scholarly journals Junín Virus Promotes Autophagy To Facilitate the Virus Life Cycle

2019 ◽  
Vol 93 (15) ◽  
Author(s):  
Julieta S. Roldán ◽  
Nélida A. Candurra ◽  
María I. Colombo ◽  
Laura R. Delgui
Keyword(s):  
Hemorrhagic Fever ◽  
Replication Capacity ◽  
Epidemic Disease ◽  
Junin Virus ◽  
Hemorrhagic Fevers ◽  
Argentine Hemorrhagic Fever ◽  
The Family ◽  
Infected Cells ◽  
Junín Virus

ABSTRACTJunín virus (JUNV), a member of the familyArenaviridae, is the etiological agent of Argentine hemorrhagic fever (AHF), a potentially deadly endemic-epidemic disease affecting the population of the most fertile farming land of Argentina. Autophagy is a degradative process with a crucial antiviral role; however, several viruses subvert the pathway to their benefit. We determined the role of autophagy in JUNV-infected cells by analyzing LC3, a cytoplasmic protein (LC3-I) that becomes vesicle membrane associated (LC3-II) upon induction of autophagy. Cells overexpressing enhanced green fluorescent protein (EGFP)-LC3 and infected with JUNV showed an increased number of LC3 punctate structures, similar to those obtained after starvation or bafilomycin A1 treatment, which leads to autophagosome induction or accumulation, respectively. We also monitored the conversion of LC3-I to LC3-II, observing LC3-II levels in JUNV-infected cells similar to those observed in starved cells. Additionally, we kinetically studied the number of LC3 dots after JUNV infection and found that the virus activated the pathway as early as 2 h postinfection (p.i.), whereas the UV-inactivated virus did not induce the pathway. Cells subjected to starvation or pretreated with rapamycin, a pharmacological autophagy inductor, enhanced virus yield. Also, we assayed the replication capacity of JUNV in Atg5 knockout or Beclin 1 knockdown cells (both critical components of the autophagic pathway) and found a significant decrease in JUNV replication. Taken together, our results constitute the first study indicating that JUNV infection induces an autophagic response, which is functionally required by the virus for efficient propagation.IMPORTANCEMammalian arenaviruses are zoonotic viruses that cause asymptomatic and persistent infections in their rodent hosts but may produce severe and lethal hemorrhagic fevers in humans. Currently, there are neither effective therapeutic options nor effective vaccines for viral hemorrhagic fevers caused by human-pathogenic arenaviruses, except the vaccine Candid no. 1 against Argentine hemorrhagic fever (AHF), licensed for human use in areas of endemicity in Argentina. Since arenaviruses remain a severe threat to global public health, more in-depth knowledge of their replication mechanisms would improve our ability to fight these viruses. Autophagy is a lysosomal degradative pathway involved in maintaining cellular homeostasis, representing powerful anti-infective machinery. We show, for the first time for a member of the familyArenaviridae, a proviral role of autophagy in JUNV infection, providing new knowledge in the field of host-virus interaction. Therefore, modulation of virus-induced autophagy could be used as a strategy to block arenavirus infections.

scholarly journals Novel Arenavirus Entry Inhibitors Discovered by Using a Minigenome Rescue System for High-Throughput Drug Screening

2015 ◽  
Vol 89 (16) ◽  
pp. 8428-8443 ◽  
Author(s):  
Jessica Y. Rathbun ◽  
Magali E. Droniou ◽  
Robert Damoiseaux ◽  
Kevin G. Haworth ◽  
Jill E. Henley ◽  
...  
Keyword(s):  
High Throughput ◽  
Causative Agent ◽  
High Throughput Screening ◽  
Hemorrhagic Fever ◽  
Human Pathogens ◽  
Junin Virus ◽  
Hemorrhagic Fevers ◽  
Argentine Hemorrhagic Fever ◽  
Rescue System ◽  
Junín Virus

ABSTRACTCertain members of theArenaviridaefamily are category A agents capable of causing severe hemorrhagic fevers in humans. Specific antiviral treatments do not exist, and the only commonly used drug, ribavirin, has limited efficacy and can cause severe side effects. The discovery and development of new antivirals are inhibited by the biohazardous nature of the viruses, making them a relatively poorly understood group of human pathogens. We therefore adapted a reverse-genetics minigenome (MG) rescue system based on Junin virus, the causative agent of Argentine hemorrhagic fever, for high-throughput screening (HTS). The MG rescue system recapitulates all stages of the virus life cycle and enables screening of small-molecule libraries under biosafety containment level 2 (BSL2) conditions. The HTS resulted in the identification of four candidate compounds with potent activity against a broad panel of arenaviruses, three of which were completely novel. The target for all 4 compounds was the stage of viral entry, which positions the compounds as potentially important leads for future development.IMPORTANCEThe arenavirus family includes several members that are highly pathogenic, causing acute viral hemorrhagic fevers with high mortality rates. No specific effective treatments exist, and although a vaccine is available for Junin virus, the causative agent of Argentine hemorrhagic fever, it is licensed for use only in areas where Argentine hemorrhagic fever is endemic. For these reasons, it is important to identify specific compounds that could be developed as antivirals against these deadly viruses.

Junin virus activity in two rural populations of the Argentine hemorrhagic fever (AHF) endemic area

1983 ◽  
Vol 12 (4) ◽  
pp. 273-280 ◽  
Author(s):  
Mercedes C. Weissenbacher ◽  
Marta S. Sabattini ◽  
María M. Avila ◽  
Patricia M. Sangiorgio ◽  
María R. F. De Sensi ◽  
...  
Keyword(s):  
Endemic Area ◽  
Hemorrhagic Fever ◽  
Rural Populations ◽  
Junin Virus ◽  
Argentine Hemorrhagic Fever ◽  
Virus Activity ◽  
Junín Virus

Endothelial cell function alteration after Junin virus infection

2003 ◽  
Vol 90 (08) ◽  
pp. 326-334 ◽  
Author(s):  
Ricardo Gomez ◽  
Roberto Pozner ◽  
Maria Lazzari ◽  
Lina D’Atri ◽  
Soledad Negrotto ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cell ◽  
Cell Function ◽  
Umbilical Vein ◽  
Hemorrhagic Fever ◽  
No Production ◽  
Epidemic Disease ◽  
Endothelial Cell Function ◽  
Junin Virus ◽  
Junín Virus

SummaryHematologic involvement is the main feature of Argentine hemorrhagic fever (AHF), an endemo-epidemic disease caused by Junin virus (JV). Since endothelial dysfunction could play a role in AHF-altered hemostasis, we studied human umbilical vein endothelial cell (HUVEC) infection with a virulent (JVv) and a non-virulent (JVa) JV strain. Cells were infected by the two JV variants with no detectable apoptosis or cytopathic effect. Both viral variants up-regulated ICAM-1 and VCAM-1 levels, while von Willebrand factor (VWF) production was decreased. Prostacyclin (PGI2) release and decay accelerating factor (DAF) expression were greater in JVv- than in JVa-infected or control cells. Furthermore, nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) expression was only raised in JVv-infected supernatants. Significant NO and PGI2 values were also detected in AHF patient sera.These data demonstrate that endothelial cell responses are triggered subsequently by JV infection, suggesting that such alterations play a major role in the pathogenesis of AHF and perhaps in other viral-induced hemorrhagic diseases.

ChemInform Abstract: Imidazo[2,1-b]thiazole Carbohydrate Derivatives: Synthesis and Antiviral Activity Against Junin Virus, Agent of Argentine Hemorrhagic Fever.

ChemInform ◽  
2011 ◽  
Vol 42 (22) ◽  
pp. no-no
Author(s):  
Jose Sebastian Barradas ◽  
Maria Ines Errea ◽  
Norma B. D'Accorso ◽  
Claudia Soledad Sepulveda ◽  
Elsa Beatriz Damonte
Keyword(s):  
Antiviral Activity ◽  
Hemorrhagic Fever ◽  
Junin Virus ◽  
Argentine Hemorrhagic Fever ◽  
Junín Virus

scholarly journals The Glycoprotein of the Live-Attenuated Junin Virus Vaccine Strain Induces Endoplasmic Reticulum Stress and Forms Aggregates prior to Degradation in the Lysosome

2020 ◽  
Vol 94 (8) ◽  
Author(s):  
John T. Manning ◽  
Nadya E. Yun ◽  
Alexey V. Seregin ◽  
Takaaki Koma ◽  
Rachel A. Sattler ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Vaccine Strain ◽  
Hemorrhagic Fever ◽  
Wild Type ◽  
Live Attenuated Vaccine ◽  
Hemorrhagic Fevers ◽  
Attenuated Vaccine ◽  
Argentine Hemorrhagic Fever ◽  
Viral Hemorrhagic Fevers ◽  
Junín Virus

ABSTRACT Argentine hemorrhagic fever is a potentially lethal disease that is caused by Junin virus (JUNV). There are currently around 5 million individuals at risk of infection within regions of endemicity in Argentina. The live attenuated vaccine strain Candid #1 (Can) is approved for use in regions of endemicity and has substantially decreased the number of annual Argentine hemorrhagic fever (AHF) cases. The glycoprotein (GPC) gene is primarily responsible for attenuation of the Can strain, and we have shown that the absence of an N-linked glycosylation motif in the subunit G1 of the glycoprotein complex of Can, which is otherwise present in the wild-type pathogenic JUNV, causes GPC retention in the endoplasmic reticulum (ER). Here, we show that Can GPC aggregates in the ER of infected cells, forming incorrect cross-chain disulfide bonds, which results in impaired GPC processing into G1 and G2. The GPC fails to cleave into its G1 and G2 subunits and is targeted for degradation within lysosomes. Cells infected with the wild-type Romero (Rom) strain do not produce aggregates that are observed in Can infection, and the stress on the ER remains minimal. While the mutation of the N-linked glycosylation motif (T168A) is primarily responsible for the formation of aggregates, other mutations within G1 that occurred earlier in the passage history of the Can strain also contribute to aggregation of the GPC within the ER. IMPORTANCE The development of vaccines and therapeutics to combat viral hemorrhagic fevers remains a top priority within the Implementation Plan of the U.S. Department of Health and Human Services Public Health Emergency Medical Countermeasures Enterprise. The Can strain, derived from the pathogenic XJ strain of JUNV, has been demonstrated to be both safe and protective against AHF. While the vaccine strain is approved for use in regions of endemicity within Argentina, the mechanisms of Can attenuation have not been elucidated. A better understanding of the viral genetic determinants of attenuation will improve our understanding of the mechanisms contributing to disease pathogenesis and provide critical information for the rational design of live attenuated vaccine candidates for other viral hemorrhagic fevers.

Prevalence of Infection with Junin Virus in Rodent Populations in the Epidemic Area of Argentine Hemorrhagic Fever

1994 ◽  
Vol 51 (5) ◽  
pp. 554-562 ◽  
Author(s):  
James N. Mills ◽  
C. J. Peters ◽  
James E. Childs ◽  
Kelly T. McKee ◽  
Thomas G. Ksiazek ◽  
...  
Keyword(s):  
Hemorrhagic Fever ◽  
Junin Virus ◽  
Argentine Hemorrhagic Fever ◽  
Epidemic Area ◽  
Rodent Populations ◽  
Junín Virus

Junin Virus Isolation from Lympho-Mononuclear Cells of Patients with Argentine Hemorrhagic Fever

Intervirology ◽  
1986 ◽  
Vol 25 (2) ◽  
pp. 97-102 ◽  
Author(s):  
Ana M. Ambrosio ◽  
Delia A. Enria ◽  
Julio I. Maiztegui
Keyword(s):  
Mononuclear Cells ◽  
Virus Isolation ◽  
Hemorrhagic Fever ◽  
Junin Virus ◽  
Argentine Hemorrhagic Fever ◽  
Junín Virus

scholarly journals Human Plasmacytoid Dendritic Cells Elicited Different Responses after Infection with Pathogenic and Nonpathogenic Junin Virus Strains

2015 ◽  
Vol 89 (14) ◽  
pp. 7409-7413 ◽  
Author(s):  
Soledad Negrotto ◽  
Hebe A. Mena ◽  
Agustin E. Ure ◽  
Carolina Jaquenod De Giusti ◽  
Mariela Bollati-Fogolín ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Peripheral Blood ◽  
Human Peripheral Blood ◽  
Hemorrhagic Fever ◽  
Plasmacytoid Dendritic Cells ◽  
Etiologic Agent ◽  
Junin Virus ◽  
Argentine Hemorrhagic Fever ◽  
Junín Virus ◽  
Virus Strains

The arenavirus Junin virus (JUNV) is the etiologic agent of Argentine hemorrhagic fever. We characterized the JUNV infection of human peripheral blood-derived plasmacytoid dendritic cells (hpDC), demonstrating that hpDC are susceptible to infection with the C#1 strain (attenuated) and even more susceptible to infection with the P (virulent) JUNV strain. However, hpDC elicited different responses in terms of viability, activation, maturation, and cytokine expression after infection with both JUNV strains.

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