scholarly journals Host Protein BAG3 is a Negative Regulator of Lassa VLP Egress

Diseases ◽  
2018 ◽  
Vol 6 (3) ◽  
pp. 64 ◽  
Author(s):  
Ziying Han ◽  
Michael Schwoerer ◽  
Philip Hicks ◽  
Jingjing Liang ◽  
Gordon Ruthel ◽  
...  
Keyword(s):  
Defense Mechanism ◽  
Hemorrhagic Fever ◽  
Lassa Fever ◽  
Cellular Protein ◽  
Negative Regulator ◽  
Host Protein ◽  
Ww Domain ◽  
Host Defense Mechanism ◽  
Lassa Fever Virus ◽  
Novel Host

Lassa fever virus (LFV) belongs to the Arenaviridae family and can cause acute hemorrhagic fever in humans. The LFV Z protein plays a central role in virion assembly and egress, such that independent expression of LFV Z leads to the production of virus-like particles (VLPs) that mimic egress of infectious virus. LFV Z contains both PTAP and PPPY L-domain motifs that are known to recruit host proteins that are important for mediating efficient virus egress and spread. The viral PPPY motif is known to interact with specific host WW-domain bearing proteins. Here we identified host WW-domain bearing protein BCL2 Associated Athanogene 3 (BAG3) as a LFV Z PPPY interactor using our proline-rich reading array of WW-domain containing mammalian proteins. BAG3 is a stress-induced molecular co-chaperone that functions to regulate cellular protein homeostasis and cell survival via Chaperone-Assisted Selective Autophagy (CASA). Similar to our previously published findings for the VP40 proteins of Ebola and Marburg viruses, our results using VLP budding assays, BAG3 knockout cells, and confocal microscopy indicate that BAG3 is a WW-domain interactor that negatively regulates egress of LFV Z VLPs, rather than promoting VLP release. Our results suggest that CASA and specifically BAG3 may represent a novel host defense mechanism, whereby BAG3 may dampen egress of several hemorrhagic fever viruses by interacting and interfering with the budding function of viral PPxY-containing matrix proteins.

An Overview of Newly Emerging Viral Plagues: The Hemorrhagic Fevers and a Newly Mysterious Suspect of Viral Disease, Acute Flaccid Paralysis

2020 ◽  
pp. 203-214
Author(s):  
Michael B. A. Oldstone
Keyword(s):  
Ebola Virus ◽  
Signs And Symptoms ◽  
Hemorrhagic Fever ◽  
Viral Disease ◽  
Lassa Fever ◽  
Pericardial Cavity ◽  
Blood Flows ◽  
Acute Flaccid Myelitis ◽  
Lassa Fever Virus ◽  
Serious Disease

This chapter highlights three of the recently identified viruses: Lassa fever virus, Ebola virus, and hantavirus. All three are equally lethal infectious agents, but they are members of different viral families. They share the ability to cause hemorrhagic fever. Once infected with any of these viruses, the victim soon suffers profuse breaks in small blood vessels, causing blood to ooze from the skin, mouth, gastrointestinal tract, and rectum. Internally, blood flows into the pleural cavity where the lungs are located, into the pericardial cavity surrounding the heart, into the abdomen, and into organs like the liver, kidney, heart, spleen, and lungs. Eventually, this uncontrolled bleeding causes unconsciousness and death. There is currently no established vaccine to prevent these potential plagues, although several are in various stages of development, and an Ebola vaccine is currently undergoing trial in Africa. The chapter also considers a newly emerging and undefined but serious disease of children, which arose primarily in 2014. Based on clinical observations, the disease is identified by the signs and symptoms of acute flaccid myelitis.

scholarly journals Angiomotin Counteracts the Negative Regulatory Effect of Host WWOX on Viral PPxY-Mediated Egress

2021 ◽  
Author(s):  
Jingjing Liang ◽  
Gordon Ruthel ◽  
Cari A. Sagum ◽  
Mark T. Bedford ◽  
Sachdev S. Sidhu ◽  
...  
Keyword(s):  
Hemorrhagic Fever ◽  
Host Protein ◽  
Lassa Virus ◽  
Dependent Manner ◽  
Emerging Pathogens ◽  
Live Virus ◽  
Ww Domain ◽  
Ww Domains ◽  
Virus Like Particles ◽  
Virus Egress

Filoviridae family members Ebola (EBOV) and Marburg (MARV) viruses and Arenaviridae family member Lassa virus (LASV) are emerging pathogens that can cause hemorrhagic fever and high rates of mortality in humans. A better understanding of the interplay between these viruses and the host will inform about the biology of these pathogens, and may lead to the identification of new targets for therapeutic development. Notably, expression of the filovirus VP40 and LASV Z matrix proteins alone drives assembly and egress of virus-like particles (VLPs). The conserved PPxY Late (L) domain motifs in the filovirus VP40 and LASV Z proteins play a key role in the budding process by mediating interactions with select host WW-domain containing proteins that then regulate virus egress and spread. To identify the full complement of host WW-domain interactors, we utilized WT and PPxY mutant peptides from EBOV and MARV VP40 and LASV Z proteins to screen an array of GST-WW-domain fusion proteins. We identified WW domain-containing oxidoreductase (WWOX) as a novel PPxY-dependent interactor, and we went on to show that full-length WWOX physically interacts with eVP40, mVP40 and LASV Z to negatively regulate egress of VLPs and of a live VSV/Ebola recombinant virus (M40). Interestingly, WWOX is a versatile host protein that regulates multiple signaling pathways and cellular processes via modular interactions between its WW-domains and PPxY motifs of select interacting partners, including host angiomotin (AMOT). Notably, we demonstrated recently that expression of endogenous AMOT not only positively regulates egress of VLPs, but also promotes egress and spread of live EBOV and MARV. Toward the mechanism of action, we show that the competitive and modular interplay among WWOX-AMOT-VP40/Z regulates VLP and M40 virus egress. Thus, WWOX is the newest member of an emerging group of host WW-domain interactors (e.g. BAG3; YAP/TAZ) that negatively regulate viral egress. These findings further highlight the complex interplay of virus-host PPxY/WW-domain interactions and their potential impact on the biology of both the virus and the host during infection. Author Summary Filoviruses (Ebola [EBOV] and Marburg [MARV]) and arenavirus (Lassa virus; LASV) are zoonotic, emerging pathogens that cause outbreaks of severe hemorrhagic fever in humans. A fundamental understanding of the virus-host interface is critical for understanding the biology of these viruses and for developing future strategies for therapeutic intervention. Here, we identified host WW-domain containing protein WWOX as a novel interactor with VP40 and Z, and showed that WWOX inhibited budding of VP40/Z virus-like particles (VLPs) and live virus in a PPxY/WW-domain dependent manner. Our findings are important to the field as they expand the repertoire of host interactors found to regulate PPxY-mediated budding of RNA viruses, and further highlight the competitive interplay and modular virus-host interactions that impact both the virus lifecycle and the host cell.

scholarly journals HSC70 Inhibits Spring Viremia of Carp Virus Replication by Inducing MARCH8-Mediated Lysosomal Degradation of G Protein

2021 ◽  
Vol 12 ◽  
Author(s):  
Chen Li ◽  
Lin Shi ◽  
Yan Gao ◽  
Yuanan Lu ◽  
Jing Ye ◽  
...  
Keyword(s):  
G Protein ◽  
Defense Mechanism ◽  
Affinity Purification ◽  
Mass Spectrometry Analysis ◽  
Lysosomal Degradation ◽  
Spectrometry Analysis ◽  
Glycoprotein G ◽  
Multicomponent Complex ◽  
Host Defense Mechanism ◽  
Novel Host

As a fierce pathogen, spring viremia of carp virus (SVCV) can cause high mortality in the common carp, and its glycoprotein (G protein) is a component of the viral structure on the surface of virion, which is crucial in viral life cycle. This report adopted tandem affinity purification (TAP), mass spectrometry analysis (LC-MS/MS), immunoprecipitation, and confocal microscopy assays to identify Heat shock cognate protein 70 (HSC70) as an interaction partner of SVCV G protein. It was found that HSC70 overexpression dramatically inhibited SVCV replication, whereas its loss of functions elicited opposing effects on SVCV replication. Mechanistic studies indicate that HSC70 induces lysosomal degradation of ubiquitinated-SVCV G protein. This study further demonstrates that Membrane-associated RING-CH 8 (MARCH8), an E3 ubiquitin ligase, is critical for SVCV G protein ubiquitylation and leads to its lysosomal degradation. Furthermore, the MARCH8 mediated ubiquitylation of SVCV G protein required the participation of HSC70 through forming a multicomponent complex. Taken together, these results demonstrate that HSC70 serves as a scaffold for MARCH8 and SVCV G, which leads to the ubiquitylation and degradation of SVCV G protein and thus inhibits viral replication. These findings have established a novel host defense mechanism against SVCV.

scholarly journals 887 Intraluminal Release of Galectin 4 in EHEC Infection Provides a Novel Host Defense Mechanism

2013 ◽  
Vol 144 (5) ◽  
pp. S-156
Author(s):  
Julie In ◽  
Sabine André ◽  
Hans-Joachim Gabius ◽  
Olga Kovbasnjuk
Keyword(s):  
Host Defense ◽  
Defense Mechanism ◽  
Host Defense Mechanism ◽  
Novel Host

scholarly journals Arenavirus Z-Glycoprotein Association Requires Z Myristoylation but Not Functional RING or Late Domains

2007 ◽  
Vol 81 (17) ◽  
pp. 9451-9460 ◽  
Author(s):  
Althea A. Capul ◽  
Mar Perez ◽  
Emily Burke ◽  
Stefan Kunz ◽  
Michael J. Buchmeier ◽  
...  
Keyword(s):  
Function Analysis ◽  
Ring Finger ◽  
Hemorrhagic Fever ◽  
Lassa Fever ◽  
Lymphocytic Choriomeningitis ◽  
Viral Envelope ◽  
Surface Glycoprotein ◽  
Glycoprotein Precursor ◽  
Biochemical Interaction ◽  
Lassa Fever Virus

ABSTRACT Generation of infectious arenavirus-like particles requires the virus RING finger Z protein and surface glycoprotein precursor (GPC) and the correct processing of GPC into GP1, GP2, and a stable signal peptide (SSP). Z is the driving force of arenavirus budding, whereas the GP complex (GPc), consisting of hetero-oligomers of SSP, GP1, and GP2, forms the viral envelope spikes that mediate receptor recognition and cell entry. Based on the roles played by Z and GP in the arenavirus life cycle, we hypothesized that Z and the GPc should interact in a manner required for virion formation. Here, using confocal microscopy and coimmunoprecipitation assays, we provide evidence for subcellular colocalization and biochemical interaction, respectively, of Z and the GPc. Our results from mutation-function analysis reveal that Z myristoylation, but not the Z late (L) or RING domain, is required for Z-GPc interaction. Moreover, Z interacted directly with SSP in the absence of other components of the GPc. We obtained similar results with Z and GPC from the prototypical arenavirus lymphocytic choriomeningitis virus and the hemorrhagic fever arenavirus Lassa fever virus.

scholarly journals Cells Expressing the RING Finger Z Protein Are Resistant to Arenavirus Infection

2004 ◽  
Vol 78 (6) ◽  
pp. 2979-2983 ◽  
Author(s):  
Tatjana I. Cornu ◽  
Heinz Feldmann ◽  
Juan Carlos de la Torre
Keyword(s):  
Recombinant Adenovirus ◽  
Ring Finger ◽  
Hemorrhagic Fever ◽  
Lassa Fever ◽  
Lymphocytic Choriomeningitis ◽  
Surface Glycoprotein ◽  
Protein Z ◽  
Virus Transcription ◽  
Lassa Fever Virus ◽  
Z Protein

ABSTRACT Arenaviruses include Lassa fever virus (LFV) and the South American hemorrhagic fever viruses. These viruses cause severe human disease, and they pose a threat as agents of bioterrorism. Arenaviruses are enveloped viruses with a bisegmented negative-strand RNA genome whose proteomic capability is limited to four polypeptides: nucleoprotein (NP); surface glycoprotein (GP), which is proteolytically processed into GP1 and GP2; polymerase (L); and a small (11-kDa) RING finger protein (Z). Our investigators have previously shown that Z has a strong inhibitory activity on RNA synthesis mediated by the polymerase of the prototypic arenavirus, lymphocytic choriomeningitis virus (LCMV). In this report we show that cells transduced with a replication-deficient recombinant adenovirus expressing Z (rAd-Z) are resistant to LCMV and LFV infection. Virus cell entry mediated by LCMV or LFV GP was not affected in rAd-Z-transduced cells, but both virus transcription and replication were strongly and specifically inhibited, which resulted in a dramatic reduction in production of infectious virus. These findings open new avenues for developing antiviral strategies to combat the highly pathogenic human arenaviruses, including LFV.

scholarly journals Angiomotin Counteracts the Negative Regulatory Effect of Host WWOX on Viral PPxY-Mediated Egress

2021 ◽  
Author(s):  
Jingjing Liang ◽  
Gordon Ruthel ◽  
Cari A. Sagum ◽  
Mark T. Bedford ◽  
Sachdev S. Sidhu ◽  
...  
Keyword(s):  
Hemorrhagic Fever ◽  
Host Protein ◽  
Lassa Virus ◽  
Dependent Manner ◽  
Emerging Pathogens ◽  
Live Virus ◽  
Ww Domain ◽  
Ww Domains ◽  
Virus Like Particles ◽  
Virus Egress

AbstractFiloviridae family members Ebola (EBOV) and Marburg (MARV) viruses and Arenaviridae family member Lassa virus (LASV) are emerging pathogens that can cause hemorrhagic fever and high rates of mortality in humans. A better understanding of the interplay between these viruses and the host will inform about the biology of these pathogens, and may lead to the identification of new targets for therapeutic development. Notably, expression of the filovirus VP40 and LASV Z matrix proteins alone drives assembly and egress of virus-like particles (VLPs). The conserved PPxY Late (L) domain motifs in the filovirus VP40 and LASV Z proteins play a key role in the budding process by mediating interactions with select host WW-domain containing proteins that then regulate virus egress and spread. To identify the full complement of host WW-domain interactors, we utilized WT and PPxY mutant peptides from EBOV and MARV VP40 and LASV Z proteins to screen an array of GST-WW-domain fusion proteins. We identified WW domain-containing oxidoreductase (WWOX) as a novel PPxY-dependent interactor, and we went on to show that full-length WWOX physically interacts with eVP40, mVP40 and LASV Z to negatively regulate egress of VLPs and of a live VSV/Ebola recombinant virus (M40). Interestingly, WWOX is a versatile host protein that regulates multiple signaling pathways and cellular processes via modular interactions between its WW-domains and PPxY motifs of select interacting partners, including host angiomotin (AMOT). Notably, we demonstrated recently that expression of endogenous AMOT not only positively regulates egress of VLPs, but also promotes egress and spread of live EBOV and MARV. Toward the mechanism of action, we show that the competitive and modular interplay among WWOX-AMOT-VP40/Z regulates VLP and M40 virus egress. Thus, WWOX is the newest member of an emerging group of host WW-domain interactors (e.g. BAG3; YAP/TAZ) that negatively regulate viral egress. These findings further highlight the complex interplay of virus-host PPxY/WW-domain interactions and their potential impact on the biology of both the virus and the host during infection.Author SummaryFiloviruses (Ebola [EBOV] and Marburg [MARV]) and arenavirus (Lassa virus; LASV) are zoonotic, emerging pathogens that cause outbreaks of severe hemorrhagic fever in humans. A fundamental understanding of the virus-host interface is critical for understanding the biology of these viruses and for developing future strategies for therapeutic intervention. Here, we identified host WW-domain containing protein WWOX as a novel interactor with VP40 and Z, and showed that WWOX inhibited budding of VP40/Z virus-like particles (VLPs) and live virus in a PPxY/WW-domain dependent manner. Our findings are important to the field as they expand the repertoire of host interactors found to regulate PPxY-mediated budding of RNA viruses, and further highlight the competitive interplay and modular virus-host interactions that impact both the virus lifecycle and the host cell.

scholarly journals Case series of outcome of newborn babies exposed to Lassa fever virus infection

2020 ◽  
Vol 1 (1) ◽  
Author(s):  
Dorathy Chinwe Obu ◽  
Obumneme Benaianh Ezeanosike ◽  
Samuel Amechi Nwukor
Keyword(s):  
Horizontal Transmission ◽  
Case Series ◽  
Hemorrhagic Fever ◽  
Positive Outcome ◽  
Lassa Fever ◽  
West African ◽  
Lassa Virus ◽  
African Countries ◽  
Lassa Fever Virus ◽  
Prompt Diagnosis

Lassa fever (LF) is an acute viral hemorrhagic fever caused by the Lassa virus, a zoonotic infection transmitted by the infected multimammate mouse which is endemic in West African countries. It affects all ages contributing to high maternal and neonatal mortality rates. Neonates are at risk of vertical and horizontal transmission of Lassa virus. We report a series of six newborns, three of whom were delivered to Lassa fever positive mothers and were managed as exposed babies while the remaining three were diagnosed with neonatal Lassa fever. None of the babies exposed to the virus became infected and two of these exposed babies had a positive outcome. All the babies with neonatal Lassa fever died days after birth even before confirming the diagnosis and initiating ribavirin treatment. This highlights the need for prompt diagnosis in utero with treatment of mother before delivery to improve the neonatal outcome. Also, the need to commence intravenous ribavirin treatment in highly suspicious cases of neonatal Lassa fever while awaiting confirmation of the diagnosis is emphasized.

scholarly journals Assessment of Knowledge and Sources of Information on Lassa Fever Infection Among the Undergraduate Students of Ebonyi State University, Nigeria

SAGE Open ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 215824402110063
Author(s):  
MaryJoy Umoke ◽  
Prince Christian Ifeanachor Umoke ◽  
Chioma Adaora Nwalieji ◽  
Rosemary N. Onwe ◽  
Ifeanyi Emmanuel Nwafor ◽  
...  
Keyword(s):  
Undergraduate Students ◽  
Signs And Symptoms ◽  
Hemorrhagic Fever ◽  
Lassa Fever ◽  
State University ◽  
Sources Of Information ◽  
Cross Sectional Survey ◽  
Cross Sectional ◽  
Endemic Diseases ◽  
Academic Level

Lassa fever is a zoonotic disease characterized by acute viral hemorrhagic fever, endemic in West Africa including Nigeria. The study assessed the knowledge and sources of information on Lassa fever infection among the undergraduate students of Ebonyi State University, Nigeria. This was a descriptive cross-sectional survey conducted among a sample of 389 students (18 years above). A self-administered questionnaire was used to collect data. Data were analyzed with SPSS (Version 20), and hypotheses were tested at p < .05 level of significance. Results showed that the majority of the students had good knowledge of Lassa fever description, 232 (60.75%); the signs and symptoms, 221 (57.9%); mode of transmission, 261 (68.41%); and preventive measures, 291 (76.13%). Radio, 23 (84.6%), and television, 307 (80.4%), were their major sources of information. Age ( p = .424), sex ( p = .082), and academic level ( p = .553) were not significant in the study, while faculty (social sciences; p = .000*) was strongly associated with the knowledge of Lassa fever. In conclusion, the overall knowledge of Lassa fever was good among students, though knowledge gaps were observed in the signs and symptoms. We recommend that health education on endemic diseases in the state be made a compulsory course as a general study (GST) in the university. Also, the internet, social media, and campus campaign be further used to educate and sensitize students on the effect of Lassa fever.

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