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

Viruses ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 907
Author(s):  
Qinfeng Huang ◽  
Xiaoying Liu ◽  
Morgan Brisse ◽  
Hinh Ly ◽  
Yuying Liang
Keyword(s):  
Matrix Protein ◽  
Neurological Diseases ◽  
Clinical Manifestations ◽  
Hemorrhagic Fever ◽  
Lassa Virus ◽  
Type I ◽  
Human Pathogens ◽  
Protein Z ◽  
Disease Heterogeneity ◽  
Viral Virulence

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.

scholarly journals Crystal Structure of the Oligomeric Form of Lassa Virus Matrix Protein Z

2016 ◽  
Vol 90 (9) ◽  
pp. 4556-4562 ◽  
Author(s):  
Kathryn M. Hastie ◽  
Michelle Zandonatti ◽  
Tong Liu ◽  
Sheng Li ◽  
Virgil L. Woods ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Life Cycle ◽  
Matrix Protein ◽  
Hemorrhagic Fever ◽  
Viral Life Cycle ◽  
Lassa Virus ◽  
Protein Z ◽  
Basic Center ◽  
Oligomeric Form ◽  
Oligomeric Forms

ABSTRACTThe arenavirus matrix protein Z is highly multifunctional and occurs in both monomeric and oligomeric forms. The crystal structure of a dodecamer of Z from Lassa virus, presented here, illustrates a ring-like structure with a highly basic center. Mutagenesis demonstrates that the dimeric interface within the dodecamer and a Lys-Trp-Lys triad at the center of the ring are important for oligomerization. This structure provides an additional template to explore the many functions of Z.IMPORTANCEThe arenavirus Lassa virus causes hundreds of thousands of infections each year, many of which develop into fatal hemorrhagic fever. The arenavirus matrix protein Z is multifunctional, with at least four distinct roles. Z exists in both monomeric and oligomeric forms, each of which likely serves a specific function in the viral life cycle. Here we present the dodecameric form of Lassa virus Z and demonstrate that Z forms a “wreath” with a highly basic center. This structure and that of monomeric Z now provide a pair of critical templates by which the multiple roles of Z in the viral life cycle may be interpreted.

scholarly journals Host-Driven Phosphorylation Appears to Regulate the Budding Activity of the Lassa Virus Matrix Protein

Pathogens ◽  
2018 ◽  
Vol 7 (4) ◽  
pp. 97 ◽  
Author(s):  
Christopher Ziegler ◽  
Philip Eisenhauer ◽  
Inessa Manuelyan ◽  
Marion Weir ◽  
Emily Bruce ◽  
...  
Keyword(s):  
Protein Function ◽  
Matrix Protein ◽  
Rna Virus ◽  
Hemorrhagic Fever ◽  
Polymerase Activity ◽  
Lassa Fever ◽  
Lassa Virus ◽  
Protein Z ◽  
Western Africa ◽  
Z Protein

Lassa mammarenavirus (LASV) is an enveloped RNA virus that can cause Lassa fever, an acute hemorrhagic fever syndrome associated with significant morbidity and high rates of fatality in endemic regions of western Africa. The arenavirus matrix protein Z has several functions during the virus life cycle, including coordinating viral assembly, driving the release of new virus particles, regulating viral polymerase activity, and antagonizing the host antiviral response. There is limited knowledge regarding how the various functions of Z are regulated. To investigate possible means of regulation, mass spectrometry was used to identify potential sites of phosphorylation in the LASV Z protein. This analysis revealed that two serines (S18, S98) and one tyrosine (Y97) are phosphorylated in the flexible N- and C-terminal regions of the protein. Notably, two of these sites, Y97 and S98, are located in (Y97) or directly adjacent to (S98) the PPXY late domain, an important motif for virus release. Studies with non-phosphorylatable and phosphomimetic Z proteins revealed that these sites are important regulators of the release of LASV particles and that host-driven, reversible phosphorylation may play an important role in the regulation of LASV Z protein function.

scholarly journals A proteomic survey of Junín virus interactions with human proteins reveals host factors required for arenavirus replication

2017 ◽  
pp. JVI.01565-17 ◽  
Author(s):  
Christopher M. Ziegler ◽  
Philip Eisenhauer ◽  
Jamie A. Kelly ◽  
Loan N. Dang ◽  
Vedran Beganovic ◽  
...  
Keyword(s):  
Ribosomal Proteins ◽  
Large Scale ◽  
Matrix Protein ◽  
Hemorrhagic Fever ◽  
Etiologic Agent ◽  
Human Pathogens ◽  
Host Proteins ◽  
Protein Z ◽  
Argentine Hemorrhagic Fever ◽  
Human Proteins

Arenaviruses are negative-strand, enveloped RNA viruses that cause significant human disease. In particular, Junín mammarenvirus (JUNV) is the etiologic agent of Argentine hemorrhagic fever. At present, little is known about the cellular proteins that the arenavirus matrix protein (Z) hijacks to accomplish its various functions, including driving the process of virus release. Further, there is a little knowledge regarding host proteins incorporated into arenavirus particles and their importance for virion function. To address these deficiencies, we used mass spectrometry to identify human proteins that (i) interact with the JUNV matrix protein inside of cells or within virus-like particles (VLPs) and/or (ii) are incorporated intobona fideJUNV strain Candid #1 particles. Bioinformatic analyses revealed that multiple classes of human proteins were overrepresented in the datasets, including ribosomal proteins, Ras superfamily proteins, and endosomal sorting complex required for transport (ESCRT) proteins. Several of these proteins were required for the propagation of JUNV (ARF1, ATP6V0D1 and PRDX3), lymphocytic choriomeningitis mammarenavirus (LCMV) (Rab5c), or both viruses (ATP5B, IMPDH2). Further, we show that release of infectious JUNV particles, but not LCMV particles, requires a functional ESCRT pathway and that ATP5B and IMPDH2 are required for JUNV budding. In summary, we have provided a large-scale map of host machinery that associates with JUNV and identified key human proteins required for its propagation. This dataset provides a resource for the field to guide antiviral target discovery and to better understand the biology of the arenavirus matrix protein and the importance of host proteins for virion function.IMPORTANCEArenaviruses are deadly human pathogens for which there are no United States Food and Drug Administration-approved vaccines and only limited treatment options. Little is known about the host proteins that are incorporated into arenavirus particles or that associate with its multifunctional matrix protein. Using Junín mammarenavirus (JUNV), the causative agent of Argentine hemorrhagic fever, as a model organism, we mapped the human proteins that are incorporated into JUNV particles or that associate with the JUNV matrix protein. Functional analysis revealed host machinery that is required for JUNV propagation, including the cellular ESCRT pathway. This study improves our understanding of critical arenavirus-host interactions and provides a dataset that will guide future studies to better understand arenavirus pathogenesis and identify novel host proteins that can be therapeutically targeted.

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 A Single Dose of Modified Vaccinia Ankara Expressing Lassa Virus-like Particles Protects Mice from Lethal Intra-cerebral Virus Challenge

Pathogens ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 133 ◽  
Author(s):  
Maria S. Salvato ◽  
Arban Domi ◽  
Camila Guzmán-Cardozo ◽  
Sandra Medina-Moreno ◽  
Juan Carlos Zapata ◽  
...  
Keyword(s):  
Single Dose ◽  
Matrix Protein ◽  
Lethal Dose ◽  
Health Impact ◽  
Lassa Virus ◽  
Protein Z ◽  
Glycoprotein Precursor ◽  
Lethal Challenge ◽  
Virus Like Particles ◽  
Virus Challenge

Lassa fever surpasses Ebola, Marburg, and all other hemorrhagic fevers except Dengue in its public health impact. Caused by Lassa virus (LASV), the disease is a scourge on populations in endemic areas of West Africa, where reported incidence is higher. Here, we report construction, characterization, and preclinical efficacy of a novel recombinant vaccine candidate GEO-LM01. Constructed in the Modified Vaccinia Ankara (MVA) vector, GEO-LM01 expresses the glycoprotein precursor (GPC) and zinc-binding matrix protein (Z) from the prototype Josiah strain lineage IV. When expressed together, GP and Z form Virus-Like Particles (VLPs) in cell culture. Immunogenicity and efficacy of GEO-LM01 was tested in a mouse challenge model. A single intramuscular dose of GEO-LM01 protected 100% of CBA/J mice challenged with a lethal dose of ML29, a Mopeia/Lassa reassortant virus, delivered directly into the brain. In contrast, all control animals died within one week. The vaccine induced low levels of antibodies but Lassa-specific CD4+ and CD8+ T cell responses. This is the first report showing that a single dose of a replication-deficient MVA vector can confer full protection against a lethal challenge with ML29 virus.

scholarly journals Analysis of Assembly and Budding of Lujo Virus

2015 ◽  
Vol 90 (6) ◽  
pp. 3257-3261 ◽  
Author(s):  
Shuzo Urata ◽  
Jacqueline Weyer ◽  
Nadia Storm ◽  
Yukiko Miyazaki ◽  
Petrus Jansen van Vuren ◽  
...  
Keyword(s):  
Cell Surface ◽  
Matrix Protein ◽  
Hemorrhagic Fever ◽  
Surface Glycoprotein ◽  
Protein Z ◽  
Glycoprotein Precursor ◽  
Cell Surface Glycoprotein ◽  
Particle Release ◽  
Viral Release ◽  
Virus Like Particle

The recently identified arenavirus Lujo virus (LUJV) causes fatal hemorrhagic fever in humans. We analyzed its mechanism of viral release driven by matrix protein Z and the cell surface glycoprotein precursor GPC. The L domains in Z are required for efficient virus-like particle release, but Tsg101, ALIX/AIP1, and Vps4A/B are unnecessary for budding. LUJV GPC is cleaved by site 1 protease (S1P) at the RKLM motif, and treatment with the S1P inhibitor PF-429242 reduced LUJV production.

scholarly journals Autophagy Promotes Infectious Particle Production of Mopeia and Lassa Viruses

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 293 ◽  
Author(s):  
Nicolas Baillet ◽  
Sophie Krieger ◽  
Alexandra Journeaux ◽  
Valérie Caro ◽  
Frédéric Tangy ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Particle Production ◽  
Defense Mechanism ◽  
Viral Infections ◽  
Hybrid Approach ◽  
Hemorrhagic Fever ◽  
Lassa Virus ◽  
Infectious Particle ◽  
Cellular Defense ◽  
Infected Cells

Lassa virus (LASV) and Mopeia virus (MOPV) are two closely related Old-World mammarenaviruses. LASV causes severe hemorrhagic fever with high mortality in humans, whereas no case of MOPV infection has been reported. Comparing MOPV and LASV is a powerful strategy to unravel pathogenic mechanisms that occur during the course of pathogenic arenavirus infection. We used a yeast two-hybrid approach to identify cell partners of MOPV and LASV Z matrix protein in which two autophagy adaptors were identified, NDP52 and TAX1BP1. Autophagy has emerged as an important cellular defense mechanism against viral infections but its role during arenavirus infection has not been shown. Here, we demonstrate that autophagy is transiently induced by MOPV, but not LASV, in infected cells two days after infection. Impairment of the early steps of autophagy significantly decreased the production of MOPV and LASV infectious particles, whereas a blockade of the degradative steps impaired only MOPV infectious particle production. Our study provides insights into the role played by autophagy during MOPV and LASV infection and suggests that this process could partially explain their different pathogenicity.

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

2004 ◽  
Vol 100 (2) ◽  
pp. 249-255 ◽  
Author(s):  
Robert Eichler ◽  
Thomas Strecker ◽  
Larissa Kolesnikova ◽  
Jan ter Meulen ◽  
Winfried Weissenhorn ◽  
...  
Keyword(s):  
Microscopic Study ◽  
Electron Microscopic Study ◽  
Matrix Protein ◽  
Lassa Virus ◽  
Electron Microscopic ◽  
Protein Z ◽  
Virus Like Particles

The microtubule motor protein KIF13A is involved in intracellular trafficking of the Lassa virus matrix protein Z

2013 ◽  
Vol 15 (2) ◽  
pp. 315-334 ◽  
Author(s):  
Sarah Katharina Fehling ◽  
Takeshi Noda ◽  
Andrea Maisner ◽  
Boris Lamp ◽  
Karl-Klaus Conzelmann ◽  
...  
Keyword(s):  
Intracellular Trafficking ◽  
Matrix Protein ◽  
Motor Protein ◽  
Lassa Virus ◽  
Protein Z ◽  
Microtubule Motor ◽  
Microtubule Motor Protein

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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