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.

 

Abstract

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.

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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.

 

Abstract

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.

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#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

 

ABSTRACT

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.

 

IMPORTANCE

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.

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#Aporé virus, a novel #mammarenavirus (#Bunyavirales: #Arenaviridae) related to highly pathogenic virus from South #America (Mem Inst Oswaldo Cruz, abstract)

[Source: Memoria do Institutos Oswaldo Cruz, full page: (LINK). Abstract, edited.]

Aporé virus, a novel mammarenavirus (Bunyavirales: Arenaviridae) related to highly pathogenic virus from South America

[ACCEPTED ARTICLES / PRELIMINARY VERSION]

Jorlan Fernandes1,+, Alexandro Guterres1, Renata Carvalho de Oliveira1, Rodrigo Jardim2, Alberto Martín Rivera Dávila2, Roger Hewson3, Elba Regina Sampaio de Lemos1

1 Laboratório de Hantaviroses e Rickettsioses, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro – RJ, Brasil; 2 Laboratório de Biologia Computacional e Sistemas, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro – RJ, Brasil; 3 National Infection Service, Public Health England, Salisbury, United Kingdom

DOI: 10.1590/0074-02760180586

 

ABSTRACT

Here, we report the complete genome sequence of the Aporé virus (Bunyavirales: Arenaviridae), obtained from a wild rodent Oligoryzomys mattogrossae captured in Mato Grosso do Sul state, Brazil. The genome of this virus showed strong similarity to highly pathogenic mammarenavirus from South America.

key words: Oligoryzomys – mattogrossae rodent mammarenavirus – arenavirus – Aporé virus

Financial support: FIOCRUZ, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – CAPES and Conselho Nacional para o Desenvolvimento Científico e Tecnológico (CNPq), grant number 404762/2016-6.

+ Corresponding author: jorlan@ioc.fiocruz.br

Received 14 December 2018  – Accepted 29 April 2019

Keywords: Mammarenavirus; Bunyavirus; Arenavirus; Aporé virus; Brazil.

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Quantifying the seasonal #drivers of #transmission for #Lassa fever in #Nigeria (Philos Transact Roy Soc B., abstract)

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

Philos Trans R Soc Lond B Biol Sci. 2019 Jun 24;374(1775):20180268. doi: 10.1098/rstb.2018.0268.

Quantifying the seasonal drivers of transmission for Lassa fever in Nigeria.

Akhmetzhanov AR1, Asai Y1, Nishiura H1.

Author information: 1 Graduate School of Medicine, Hokkaido University , Sapporo, Hokkaido , Japan.

 

Abstract

Lassa fever (LF) is a zoonotic disease that is widespread in West Africa and involves animal-to-human and human-to-human transmission. Animal-to-human transmission occurs upon exposure to rodent excreta and secretions, i.e. urine and saliva, and human-to-human transmission occurs via the bodily fluids of an infected person. To elucidate the seasonal drivers of LF epidemics, we employed a mathematical model to analyse the datasets of human infection, rodent population dynamics and climatological variations and capture the underlying transmission dynamics. The surveillance-based incidence data of human cases in Nigeria were explored, and moreover, a mathematical model was used for describing the transmission dynamics of LF in rodent populations. While quantifying the case fatality risk and the rate of exposure of humans to animals, we explicitly estimated the corresponding contact rate of humans with infected rodents, accounting for the seasonal population dynamics of rodents. Our findings reveal that seasonal migratory dynamics of rodents play a key role in regulating the cyclical pattern of LF epidemics. The estimated timing of high exposure of humans to animals coincides with the time shortly after the start of the dry season and can be associated with the breeding season of rodents in Nigeria. This article is part of the theme issue ‘Modelling infectious disease outbreaks in humans, animals and plants: approaches and important themes’. This issue is linked with the subsequent theme issue ‘Modelling infectious disease outbreaks in humans, animals and plants: epidemic forecasting and control’.

KEYWORDS: Arenaviridae; Lassa haemorrhagic fever; multimammate rat; reservoir host; seasonality

PMID: 31056054 DOI: 10.1098/rstb.2018.0268

Keywords: Arenavirus; Lassa fever; West Africa.

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Identification of a #clinical #compound #losmapimod that blocks #Lassa virus entry (Antiviral Res., abstract)

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

Antiviral Res. 2019 Apr 3. pii: S0166-3542(18)30780-0. doi: 10.1016/j.antiviral.2019.03.014. [Epub ahead of print]

Identification of a clinical compound losmapimod that blocks Lassa virus entry.

Zhang X1, Yan F2, Tang K1, Chen Q1, Guo J3, Zhu W4, He S4, Banadyga L4, Qiu X5, Guo Y6.

Author information: 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. 2 Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, R3E 3R2, Canada; Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, R3E 0J9, Canada; Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Science, Changchun, China. 3 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. 4 Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, R3E 3R2, Canada. 5 Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, R3E 3R2, Canada; Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, R3E 0J9, Canada. Electronic address: xiangguo.qiu@canada.ca. 6 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: yingguo6@imm.ac.cn.

 

Abstract

Lassa virus (LASV) causes Lassa hemorrhagic fever in humans and poses a significant threat to public health in West Africa. Current therapeutic treatments for Lassa fever are limited, making the development of novel countermeasures an urgent priority. In this study, we identified losmapimod, a p38 mitogen-activated protein kinase (MAPK) inhibitor, from 102 screened compounds as an inhibitor of LASV infection. Losmapimod exerted its inhibitory effect against LASV after p38 MAPK down-regulation, and, interestingly, had no effect on other arenaviruses capable of causing viral hemorrhagic fever. Mechanistic studies showed that losmapimod inhibited LASV entry by affecting the stable signal peptide (SSP)-GP2 subunit interface of the LASV glycoprotein, thereby blocking pH-dependent viral fusion. As an aryl heteroaryl bis-carboxyamide derivative, losmapimod represents a novel chemical scaffold with anti-LASV activity, and it provides a new lead structure for the future development of LASV fusion inhibitors.

Copyright © 2019. Published by Elsevier B.V.

KEYWORDS: Drug repurposing; Entry inhibitor; Lassa virus; Losmapimod; SSP-GP2

PMID: 30953674 DOI: 10.1016/j.antiviral.2019.03.014

Keywords: Antivirals; Arenavirus; Lassa fever; Losmapimod.

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Differential #Antibody-Based Immune #Response Against Isolated GP1 #RBDs from #Lassa and #Junín Viruses (J Virol., abstract)

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

Differential Antibody-Based Immune Response Against Isolated GP1 Receptor-Binding Domains from Lassa and Junín Viruses

Aliza Borenstein-Katz, Anastasiya Shulman, Hedva Hamawi, Orith Leitner, Ron Diskin

DOI: 10.1128/JVI.00090-19

 

ABSTRACT

There are two predominant subgroups in the Arenaviridae family of viruses, the Old-World and the New-World viruses that use distinct cellular receptors for entry. While New-World viruses typically elicit good neutralizing antibody responses, the Old-World viruses generally evade such responses. Antibody based immune responses are directed against the glycoprotein spike complexes that decorate the viruses. A thick coat of glycans reduces the accessibility of antibodies to the surface of spike complexes from Old-World viruses but other mechanisms may further hamper the development of efficient humoral responses. Specifically, it was suggested that the GP1 receptor-binding module of the Old-World Lassa virus might help evading humoral response. Here we investigate the immunogenicity of the GP1 domain from Lassa virus and compare it to GP1 domain from the New-World Junín virus. We found striking differences in the ability of antibodies that were developed against these immunogens to target the same GP1 receptor-binding domains in the context of the native spike complexes. Whereas GP1 from Junín virus elicited productive neutralizing responses, GP1 from Lassa virus elicited only non-productive responses. These differences can be rationalized by conformational changes that GP1 from Lassa virus but not from Junín virus, undergoes after dissociating from the trimeric spike complex. Hence shedding of GP1 in the case of Lassa virus can indeed serve as a mechanism to subvert the humoral immune response. Moreover, the realization of using a recombinant protein for eliciting productive response against the New-World Junín virus may suggests a novel and safe way to design future vaccines.

 

IMPORTANCE

Some viruses that belong to the Arenaviridae family like Lassa and Junín viruses are notorious human pathogens, which may lead to fatal outcomes when they infect people. It is thus important to develop means to combat these viruses. For developing effective vaccines, it is vital to understand the basic mechanisms that these viruses utilize in order to evade or overcome host immune responses. It was previously noted that the GP1 receptor-binding domain from Lassa virus is shedded and accumulates in the sera of infected individuals. This raised the possibility that Lassa GP1 may function as an immunological decoy. Here we demonstrate that mice develop non-productive immune responses against GP1 from Lassa virus, which is in contrast to effective neutralizing responses that GP1 from Junín virus elicits. Thus, GP1 from Lassa virus is indeed an immunological decoy and GP1 from Junín virus may serve as a constituent of a future vaccine.

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

Keywords: Arenavirus; Lassa fever; Junin virus; Animal models.

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