Quadrivalent #VesiculoVax #vaccine protects nonhuman #primates from viral-induced #hemorrhagic fever and death (J Clin Invest., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

J Clin Invest. 2019 Oct 22. [Epub ahead of print]

Quadrivalent VesiculoVax vaccine protects nonhuman primates from viral-induced hemorrhagic fever and death

Cross RW.



Recent occurrences of filoviruses and the arenavirus Lassa virus (LASV) in overlapping endemic areas of Africa highlight the need for a prophylactic vaccine that would confer protection against all of these viruses that cause lethal hemorrhagic fever (HF). We developed a quadrivalent formulation of VesiculoVax that contains recombinant vesicular stomatitis virus (rVSV) vectors expressing filovirus glycoproteins and that also contains a rVSV vector expressing the glycoprotein of a lineage IV strain of LASV. Cynomolgus macaques were vaccinated twice with the quadrivalent formulation, followed by challenge 28 days after the boost vaccination with each of the 3 corresponding filoviruses (Ebola, Sudan, Marburg) or a heterologous contemporary lineage II strain of LASV. Serum IgG and neutralizing antibody responses specific for all 4 glycoproteins were detected in all vaccinated animals. A modest and balanced cell-mediated immune response specific for the glycoproteins was also detected in most of the vaccinated macaques. Regardless of the level of total glycoprotein-specific immune response detected after vaccination, all immunized animals were protected from disease and death following lethal challenges. These findings indicate that vaccination with attenuated rVSV vectors each expressing a single HF virus glycoprotein may provide protection against those filoviruses and LASV most commonly responsible for outbreaks of severe HF in Africa.

PMID: 31820871 DOI: 10.1172/JCI131958

Keywords: Viral hemorrhagic fever; Filovirus; Arenavirus; Lassa fever; Ebola; Marburg; Vaccines; Animal models.


#Monoclonal #antibodies with neutralizing activity and Fc-effector functions against the #Machupo virus glycoprotein (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Monoclonal antibodies with neutralizing activity and Fc-effector functions against the Machupo virus glycoprotein

Fatima Amanat, James Duehr, Cheng Huang, Slobodan Paessler, Gene Tan, Florian Krammer

DOI: 10.1128/JVI.01741-19



Machupo virus (MACV), the causative agent of Bolivian hemorrhagic fever (BHF), is a New World arenavirus that was first isolated in Bolivia from a human spleen in 1963. Due to the lack of a specific vaccine or therapy, this virus is considered a major risk to public health and is classified as a Category A Priority Pathogen by the US National Institutes of Health. In this study, we used DNA vaccination against the MACV glycoprotein precursor complex (GPC) and murine hybridoma technology to generate 25 mouse monoclonal antibodies (mAbs) against the GPC of MACV. Out of 25, five mAbs were found to have potent neutralization activity in vitro against a recombinant vesicular stomatitis virus expressing MACV GPC (VSV-MACV) as well as authentic MACV. Furthermore, the five neutralizing mAbs exhibited strong antibody-dependent cellular cytotoxicity (ADCC) activity in a reporter assay. When tested in vivo using VSV-MACV in a Stat2-/- mouse model, three mAbs significantly lowered viral loads in the spleen. Our work provides valuable insights into epitopes targeted by neutralizing antibodies that could be potent targets for vaccines and therapeutics, and shed light towards the importance of effector functions in immunity against MACV.



MACV infections are a significant public health concern and lead to high case fatality rates. No specific treatment or vaccine for MACV infections exist. However, cases of Junin virus infection, a related virus, can be treated with convalescent serum. This indicates, that a mAb-based therapy for MACV could be effective. Here, we describe several mAbs that neutralize MACV and could be used for this purpose.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Arenavirus; Machupo virus; Monoclonal antibodies; Bolivian Hemorrhagic Fever.


#Junin Virus Triggers #Macrophage Activation and Modulates Polarization According to Viral Strain #Pathogenicity (Front Immunol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Front Immunol. 2019 Oct 22;10:2499. doi: 10.3389/fimmu.2019.02499. eCollection 2019.

Junin Virus Triggers Macrophage Activation and Modulates Polarization According to Viral Strain Pathogenicity.

Ferrer MF1, Thomas P1, López Ortiz AO1,2, Errasti AE3, Charo N2, Romanowski V1,4, Gorgojo J5, Rodriguez ME5, Carrera Silva EA2, Gómez RM1,4.

Author information: 1 Laboratorio de Virus Animales, Instituto de Biotecnología y Biología Molecular, CONICET-Universidad Nacional de La Plata, La Plata, Argentina. 2 Laboratorio de Trombosis Experimental, Instituto de Medicina Experimental, CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina. 3 Facultad de Medicina, Instituto de Farmacologia, University of Buenos Aries, Buenos Aires, Argentina. 4 Global Viral Network, Baltimore, MD, United States. 5 Centro de Investigación y Desarrollo en Fermentaciones Industriales, CONICET-Universidad Nacional de La Plata, La Plata, Argentina.



The New World arenavirus Junin (JUNV) is the etiological agent of Argentine hemorrhagic fever (AHF). Previous studies of human macrophage infection by the Old-World arenaviruses Mopeia and Lassa showed that while the non-pathogenic Mopeia virus replicates and activates human macrophages, the pathogenic Lassa virus replicates but fails to activate human macrophages. Less is known in regard to the impact of New World arenavirus infection on the human macrophage immune response. Macrophage activation is critical for controlling infections but could also be usurped favoring immune evasion. Therefore, it is crucial to understand how the JUNV infection modulates macrophage plasticity to clarify its role in AHF pathogenesis. With this aim in mind, we compared infection with the attenuated Candid 1 (C#1) or the pathogenic P strains of the JUNV virus in human macrophage cultures. The results showed that both JUNV strains similarly replicated and induced morphological changes as early as 1 day post-infection. However, both strains differentially induced the expression of CD71, the receptor for cell entry, the activation and maturation molecules CD80, CD86, and HLA-DR and selectively modulated cytokine production. Higher levels of TNF-α, IL-10, and IL-12 were detected with C#1 strain, while the P strain induced only higher levels of IL-6. We also found that C#1 strain infection skewed macrophage polarization to M1, whereas the P strain shifted the response to an M2 phenotype. Interestingly, the MERTK receptor, that negatively regulates the immune response, was down-regulated by C#1 strain and up-regulated by P strain infection. Similarly, the target genes of MERTK activation, the cytokine suppressors SOCS1 and SOCS3, were also increased after P strain infection, in addition to IRF-1, that regulates type I IFN levels, which were higher with C#1 compared with P strain infection. Together, this differential activation/polarization pattern of macrophages elicited by P strain suggests a more evasive immune response and may have important implications in the pathogenesis of AHF and underpinning the development of new potential therapeutic strategies.

Copyright © 2019 Ferrer, Thomas, López Ortiz, Errasti, Charo, Romanowski, Gorgojo, Rodriguez, Carrera Silva and Gómez.

KEYWORDS: IFN-I; TAM receptors; human macrophages; junin virus; macrophage activation; macrophage polarization

PMID: 31695702 PMCID: PMC6817498 DOI: 10.3389/fimmu.2019.02499

Keywords: Arenavirus; Junin virus; Argentine Hemorrhagic Fever; Mopeia virus; Lassa fever virus; Viral pathogenesis.


#Density-dependence and #persistence of #Morogoro #arenavirus #transmission in a fluctuating population of its reservoir host (J Anim Ecol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

J Anim Ecol. 2019 Sep 23. doi: 10.1111/1365-2656.13107. [Epub ahead of print]

Density-dependence and persistence of Morogoro arenavirus transmission in a fluctuating population of its reservoir host.

Mariën J1, Borremans B1,2,3, Verhaeren C1, Kirkpatrick L1, Gryseels S1,4,5, Goüy de Bellocq J6, Günther S7, Sabuni CA8, Massawe AW8, Reijniers J1,9, Leirs H1.

Author information: 1 Evolutionary Ecology Group, University of Antwerp, Antwerp, Belgium. 2 Department of Ecology and Evolutionary Biology, University of California, Los Angeles, USA. 3 Interuniversity Institute for Biostatistics and statistical Bioinformatics (I-BIOSTAT), Hasselt University, Hasselt, Belgium. 4 Department of Ecology and Evolutionary Biology, University of Arizona, Tucson, USA. 5 Clinical and Epidemiological Virology, Rega Institute, KU Leuven, Leuven, Belgium. 6 Institute of Vertebrate Biology, Research Facility Studenec, The Czech Academy of Sciences, Brno, Czech Republic. 7 Bernhard-Nocht-Institute for Tropical Medicine, Hamburg, Germany. 8 PestManagement Centre, Sokoine University of Agriculture, Morogoro, Tanzania. 9 Department of Engineering Management, University of Antwerp, Antwerp, Belgium.



1.A key aim in wildlife disease ecology is to understand how host and parasite characteristics influence parasite transmission and persistence. Variation in host population density can have strong impacts on transmission and outbreaks, and theory predicts particular transmission-density patterns depending on how parasites are transmitted between individuals. Here, we present the results of a study on the dynamics of Morogoro arenavirus in a population of multimammate mice (Mastomys natalensis). This widespread African rodent, which is also the reservoir host of Lassa arenavirus in West Africa, is known for its strong seasonal density fluctuations driven by food availability.

2.We investigated to what degree virus transmission changes with host population density and how the virus might be able to persist during periods of low host density.

3.A seven-year capture-mark-recapture study was conducted in Tanzania where rodents were trapped monthly and screened for the presence of antibodies against Morogoro virus. Observed seasonal seroprevalence patterns were compared with those generated by mathematical transmission models to test different hypotheses regarding the degree of density-dependence and the role of chronically infected individuals.

4.We observed that Morogoro virus seroprevalence correlates positively with host density with a lag of one to four months. Model results suggest that the observed seasonal seroprevalence dynamics can be best explained by a combination of vertical and horizontal transmission, and that a small number of animals needs to be infected chronically to ensure viral persistence.

5.Transmission dynamics and viral persistence were best explained by the existence of both acutely and chronically infected individuals, and by seasonally changing transmission rates. Due to the presence of chronically infected rodents, rodent control is unlikely to be a feasible approach for eliminating arenaviruses such as Lassa virus from Mastomys populations.

© 2019 The Authors. Journal of Animal Ecology © 2019 British Ecological Society.

PMID: 31545505 DOI: 10.1111/1365-2656.13107

Keywords: Arenavirus; Wildlife; Rodents; Morogoro virus; Seroprevalence; Tanzania.


Convergent #Structures Illuminate #Features for #Germline #Antibody Binding and Pan- #Lassa Virus Neutralization (Cell, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Cell. 2019 Aug 8;178(4):1004-1015.e14. doi: 10.1016/j.cell.2019.07.020.

Convergent Structures Illuminate Features for Germline Antibody Binding and Pan-Lassa Virus Neutralization.

Hastie KM1, Cross RW2, Harkins SS1, Zandonatti MA1, Koval AP3, Heinrich ML3, Rowland MM3, Robinson JE4, Geisbert TW2, Garry RF5, Branco LM3, Saphire EO6.

Author information: 1 La Jolla Institute for Immunology, La Jolla, CA, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA. 2 University of Texas Medical Branch, Galveston National Laboratory, Galveston, TX, USA. 3 Zalgen Labs, Germantown, MD, USA. 4 Department of Pediatrics, School of Medicine, Tulane University, New Orleans, LA, USA. 5 Zalgen Labs, Germantown, MD, USA; Department of Microbiology and Immunology, Tulane University, New Orleans, LA, USA. 6 La Jolla Institute for Immunology, La Jolla, CA, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA; Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA. Electronic address: erica@lji.org.



Lassa virus (LASV) causes hemorrhagic fever and is endemic in West Africa. Protective antibody responses primarily target the LASV surface glycoprotein (GPC), and GPC-B competition group antibodies often show potent neutralizing activity in humans. However, which features confer potent and broadly neutralizing antibody responses is unclear. Here, we compared three crystal structures of LASV GPC complexed with GPC-B antibodies of varying neutralization potency. Each GPC-B antibody recognized an overlapping epitope involved in binding of two adjacent GPC monomers and preserved the prefusion trimeric conformation. Differences among GPC-antibody interactions highlighted specific residues that enhance neutralization. Using structure-guided amino acid substitutions, we increased the neutralization potency and breadth of these antibodies to include all major LASV lineages. The ability to define antibody residues that allow potent and broad neutralizing activity, together with findings from analyses of inferred germline precursors, is critical to develop potent therapeutics and for vaccine design and assessment.

Copyright © 2019 Elsevier Inc. All rights reserved.

KEYWORDS: Lassa virus; antibody; arenavirus; germline; neutralization; protein engineering; structural biology

PMID: 31398326 DOI: 10.1016/j.cell.2019.07.020

Keywords: Arenavirus; Lassa fever.


A short #history of #Lassa fever: the first 10-15 years after #discovery (Curr Opin Virol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Curr Opin Virol. 2019 Jul 16;37:77-83. doi: 10.1016/j.coviro.2019.06.005. [Epub ahead of print]

A short history of Lassa fever: the first 10-15 years after discovery.

Monath TP1.

Author information: 1 Crozet BioPharma LLC, 94 Jackson Road Suite 108, Devens, MA 01434, United States. Electronic address: tom.monath@crozetbiopharma.com.



This brief review is focused on the events surrounding the initial discovery of a new viral hemorrhagic fever in 1969 and the subsequent 10-15 years during which a substantial understanding of the disease was gained. In 1969, a series of sequential life-threating or fatal infections occurred among health care workers in Nigeria and the laboratory scientist who isolated and characterized the causative agent. The agent, Lassa virus was named after the geographical location of the first recognized human case. The new virus was shown to be related to lymphocytic choriomeningitis and to previously unclassified neotropical viruses, including Argentine and Bolivian hemorrhagic fevers, and a new taxonomic grouping, the Arenaviruses, was proposed. In 1970-72, three further epidemics occurred in Nigeria, Liberia and Sierra Leone, the first two involved nosocomial transmission, and the third was a community-based outbreak, during which the rodent reservoir host was identified. In 1976, a long-term research project commenced in Sierra Leone, which produced a rich body of data from prospectively designed studies on the clinical features, transmission, and treatment of the disease.

Copyright © 2019. Published by Elsevier B.V.

PMID: 31323506 DOI: 10.1016/j.coviro.2019.06.005

Keywords: Arenavirus; Lassa fever.


#Junín Virus Promotes #Autophagy to Facilitate Viral Life Cycle (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Junín Virus Promotes Autophagy to Facilitate Viral Life Cycle

Julieta S. Roldán, Nélida A. Candurra, María I. Colombo, Laura R. Delgui

DOI: 10.1128/JVI.02307-18



Junín virus (JUNV), a member of Arenaviridae family, 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 anti-viral role; however, several viruses subvert this pathway in their benefit. We determined the role of autophagy in JUNV-infected cells analyzing LC3, a cytoplasmic protein (LC3-I) which becomes vesicle membrane-associated (LC3-II) upon induction of autophagy. Cells overexpressing EGFP-LC3 and infected with JUNV showed an increased number of LC3 puncta structures, similar to that 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 that 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 p.i. whereas the UV-inactivated virus did not induce the pathway. Cells subjected to starvation or pre-treated with rapamycin, a pharmacological autophagy inductor, enhanced virus yield. Also, we assayed the replication capacity of JUNV in Atg 5 knock-out or Beclin-1 knock-down 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.



Mammalian arenaviruses are zoonotic viruses causing asymptomatic and persistent infections in their rodent hosts, but may produce severe and lethal haemorrhagic fevers in humans. Currently, there are neither effective therapeutic options nor effective vaccines, for viral haemorrhagic fevers caused by human pathogenic arenaviruses, except the vaccine Candid #1 against AHF, licensed for human use in endemic areas from 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 against these viruses. Autophagy is a lysosomal degradative pathway involved in maintaining the cellular homeostasis, representing powerful anti-infective machinery. We showed, for the first time for a member of the Arenaviridae family, a pro-viral role of autophagy in JUNV infection, providing new knowledge in the edge of host-virus interaction. Therefore, modulation of virus-induced autophagy could be used as a strategy to block arenaviruses infections.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Arenavirus; Junin virus; Argentina Hemorrhagic Fever; Viral pathogenesis.