital role in several aspects of the viral life cycle. Therefore, an effective inhibitor of LASV nucleoprotein will potentially control the replication of LASV. To evaluate the inhibitory effect of Dandelion phyto-compounds on LASV nucleoprotein, Glide-SP, and –XP docking was performed for hit identification. The hit compounds were further subjected to Induced Fit Docking (IFD) followed by Prime MM-GBSA calculation and ADME studies. Dandelion phyto-compounds, carfentrazone, luteolin, caffeic acid, and riboflavin recorded better binding affinity than the reference drug, ribavirin, and interacted with key amino acids residues. ADME studies also showed that our hit compounds are drug-like. This study showed that phyto-compounds of dandelion could be a better and effective therapeutics in LF treatment.

scholarly journals Lassa Virus Circulation in Small Mammal Populations in Bo District, Sierra Leone

Biology ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 28
Author(s):  
Umaru Bangura ◽  
Jacob Buanie ◽  
Joyce Lamin ◽  
Christopher Davis ◽  
Gédéon Ngiala Bongo ◽  
...  
Keyword(s):  
Phylogenetic Analysis ◽  
Sierra Leone ◽  
Small Mammal ◽  
Hemorrhagic Fever ◽  
Lassa Fever ◽  
Lassa Virus ◽  
Sierra Leonean ◽  
Bayesian Phylogenetic Analysis ◽  
Prevalent Species ◽  
Lineage Iv

Lassa fever is a viral hemorrhagic fever caused by the Lassa virus LASV, which was first isolated in the rodent Mastomys natalensis in 1974 in Kenema, Sierra Leone. As little is known about the abundance and the presence of LASV in rodents living in the Bo area, we carried out a small mammal longitudinal population survey. A standardized trapping session was performed in various habitats and seasons in six villages over two years (2014–2016) and samples collected were tested for arenavirus IgG and LASV. A Bayesian phylogenetic analysis was performed on sequences identified by PCR. A total of 1490 small mammals were collected, and 16 rodent species were identified, with M. natalensis (355, 24%) found to be the most prevalent species. Forty-one (2.8%) samples were IgG positive, and 31 of these were trapped in homes and 10 in surrounding vegetation. Twenty-nine of 41 seropositive rodents were M. natalensis. We detected four LASV by PCR in two villages, all found in M. natalensis. Phylogenetic analysis showed that the sequences were distributed within the Sierra Leonean clade within lineage IV, distinguishing a Bo sub-clade older than a Kenema sub-clade. Compared to other settings, we found a low abundance of M. natalensis and a low circulation of LASV in rodents in villages around Bo district.

scholarly journals Differential Immune Responses to Hemorrhagic Fever-Causing Arenaviruses

Vaccines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 138 ◽  
Author(s):  
Mantlo ◽  
Paessler ◽  
Huang
Keyword(s):  
Clinical Importance ◽  
Hemorrhagic Fever ◽  
Lassa Fever ◽  
Innate Immune ◽  
Host Immune System ◽  
Lassa Virus ◽  
Type I ◽  
Highly Pathogenic ◽  
The Family ◽  
Pro Inflammatory Cytokines

The family Arenaviridae contains several pathogens of major clinical importance. The Old World (OW) arenavirus Lassa virus is endemic in West Africa and is estimated to cause up to 300,000 infections each year. The New World (NW) arenaviruses Junín and Machupo periodically cause hemorrhagic fever outbreaks in South America. While these arenaviruses are highly pathogenic in humans, recent evidence indicates that pathogenic OW and NW arenaviruses interact with the host immune system differently, which may have differential impacts on viral pathogenesis. Severe Lassa fever cases are characterized by profound immunosuppression. In contrast, pathogenic NW arenavirus infections are accompanied by elevated levels of Type I interferon and pro-inflammatory cytokines. This review aims to summarize recent findings about interactions of these pathogenic arenaviruses with the innate immune machinery and the subsequent effects on adaptive immunity, which may inform the development of vaccines and therapeutics against arenavirus infections.

scholarly journals Phylogeography of Lassa Virus in Nigeria

2019 ◽  
Vol 93 (21) ◽  
Author(s):  
Deborah U. Ehichioya ◽  
Simon Dellicour ◽  
Meike Pahlmann ◽  
Toni Rieger ◽  
Lisa Oestereich ◽  
...  
Keyword(s):  
West Africa ◽  
Case Fatality ◽  
Hemorrhagic Fever ◽  
Lassa Fever ◽  
Future Research ◽  
Lassa Virus ◽  
Southeastern Part ◽  
Data Set ◽  
Content Type ◽  
Virus Strains

ABSTRACT Lassa virus is genetically diverse with several lineages circulating in West Africa. This study aimed at describing the sequence variability of Lassa virus across Nigeria and inferring its spatiotemporal evolution. We sequenced and isolated 77 Lassa virus strains from 16 Nigerian states. The final data set, including previous works, comprised metadata and sequences of 219 unique strains sampled between 1969 and 2018 in 22 states. Most of this data originated from Lassa fever patients diagnosed at Irrua Specialist Teaching Hospital, Edo State, Nigeria. The majority of sequences clustered with the main Nigerian lineages II and III, while a few sequences formed a new cluster related to Lassa virus strains from Hylomyscus pamfi. Within lineages II and III, seven and five sublineages, respectively, were distinguishable. Phylogeographic analysis suggests an origin of lineage II in the southeastern part of the country around Ebonyi State and a main vector of dispersal toward the west across the Niger River, through Anambra, Kogi, Delta, and Edo into Ondo State. The frontline of virus dispersal appears to be in Ondo. Minor vectors are directed northeast toward Taraba and Adamawa and south toward Imo and Rivers. Lineage III might have spread from northern Plateau State into Kaduna, Nasarawa, Federal Capital Territory, and Bauchi. One sublineage moved south and crossed the Benue River into Benue State. This study provides a geographic mapping of lineages and phylogenetic clusters in Nigeria at a higher resolution. In addition, we estimated the direction and time frame of virus dispersal in the country. IMPORTANCE Lassa virus is the causative agent of Lassa fever, a viral hemorrhagic fever with a case fatality rate of approximately 30% in Africa. Previous studies disclosed a geographical pattern in the distribution of Lassa virus strains and a westward movement of the virus across West Africa during evolution. Our study provides a deeper understanding of the geography of genetic lineages and sublineages of the virus in Nigeria. In addition, we modeled how the virus spread in the country. This knowledge allows us to predict into which geographical areas the virus might spread in the future and prioritize areas for Lassa fever surveillance. Our study not only aimed to generate Lassa virus sequences from across Nigeria but also to isolate and conserve the respective viruses for future research. Both isolates and sequences are important for the development and evaluation of medical countermeasures to treat and prevent Lassa fever, such as diagnostics, therapeutics, and vaccines.

scholarly journals 25-Hydroxycholesterol Inhibition of Lassa Virus Infection through Aberrant GP1 Glycosylation

mBio ◽  
2016 ◽  
Vol 7 (6) ◽  
Author(s):  
Punya Shrivastava-Ranjan ◽  
Éric Bergeron ◽  
Ayan K. Chakrabarti ◽  
César G. Albariño ◽  
Mike Flint ◽  
...  
Keyword(s):  
Cholesterol Biosynthesis ◽  
Hemorrhagic Fever ◽  
Lassa Fever ◽  
Health Concern ◽  
Virus Infectivity ◽  
Lassa Virus ◽  
Critical Feature ◽  
Course Of Illness ◽  
Enveloped Virus ◽  
Alpha Dystroglycan

ABSTRACT Lassa virus (LASV) infection is a major public health concern due to high fatality rates and limited effective treatment. The interferon-stimulated gene cholesterol 25-hydroxylase ( CH25H ) encodes an enzyme that catalyzes the production of 25-hydroxycholesterol (25HC). 25HC is involved in regulating cholesterol biosynthesis and has recently been identified as a potent antiviral targeting enveloped virus entry. Here, we show a previously unrecognized role of CH25H in inhibiting LASV glycoprotein glycosylation and the production of infectious virus. Overexpression of CH25H or treatment with 25HC decreased LASV G1 glycoprotein N -glycan maturation and reduced the production of infectious LASV. Depletion of endogenous CH25H using small interfering RNA (siRNA) enhanced the levels of fully glycosylated G1 and increased infectious LASV production. Finally, LASV particles produced from 25HC-treated cells were found to be less infectious, to incorporate aberrantly glycosylated GP1 species, and to be defective in binding alpha-dystroglycan, an attachment and entry receptor. Our findings identify a novel role for CH25H in controlling LASV propagation and indicate that manipulation of the expression of CH25H or the administration of 25HC may be a useful anti-LASV therapy. IMPORTANCE Lassa fever is an acute viral hemorrhagic fever in humans caused by Lassa virus (LASV). No vaccine for LASV is currently available. Treatment is limited to the administration of ribavirin, which is only effective when given early in the course of illness. Cholesterol 25-hydroxylase ( CH25H ) is a recently identified interferon-stimulated gene (ISG); it encodes an enzyme that catalyzes the production of 25-hydroxycholesterol (25HC), which inhibits several viruses. Here, we identify a novel antiviral mechanism of 25HC that is dependent on inhibiting the glycosylation of Lassa virus (LASV) glycoprotein and reducing the infectivity of LASV as a means of suppressing viral replication. Since N-linked glycosylation is a critical feature of other enveloped-virus glycoproteins, 25HC may be a broad inhibitor of virus infectivity.

scholarly journals Systemic viral spreading and defective host responses are associated with fatal Lassa fever in macaques

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Nicolas Baillet ◽  
Stéphanie Reynard ◽  
Emeline Perthame ◽  
Jimmy Hortion ◽  
Alexandra Journeaux ◽  
...  
Keyword(s):  
T Cell ◽  
Multiorgan Failure ◽  
Severe Disease ◽  
T Cell Responses ◽  
Hemorrhagic Fever ◽  
Lassa Fever ◽  
Diagnostic Tools ◽  
Lassa Virus ◽  
Full Characterization ◽  
Cell Responses

AbstractLassa virus (LASV) is endemic in West Africa and induces a viral hemorrhagic fever (VHF) with up to 30% lethality among clinical cases. The mechanisms involved in control of Lassa fever or, in contrast, the ensuing catastrophic illness and death are poorly understood. We used the cynomolgus monkey model to reproduce the human disease with asymptomatic to mild or fatal disease. After initial replication at the inoculation site, LASV reached the secondary lymphoid organs. LASV did not spread further in nonfatal disease and was rapidly controlled by balanced innate and T-cell responses. Systemic viral dissemination occurred during severe disease. Massive replication, a cytokine/chemokine storm, defective T-cell responses, and multiorgan failure were observed. Clinical, biological, immunological, and transcriptomic parameters resembled those observed during septic-shock syndrome, suggesting that similar pathogenesis is induced during Lassa fever. The outcome appears to be determined early, as differentially expressed genes in PBMCs were associated with fatal and non-fatal Lassa fever outcome very early after infection. These results provide a full characterization and important insights into Lassa fever pathogenesis and could help to develop early diagnostic tools.

scholarly journals The Janus Kinase Inhibitor Ruxolitinib Prevents Terminal Shock in a Mouse Model of Arenavirus Hemorrhagic Fever

2021 ◽  
Vol 9 (3) ◽  
pp. 564
Author(s):  
Mehmet Sahin ◽  
Melissa M. Remy ◽  
Doron Merkler ◽  
Daniel D. Pinschewer
Keyword(s):  
Kinase Inhibitor ◽  
Antibody Therapy ◽  
Hemorrhagic Fever ◽  
Lassa Fever ◽  
Lymphocytic Choriomeningitis ◽  
Janus Kinase ◽  
Lassa Virus ◽  
Jak Inhibitor ◽  
Medical Needs ◽  
Ifn Γ

Arenaviruses such as Lassa virus cause arenavirus hemorrhagic fever (AVHF), but protective vaccines and effective antiviral therapy remain unmet medical needs. Our prior work has revealed that inducible nitric oxide synthase (iNOS) induction by IFN-γ represents a key pathway to microvascular leak and terminal shock in AVHF. Here we hypothesized that Ruxolitinib, an FDA-approved JAK inhibitor known to prevent IFN-γ signaling, could be repurposed for host-directed therapy in AVHF. We tested the efficacy of Ruxolitinib in MHC-humanized (HHD) mice, which develop Lassa fever-like disease upon infection with the monkey-pathogenic lymphocytic choriomeningitis virus strain WE. Anti-TNF antibody therapy was tested as an alternative strategy owing to its expected effect on macrophage activation. Ruxolitinib but not anti-TNF antibody prevented hypothermia and terminal disease as well as pleural effusions and skin edema, which served as readouts of microvascular leak. As expected, neither treatment influenced viral loads. Intriguingly, however, and despite its potent disease-modifying activity, Ruxolitinib did not measurably interfere with iNOS expression or systemic NO metabolite levels. These findings suggest that the FDA-approved JAK-inhibitor Ruxolitinib has potential in the treatment of AVHF. Moreover, our observations indicate that besides IFN-γ-induced iNOS additional druggable pathways contribute essentially to AVHF and are amenable to host-directed therapy.

scholarly journals Predicting the evolution of Lassa Virus endemic area and population at risk over the next decades

2021 ◽  
Author(s):  
Raphaëlle Klitting ◽  
Liana E. Kafetzopoulou ◽  
Wim Thiery ◽  
Gytis Dudas ◽  
Sophie Gryseels ◽  
...  
Keyword(s):  
At Risk ◽  
West Africa ◽  
Endemic Area ◽  
Hemorrhagic Fever ◽  
Lassa Fever ◽  
Environmental Data ◽  
World Health ◽  
Lassa Virus ◽  
Viral Genomes ◽  
Health Organization

AbstractLassa fever is listed among the diseases that pose the greatest risks to public health by the World Health Organization. This severe viral hemorrhagic fever is caused by Lassa virus, a zoonotic pathogen that repeatedly spills over to humans from its rodent reservoirs. It is currently not known how climate change, transformations in land use, and human population growth could affect the endemic area of this virus, currently limited to parts of West Africa. By exploring the environmental data associated with virus occurrence, we show how temperature, precipitation and the presence of pastures determine ecological suitability for virus circulation. We project that regions in Central and East Africa will likely become suitable for Lassa virus over the next decades and estimate that the total population living in areas suitable for Lassa virus may grow from about 100 million to 700 million by 2070. By analysing geotagged viral genomes, we find that in the event of Lassa virus being introduced into a new suitable region, its spread might remain spatially limited over the first decades. Our results highlight how the endemic area of Lassa virus may expand well beyond West Africa in the next decades due to human impact on the environment, putting hundreds of million more people at risk of infection.

scholarly journals Delayed Inflammatory and Cell Death Responses Are Associated with Reduced Pathogenicity in Lujo Virus-Infected Cynomolgus Macaques

2014 ◽  
Vol 89 (5) ◽  
pp. 2543-2552 ◽  
Author(s):  
Angela L. Rasmussen ◽  
Nicolas Tchitchek ◽  
David Safronetz ◽  
Victoria S. Carter ◽  
Christopher M. Williams ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Disease Severity ◽  
Molecular Mechanisms ◽  
Hemorrhagic Fever ◽  
Lassa Fever ◽  
Host Responses ◽  
Severe Illness ◽  
Lassa Virus ◽  
Cynomolgus Macaques

ABSTRACTTo identify host factors associated with arenavirus virulence, we used a cynomolgus macaque model to evaluate the pathogenesis of Lujo virus (LUJV), a recently emerged arenavirus that caused an outbreak of severe viral hemorrhagic fever in southern Africa. In contrast to human cases, LUJV caused mild, nonlethal illness in macaques. We then compared this to contrasting clinical outcomes during arenavirus infection, specifically to samples obtained from macaques infected with three highly pathogenic lines of Lassa virus (LASV), the causative agent of Lassa fever (LF). We assessed gene expression in peripheral blood mononuclear cells (PBMC) and determined genes that significantly changed expression relative to that in uninfected animals over the course of infection. We detected a 72-h delay in the induction of host responses to infection during LUJV infection compared to that of the animals infected with LASV. This included genes associated with inflammatory and antiviral responses and was particularly apparent among groups of genes promoting cell death. We also observed early differential expression of a subset of genes specific to LUJV infection that accounts for the delayed inflammatory response. Cell type enrichment analysis suggested that host response induction delay and an LUJV-specific profile are due to a different proportion of natural killer cells responding in LUJV infection than that in the LASV-infected animals. Together, these data indicate that delayed proinflammatory and proapoptotic host responses to arenavirus infection could ameliorate disease severity. This conclusion provides insight into the cellular and molecular mechanisms of arenaviral hemorrhagic fever and suggests potential strategies for therapeutic development.IMPORTANCEOld World arenaviruses are significant human pathogens that often are associated with high mortality. However, mechanisms underlying disease severity and virulence in arenavirus hemorrhagic fever are largely unknown, particularly regarding host responses that contribute to pathogenicity. This study describes a comparison between Lujo and Lassa virus infection in cynomolgus macaques. Lujo virus-infected macaques developed only mild illness, while Lassa virus-infected macaques developed severe illness consistent with Lassa fever. We determined that mild disease is associated with a delay in host expression of genes linked to virulence, such as those causing inflammation and cell death, and with distinct cell types that may mediate this delay. This is the first study to associate the timing and directionality of gene expression with arenaviral pathogenicity and disease outcome and evokes new potential approaches for developing effective therapeutics for treating these deadly emerging pathogens.

scholarly journals Human Macrophages, but Not Dendritic Cells, Are Activated and Produce Alpha/Beta Interferons in Response to Mopeia Virus Infection

2004 ◽  
Vol 78 (19) ◽  
pp. 10516-10524 ◽  
Author(s):  
Delphine Pannetier ◽  
Caroline Faure ◽  
Marie-Claude Georges-Courbot ◽  
Vincent Deubel ◽  
Sylvain Baize
Keyword(s):  
Dendritic Cells ◽  
Adaptive Immune Response ◽  
Hemorrhagic Fever ◽  
Surface Expression ◽  
Lassa Fever ◽  
Lassa Virus ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
The Difference ◽  
Antigen Presenting

ABSTRACT Lassa virus (LV) and Mopeia virus (MV) are closely related members of the Arenavirus genus, sharing 75% amino acid sequence identity. However, LV causes hemorrhagic fever in humans and nonhuman primates, whereas MV cannot induce disease. We have previously shown that antigen-presenting cells (APC)—macrophages (MP) and dendritic cells (DC)—sustain high replication rates of LV but are not activated, suggesting that they play a role in the immunosuppression observed in severe cases of Lassa fever. Here, we infected human APC with MV and analyzed the cellular responses induced. MV infection was productive in MP and even more so in DC. Apoptosis was not induced in either cell type. Moreover, unlike DC, MP were early and strongly activated in response to MV, as shown by the increased surface expression of CD86, CD80, CD54, CD40, and HLA-abc and by the production of mRNA encoding alpha interferon (IFN-α), IFN-β, tumor necrosis factor alpha and interleukin-6. In addition, MV-infected MP produced less of the virus than DC, which was related to the fact that these cells secreted IFN-α. Thus, the strong activation of MP is probably a major event in the control of MV infection and may be involved in the induction of an adaptive immune response in infected hosts. These results may explain the difference in pathogenicity between LV and MV.

scholarly journals E3 Ligase ITCH Interacts with the Z Matrix Protein of Lassa and Mopeia Viruses and Is Required for the Release of Infectious Particles

Viruses ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 49 ◽  
Author(s):  
Nicolas Baillet ◽  
Sophie Krieger ◽  
Xavier Carnec ◽  
Mathieu Mateo ◽  
Alexandra Journeaux ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Matrix Protein ◽  
Virus Assembly ◽  
Hemorrhagic Fever ◽  
Lassa Fever ◽  
Lymphocytic Choriomeningitis ◽  
Lassa Virus ◽  
Yeast Two Hybrid ◽  
Ubiquitin Ligase Activity ◽  
Two Hybrid

Lassa virus (LASV) and Mopeia virus (MOPV) are two closely related, rodent-born mammarenaviruses. LASV is the causative agent of Lassa fever, a deadly hemorrhagic fever endemic in West Africa, whereas MOPV is non-pathogenic in humans. The Z matrix protein of arenaviruses is essential to virus assembly and budding by recruiting host factors, a mechanism that remains partially defined. To better characterize the interactions involved, a yeast two-hybrid screen was conducted using the Z proteins from LASV and MOPV as a bait. The cellular proteins ITCH and WWP1, two members of the Nedd4 family of HECT E3 ubiquitin ligases, were found to bind the Z proteins of LASV, MOPV and other arenaviruses. The PPxY late-domain motif of the Z proteins is required for the interaction with ITCH, although the E3 ubiquitin-ligase activity of ITCH is not involved in Z ubiquitination. The silencing of ITCH was shown to affect the replication of the old-world mammarenaviruses LASV, MOPV, Lymphocytic choriomeningitis virus (LCMV) and to a lesser extent Lujo virus (LUJV). More precisely, ITCH was involved in the egress of virus-like particles and the release of infectious progeny viruses. Thus, ITCH constitutes a novel interactor of LASV and MOPV Z proteins that is involved in virus assembly and release.

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