Editorial

5 pages, 208 KiB

Open AccessEditorial

Special Issue “Arenaviruses 2020”

by Igor S. Lukashevich and Juan Carlos de la Torre

Viruses 2021, 13(4), 703; https://doi.org/10.3390/v13040703 - 18 Apr 2021

Cited by 1 | Viewed by 3003

Rodent-borne arenaviruses have been traditionally predominantly associated with certain muroid species from Mastomys/Praomys genera (African arenaviruses) or with species that belong to murid subfamily Cricetidae (New World arenaviruses) [...] Full article

(This article belongs to the Special Issue Arenaviruses 2020)

Research

Jump to: Editorial, Review

15 pages, 2212 KiB

Open AccessArticle

Lassa Virus Vaccine Candidate ML29 Generates Truncated Viral RNAs Which Contribute to Interfering Activity and Attenuation

by Dylan M. Johnson, Beatrice Cubitt, Tia L. Pfeffer, Juan Carlos de la Torre and Igor S. Lukashevich

Viruses 2021, 13(2), 214; https://doi.org/10.3390/v13020214 - 30 Jan 2021

Cited by 11 | Viewed by 3257

Abstract

Defective interfering particles (DIPs) are naturally occurring products during virus replication in infected cells. DIPs contain defective viral genomes (DVGs) and interfere with replication and propagation of their corresponding standard viral genomes by competing for viral and cellular resources, as well as promoting [...] Read more.

Defective interfering particles (DIPs) are naturally occurring products during virus replication in infected cells. DIPs contain defective viral genomes (DVGs) and interfere with replication and propagation of their corresponding standard viral genomes by competing for viral and cellular resources, as well as promoting innate immune antiviral responses. Consequently, for many different viruses, including mammarenaviruses, DIPs play key roles in the outcome of infection. Due to their ability to broadly interfere with viral replication, DIPs are attractive tools for the development of a new generation of biologics to target genetically diverse and rapidly evolving viruses. Here, we provide evidence that in cells infected with the Lassa fever (LF) vaccine candidate ML29, a reassortant that carries the nucleoprotein (NP) and glycoprotein (GP) dominant antigens of the pathogenic Lassa virus (LASV) together with the L polymerase and Z matrix protein of the non-pathogenic genetically related Mopeia virus (MOPV), L-derived truncated RNA species are readily detected following infection at low multiplicity of infection (MOI) or in persistently-infected cells originally infected at high MOI. In the present study, we show that expression of green fluorescent protein (GFP) driven by a tri-segmented form of the mammarenavirus lymphocytic choriomeningitis virus (r3LCMV-GFP/GFP) was strongly inhibited in ML29-persistently infected cells, and that the magnitude of GFP suppression was dependent on the passage history of the ML29-persistently infected cells. In addition, we found that DIP-enriched ML29 was highly attenuated in immunocompetent CBA/J mice and in Hartley guinea pigs. Likewise, STAT-1^-/- mice, a validated small animal model for human LF associated hearing loss sequelae, infected with DIP-enriched ML29 did not exhibit any hearing abnormalities throughout the observation period (62 days). Full article

(This article belongs to the Special Issue Arenaviruses 2020)

► Show Figures

Figure 1

8 pages, 906 KiB

Open AccessArticle

A Sporadic and Lethal Lassa Fever Case in Forest Guinea, 2019

by N’Faly Magassouba, Enogo Koivogui, Sory Conde, Moussa Kone, Michel Koropogui, Barrè Soropogui, Ifono Kekoura, Julia Hinzmann, Stephan Günther, Sakoba Keita, Sophie Duraffour and Elisabeth Fichet-Calvet

Viruses 2020, 12(10), 1062; https://doi.org/10.3390/v12101062 - 23 Sep 2020

Cited by 7 | Viewed by 2482

Abstract

Lassa fever is a rodent-borne disease caused by Lassa virus (LASV). It causes fever, dizziness, vertigo, fatigue, coughing, diarrhea, internal bleeding and facial edema. The disease has been known in Guinea since 1960 but only anectodical acute cases have been reported to date. [...] Read more.

Lassa fever is a rodent-borne disease caused by Lassa virus (LASV). It causes fever, dizziness, vertigo, fatigue, coughing, diarrhea, internal bleeding and facial edema. The disease has been known in Guinea since 1960 but only anectodical acute cases have been reported to date. In January 2019, a 35-year-old man, a wood merchant from Kissidougou, Forest Guinea, presented himself at several health centers with persistent fever, frequent vomiting and joint pain. He was repeatedly treated for severe malaria, and died three weeks later in Mamou regional hospital. Differential diagnosis identified LASV as the cause of death. No secondary cases were reported. The complete LASV genome was obtained using next-generation sequencing. Phylogenetic analysis showed that this strain, namely the Kissidougou strain, belongs to the clade IV circulating in Guinea and Sierra Leone, and is thought to have emerged some 150 years ago. Due to the similarity of symptoms with malaria, Lassa fever is still a disease that is difficult to recognize and that may remain undiagnosed in health centers in Guinea. Full article

(This article belongs to the Special Issue Arenaviruses 2020)

► Show Figures

Figure 1

15 pages, 1950 KiB

Open AccessArticle

Effect of Strain Variations on Lassa Virus Z Protein-Mediated Human RIG-I Inhibition

by Qinfeng Huang, Xiaoying Liu, Morgan Brisse, Hinh Ly and Yuying Liang

Viruses 2020, 12(9), 907; https://doi.org/10.3390/v12090907 - 19 Aug 2020

Cited by 6 | Viewed by 2994

Abstract

Mammarenaviruses include several known human pathogens, such as the prototypic lymphocytic choriomeningitis virus (LCMV) that can cause neurological diseases and Lassa virus (LASV) that causes endemic hemorrhagic fever infection. LASV-infected patients show diverse clinical manifestations ranging from asymptomatic infection to hemorrhage, multi-organ failures [...] Read more.

Mammarenaviruses include several known human pathogens, such as the prototypic lymphocytic choriomeningitis virus (LCMV) that can cause neurological diseases and Lassa virus (LASV) that causes endemic hemorrhagic fever infection. LASV-infected patients show diverse clinical manifestations ranging from asymptomatic infection to hemorrhage, multi-organ failures and death, the mechanisms of which have not been well characterized. We have previously shown that the matrix protein Z of pathogenic arenaviruses, including LASV and LCMV, can strongly inhibit the ability of the innate immune protein RIG-I to suppress type I interferon (IFN-I) expression, which serves as a mechanism of viral immune evasion and virulence. Here, we show that Z proteins of diverse LASV isolates derived from rodents and humans have a high degree of sequence variations at their N- and C-terminal regions and produce variable degrees of inhibition of human RIG-I (hRIG-I) function in an established IFN-β promoter-driven luciferase (LUC) reporter assay. Additionally, we show that Z proteins of four known LCMV strains can also inhibit hRIG-I at variable degrees of efficiency. Collectively, our results confirm that Z proteins of pathogenic LASV and LCMV can inhibit hRIG-I and suggest that strain variations of the Z proteins can influence their efficiency to suppress host innate immunity that might contribute to viral virulence and disease heterogeneity. Full article

(This article belongs to the Special Issue Arenaviruses 2020)

► Show Figures

Figure 1

24 pages, 2511 KiB

Open AccessArticle

Analysis of the Function of the Lymphocytic Choriomeningitis Virus S Segment Untranslated Region on Growth Capacity In Vitro and on Virulence In Vivo

by Satoshi Taniguchi, Tomoki Yoshikawa, Masayuki Shimojima, Shuetsu Fukushi, Takeshi Kurosu, Hideki Tani, Aiko Fukuma, Fumihiro Kato, Eri Nakayama, Takahiro Maeki, Shigeru Tajima, Chang-Kweng Lim, Hideki Ebihara, Shigeru Kyuwa, Shigeru Morikawa and Masayuki Saijo

Viruses 2020, 12(8), 896; https://doi.org/10.3390/v12080896 - 16 Aug 2020

Cited by 5 | Viewed by 3493

Abstract

Lymphocytic choriomeningitis virus (LCMV) is a prototypic arenavirus. The function of untranslated regions (UTRs) of the LCMV genome has not been well studied except for the extreme 19 nucleotide residues of both the 5′ and 3′ termini. There are internal UTRs composed of [...] Read more.

Lymphocytic choriomeningitis virus (LCMV) is a prototypic arenavirus. The function of untranslated regions (UTRs) of the LCMV genome has not been well studied except for the extreme 19 nucleotide residues of both the 5′ and 3′ termini. There are internal UTRs composed of 58 and 41 nucleotide residues in the 5′ and 3′ UTRs, respectively, in the LCMV S segment. Their functional roles have yet to be elucidated. In this study, reverse genetics and minigenome systems were established for LCMV strain WE and the function of these regions were analyzed. It was revealed that nucleotides 20–40 and 20–38 located downstream of the 19 nucleotides in the 5′ and 3′ termini, respectively, were involved in viral genome replication and transcription. Furthermore, it was revealed that the other internal UTRs (nucleotides 41–77 and 39–60 in the 5′ and 3′ termini, respectively) in the S segment were involved in virulence in vivo, even though these regions did not affect viral growth capacity in Vero cells. The introduction of LCMV with mutations in these regions attenuates the virus and may enable the production of LCMV vaccine candidates. Full article

(This article belongs to the Special Issue Arenaviruses 2020)

► Show Figures

Figure 1

26 pages, 3547 KiB

Open AccessArticle

The Role of Receptor Tyrosine Kinases in Lassa Virus Cell Entry

by Chiara Fedeli, Hector Moreno and Stefan Kunz

Viruses 2020, 12(8), 857; https://doi.org/10.3390/v12080857 - 06 Aug 2020

Cited by 10 | Viewed by 3424

Abstract

The zoonotic Old World mammarenavirus Lassa (LASV) causes severe hemorrhagic fever with high mortality and morbidity in humans in endemic regions. The development of effective strategies to combat LASV infections is of high priority, given the lack of a licensed vaccine and restriction [...] Read more.

The zoonotic Old World mammarenavirus Lassa (LASV) causes severe hemorrhagic fever with high mortality and morbidity in humans in endemic regions. The development of effective strategies to combat LASV infections is of high priority, given the lack of a licensed vaccine and restriction on available treatment to off-label use of ribavirin. A better understanding of the fundamental aspects of the virus’s life cycle would help to improve the development of novel therapeutic approaches. Host cell entry and restriction factors represent major barriers for emerging viruses and are promising targets for therapeutic intervention. In addition to the LASV main receptor, the extracellular matrix molecule dystroglycan (DG), the phosphatidylserine-binding receptors of the Tyro3/Axl/Mer (TAM), and T cell immunoglobulin and mucin receptor (TIM) families are potential alternative receptors of LASV infection. Therefore, the relative contributions of candidate receptors to LASV entry into a particular human cell type are a complex function of receptor expression and functional DG availability. Here, we describe the role of two receptor tyrosine kinases (RTKs), Axl and hepatocyte growth factor receptor (HGFR), in the presence and absence of glycosylated DG for LASV entry. We found that both RTKs participated in the macropinocytosis-related LASV entry and, regardless of the presence or absence of functional DG, their inhibition resulted in a significant antiviral effect. Full article

(This article belongs to the Special Issue Arenaviruses 2020)

► Show Figures

Figure 1

19 pages, 3241 KiB

Open AccessArticle

Novel Dihydroorotate Dehydrogenase Inhibitors with Potent Interferon-Independent Antiviral Activity against Mammarenaviruses In Vitro

by Yu-Jin Kim, Beatrice Cubitt, Yingyun Cai, Jens H. Kuhn, Daniel Vitt, Hella Kohlhof and Juan C. de la Torre

Viruses 2020, 12(8), 821; https://doi.org/10.3390/v12080821 - 29 Jul 2020

Cited by 8 | Viewed by 2963

Abstract

Mammarenaviruses cause chronic infections in rodents, which are their predominant natural hosts. Human infection with some of these viruses causes high-consequence disease, posing significant issues in public health. Currently, no FDA-licensed mammarenavirus vaccines are available, and anti-mammarenavirus drugs are limited to an off-label [...] Read more.

Mammarenaviruses cause chronic infections in rodents, which are their predominant natural hosts. Human infection with some of these viruses causes high-consequence disease, posing significant issues in public health. Currently, no FDA-licensed mammarenavirus vaccines are available, and anti-mammarenavirus drugs are limited to an off-label use of ribavirin, which is only partially efficacious and associated with severe side effects. Dihydroorotate dehydrogenase (DHODH) inhibitors, which block de novo pyrimidine biosynthesis, have antiviral activity against viruses from different families, including Arenaviridae, the taxonomic home of mammarenaviruses. Here, we evaluate five novel DHODH inhibitors for their antiviral activity against mammarenaviruses. All tested DHODH inhibitors were potently active against lymphocytic choriomeningitis virus (LCMV) (half-maximal effective concentrations [EC₅₀] in the low nanomolar range, selectivity index [SI] > 1000). The tested DHODH inhibitors did not affect virion cell entry or budding, but rather interfered with viral RNA synthesis. This interference resulted in a potent interferon-independent inhibition of mammarenavirus multiplication in vitro, including the highly virulent Lassa and Junín viruses. Full article

(This article belongs to the Special Issue Arenaviruses 2020)

► Show Figures

Figure 1

12 pages, 2105 KiB

Open AccessArticle

Acidic pH Triggers Lipid Mixing Mediated by Lassa Virus GP

by Uriel Bulow, Ramesh Govindan and James B. Munro

Viruses 2020, 12(7), 716; https://doi.org/10.3390/v12070716 - 02 Jul 2020

Cited by 10 | Viewed by 3045

Abstract

Lassa virus (LASV) is the causative agent of Lassa hemorrhagic fever, a lethal disease endemic to Western Africa. LASV entry is mediated by the viral envelope glycoprotein (GP), a class I membrane fusogen and the sole viral surface antigen. Previous studies have identified [...] Read more.

Lassa virus (LASV) is the causative agent of Lassa hemorrhagic fever, a lethal disease endemic to Western Africa. LASV entry is mediated by the viral envelope glycoprotein (GP), a class I membrane fusogen and the sole viral surface antigen. Previous studies have identified components of the LASV entry pathway, including several cellular receptors and the requirement of endosomal acidification for infection. Here, we first demonstrate that incubation at a physiological temperature and pH consistent with the late endosome is sufficient to render pseudovirions, bearing LASV GP, non-infectious. Antibody binding indicates that this loss of infectivity is due to a conformational change in GP. Finally, we developed a single-particle fluorescence assay to directly visualize individual pseudovirions undergoing LASV GP-mediated lipid mixing with a supported planar bilayer. We report that exposure to endosomal pH at a physiologic temperature is sufficient to trigger GP-mediated lipid mixing. Furthermore, while a cellular receptor is not necessary to trigger lipid mixing, the presence of lysosomal-associated membrane protein 1 (LAMP1) increases the kinetics of lipid mixing at an endosomal pH. Furthermore, we find that LAMP1 permits robust lipid mixing under less acidic conditions than in its absence. These findings clarify our understanding of LASV GP-mediated fusion and the role of LAMP1 binding. Full article

(This article belongs to the Special Issue Arenaviruses 2020)

► Show Figures

Figure 1

20 pages, 4443 KiB

Open AccessArticle

Natural History of Aerosol Induced Lassa Fever in Non-Human Primates

by Isaac L. Downs, Carl I. Shaia, Xiankun Zeng, Joshua C. Johnson, Lisa Hensley, David L. Saunders, Franco Rossi, Kathleen A. Cashman, Heather L. Esham, Melissa K. Gregory, William D. Pratt, John C. Trefry, Kyle A. Everson, Charles B. Larcom, Arthur C. Okwesili, Anthony P. Cardile and Anna Honko

Viruses 2020, 12(6), 593; https://doi.org/10.3390/v12060593 - 29 May 2020

Cited by 12 | Viewed by 2924

Abstract

Lassa virus (LASV), an arenavirus causing Lassa fever, is endemic to West Africa with up to 300,000 cases and between 5000 and 10,000 deaths per year. Rarely seen in the United States, Lassa virus is a CDC category A biological agent inasmuch deliberate [...] Read more.

Lassa virus (LASV), an arenavirus causing Lassa fever, is endemic to West Africa with up to 300,000 cases and between 5000 and 10,000 deaths per year. Rarely seen in the United States, Lassa virus is a CDC category A biological agent inasmuch deliberate aerosol exposure can have high mortality rates compared to naturally acquired infection. With the need for an animal model, specific countermeasures remain elusive as there is no FDA-approved vaccine. This natural history of aerosolized Lassa virus exposure in Macaca fascicularis was studied under continuous telemetric surveillance. The macaque response to challenge was largely analogous to severe human disease with fever, tachycardia, hypotension, and tachypnea. During initial observations, an increase trend of activated monocytes positive for viral glycoprotein was accompanied by lymphocytopenia. Disease uniformly progressed to high viremia followed by low anion gap, alkalosis, anemia, and thrombocytopenia. Hypoproteinemia occurred late in infection followed by increased levels of white blood cells, cytokines, chemokines, and biochemical markers of liver injury. Viral nucleic acids were detected in tissues of three non-survivors at endpoint, but not in the lone survivor. This study provides useful details to benchmark a pivotal model of Lassa fever in support of medical countermeasure development for both endemic disease and traditional biodefense purposes. Full article

(This article belongs to the Special Issue Arenaviruses 2020)

► Show Figures

Figure 1

14 pages, 594 KiB

Open AccessArticle

Population Structure of Lassa Mammarenavirus in West Africa

by Diego Forni and Manuela Sironi

Viruses 2020, 12(4), 437; https://doi.org/10.3390/v12040437 - 13 Apr 2020

Cited by 8 | Viewed by 3163

Abstract

Lassa mammarenavirus (LASV) is the etiologic agent of Lassa fever. In endemic regions in West Africa, LASV genetic diversity tends to cluster by geographic area. Seven LASV lineages are recognized, but the role of viral genetic determinants on disease presentation in humans is [...] Read more.

Lassa mammarenavirus (LASV) is the etiologic agent of Lassa fever. In endemic regions in West Africa, LASV genetic diversity tends to cluster by geographic area. Seven LASV lineages are recognized, but the role of viral genetic determinants on disease presentation in humans is uncertain. We investigated the geographic structure and distribution of LASV in West Africa. We found strong spatial clustering of LASV populations, with two major east–west and north–south diversity gradients. Analysis of ancestry components indicated that known LASV lineages diverged from an ancestral population that most likely circulated in Nigeria, although alternative locations, such as Togo, cannot be excluded. Extant sequences carrying the largest contribution of this ancestral population include the prototype Pinneo strain, the Togo isolates, and a few viruses isolated in Nigeria. The LASV populations that experienced the strongest drift circulate in Mali and the Ivory Coast. By focusing on sequences form a single LASV sublineage (IIg), we identified an ancestry component possibly associated with protection from a fatal disease outcome. Although the same ancestry component tends to associate with lower viral loads in plasma, the small sample size requires that these results are treated with extreme caution. Full article

(This article belongs to the Special Issue Arenaviruses 2020)

► Show Figures

Figure 1

Review

Jump to: Editorial, Research

29 pages, 4010 KiB

Open AccessReview

Distinct Molecular Mechanisms of Host Immune Response Modulation by Arenavirus NP and Z Proteins

by Robert J. Stott, Thomas Strecker and Toshana L. Foster

Viruses 2020, 12(7), 784; https://doi.org/10.3390/v12070784 - 21 Jul 2020

Cited by 7 | Viewed by 5279

Abstract

Endemic to West Africa and South America, mammalian arenaviruses can cross the species barrier from their natural rodent hosts to humans, resulting in illnesses ranging from mild flu-like syndromes to severe and fatal haemorrhagic zoonoses. The increased frequency of outbreaks and associated high [...] Read more.

Endemic to West Africa and South America, mammalian arenaviruses can cross the species barrier from their natural rodent hosts to humans, resulting in illnesses ranging from mild flu-like syndromes to severe and fatal haemorrhagic zoonoses. The increased frequency of outbreaks and associated high fatality rates of the most prevalent arenavirus, Lassa, in West African countries, highlights the significant risk to public health and to the socio-economic development of affected countries. The devastating impact of these viruses is further exacerbated by the lack of approved vaccines and effective treatments. Differential immune responses to arenavirus infections that can lead to either clearance or rapid, widespread and uncontrolled viral dissemination are modulated by the arenavirus multifunctional proteins, NP and Z. These two proteins control the antiviral response to infection by targeting multiple cellular pathways; and thus, represent attractive targets for antiviral development to counteract infection. The interplay between the host immune responses and viral replication is a key determinant of virus pathogenicity and disease outcome. In this review, we examine the current understanding of host immune defenses against arenavirus infections and summarise the host protein interactions of NP and Z and the mechanisms that govern immune evasion strategies. Full article

(This article belongs to the Special Issue Arenaviruses 2020)

► Show Figures

Figure 1

20 pages, 1367 KiB

Open AccessReview

Inter-Lineage Variation of Lassa Virus Glycoprotein Epitopes: A Challenge to Lassa Virus Vaccine Development

by Francis Ifedayo Ibukun

Viruses 2020, 12(4), 386; https://doi.org/10.3390/v12040386 - 31 Mar 2020

Cited by 22 | Viewed by 4077

Abstract

Lassa virus (LASV), which causes considerable morbidity and mortality annually, has a high genetic diversity across West Africa. LASV glycoprotein (GP) expresses this diversity, but most LASV vaccine candidates utilize only the Lineage IV LASV Josiah strain GP antigen as an immunogen and [...] Read more.

Lassa virus (LASV), which causes considerable morbidity and mortality annually, has a high genetic diversity across West Africa. LASV glycoprotein (GP) expresses this diversity, but most LASV vaccine candidates utilize only the Lineage IV LASV Josiah strain GP antigen as an immunogen and homologous challenge with Lineage IV LASV. In addition to the sequence variation amongst the LASV lineages, these lineages are also distinguished in their presentations. Inter-lineage variations within previously mapped B-cell and T-cell LASV GP epitopes and the breadth of protection in LASV vaccine/challenge studies were examined critically. Multiple alignments of the GP primary sequence of strains from each LASV lineage showed that LASV GP has diverging degrees of amino acid conservation within known epitopes among LASV lineages. Conformational B-cell epitopes spanning different sites in GP subunits were less impacted by LASV diversity. LASV GP diversity should influence the approach used for LASV vaccine design. Expression of LASV GP on viral vectors, especially in its prefusion configuration, has shown potential for protective LASV vaccines that can overcome LASV diversity. Advanced vaccine candidates should demonstrate efficacy against all LASV lineages for evidence of a pan-LASV vaccine. Full article

(This article belongs to the Special Issue Arenaviruses 2020)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Arenaviruses 2020

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (12 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI