Natural History of #Aerosol Induced #Lassa Fever in Non‑Human #Primates (Viruses, abstract)

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

Viruses. 2020 May 29;12(6):E593. doi: 10.3390/v12060593.

Natural History of Aerosol Induced Lassa Fever in Non‑Human Primates

Isaac L Downs 1, Carl I Shaia 1, Xiankun Zeng 1, Joshua C Johnson 1 2, Lisa Hensley 1 2, David L Saunders 1, Franco Rossi 1, Kathleen A Cashman 1, Heather L Esham 1, Melissa K Gregory 1, William D Pratt 1, John C Trefry 1 3, Kyle A Everson 1, Charles B Larcom 4, Arthur C Okwesili 1, Anthony P Cardile 1, Anna Honko 1 5

Affiliations: 1 US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA. 2 Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702, USA. 3 Defense Threat Reduction Agency, Fort Belvoir, VA 22060, USA. 4 Madigan Army Medical Center, Joint Base Lewis‑McChord, WA 98431, USA. 5 National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, MA 02118, USA.

PMID: 32485952 DOI: 10.3390/v12060593

 

Abstract

Lassa virus (LASV), an arenavirus causing Lassa fever, is endemic to West Africa with up to 300,000 cases and between 5000 and 10,000 deaths per year. Rarely seen in the United States, Lassa virus is a CDC category A biological agent inasmuch deliberate aerosol exposure can have high mortality rates compared to naturally acquired infection. With the need for an animal model, specific countermeasures remain elusive as there is no FDA-approved vaccine. This natural history of aerosolized Lassa virus exposure in Macaca fascicularis was studied under continuous telemetric surveillance. The macaque response to challenge was largely analogous to severe human disease with fever, tachycardia, hypotension, and tachypnea. During initial observations, an increase trend of activated monocytes positive for viral glycoprotein was accompanied by lymphocytopenia. Disease uniformly progressed to high viremia followed by low anion gap, alkalosis, anemia, and thrombocytopenia. Hypoproteinemia occurred late in infection followed by increased levels of white blood cells, cytokines, chemokines, and biochemical markers of liver injury. Viral nucleic acids were detected in tissues of three non‑survivors at endpoint, but not in the lone survivor. This study provides useful details to benchmark a pivotal model of Lassa fever in support of medical countermeasure development for both endemic disease and traditional biodefense purposes.

Keywords: Lassa fever; Animal models.

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Is the #COVID19 pandemic masking the deadlier #Lassa fever #epidemic in #Nigeria? (J Clin Virol., abstract)

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

Journal of Clinical Virology | Available online 13 May 2020, 104434 | In Press, Journal Pre-proof

Is the COVID-19 pandemic masking the deadlier Lassa fever epidemic in Nigeria?

Rine Christopher Reuben 1, Margaret M.A. Danladi 2, Grace Rinmecit Pennap 3

1 Department of Science Laboratory Technology, Nasarawa State Polytechnic, Lafia, Nigeria; 2 Department of Microbiology, Nasarawa State University, Keffi-Nigeria; 3 Department of Microbiology, Plateau State University, Bokkos, Nigeria

Received 8 May 2020, Accepted 10 May 2020, Available online 13 May 2020.

DOI: https://doi.org/10.1016/j.jcv.2020.104434

 

Abstract

With the COVID-19 officially declared a pandemic, Nigeria alongside other countries is directing all its resources and manpower to contain this pandemic. However, the existence of Lassa fever (LF), a more severe, zoonotic, endemic and viral haemorrhagic fever caused by Lassa virus with higher case fatality ratio (CFR) rages on across Nigeria while receiving little or no public health attention. The simultaneously increasing cases of COVID-19 and LF across Nigeria would be catastrophic unless infection prevention and control measures toward both LF and COVID-19 outbreaks are considered alongside.

Keywords: SARS-CoV-2; COVID-19; Lassa fever; Nigeria.

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#Epidemiology and Case–Control Study of #Lassa Fever #Outbreak in #Nigeria from 2018 to 2019 (J Infect., abstract)

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

Epidemiology and Case–Control Study of Lassa Fever Outbreak in Nigeria from 2018 to 2019

Oladipupo Ipadeola a,1, Yuki Furuse b,c,d,1, Elsie A Ilori e, Chioma C Dan-Nwafor e, Kachikwulu O Akabike e, Anthony Ahumibe e, Winifred Ukponu f,g, Lawal Bakare e, Gbenga Joseph e, Muhammad Saleh a, Esther Namukose Muwanguzi b, Adebola Olayinka b, Geoffrey Namara b, Dhamari Naidoo b, Akanimo Iniobong e, Michael Amedu e, Nkem Ugbogulu h, Favour Makava f, Olawunmi Adeoye i, Chukwuemeka Uzoho i, Chimezie Anueyiagu e, Tochi J Okwor e, Nwando G Mba e, Adejoke Akano e, Abiodun Ogunniyi e, Amina Mohammed e, Ayodele Adeyemo j, Dike K Ugochukwu e, Emmanuel Agogo e, Chikwe Ihekweazu e

DOI: https://doi.org/10.1016/j.jinf.2019.12.020

Published online: January 08, 2020 – Accepted: December 31, 2019

 

Abstract

Poller et al, in this Journal, provided a useful consensus for use of personal protective equipment for managing high consequence infectious disease1. Although this was driven largely by recent Ebola virus disease emergencies, we should remind your readers of the continuing problem of Lassa fever (LF) in West Africa. LF is a febrile infectious disease caused by Lassa virus. The clinical presentation of the disease is nonspecific and includes fever, fatigue, hemorrhage, gastrointestinal symptoms, respiratory symptoms, and neurological symptoms2.

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1 These first authors contributed equally to this article.

© 2020 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Keywords: Lassa fever; Nigeria.

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Large-scale #Lassa fever #outbreaks in #Nigeria: quantifying the association between disease reproduction number and local #rainfall (Epidemiol Infect., abstract)

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

Epidemiol Infect. 2020 Jan 10;148:e4. doi: 10.1017/S0950268819002267.

Large-scale Lassa fever outbreaks in Nigeria: quantifying the association between disease reproduction number and local rainfall.

Zhao S1,2,3,4, Musa SS2, Fu H5, He D2, Qin J1.

Author information: 1 School of Nursing, Hong Kong Polytechnic University, Hong Kong, China. 2 Department of Applied Mathematics, Hong Kong Polytechnic University, Hong Kong, China. 3 Division of Biostatistics, JC School of Public Health and Primary Care, Chinese University of Hong Kong, Hong Kong, China. 4 Clinical Trials and Biostatistics Lab, Shenzhen Research Institute, Chinese University of Hong Kong, Shenzhen, China. 5 Department of Crop Science and Technology, College of Agriculture, South China Agricultural University, Guangzhou, China.

 

Abstract

Lassa fever (LF) is increasingly recognised as an important rodent-borne viral haemorrhagic fever presenting a severe public health threat to sub-Saharan West Africa. In 2017-18, LF caused an unprecedented epidemic in Nigeria and the situation was worsening in 2018-19. This work aims to study the epidemiological features of epidemics in different Nigerian regions and quantify the association between reproduction number (R) and state rainfall. We quantify the infectivity of LF by the reproduction numbers estimated from four different growth models: the Richards, three-parameter logistic, Gompertz and Weibull growth models. LF surveillance data are used to fit the growth models and estimate the Rs and epidemic turning points (τ) in different regions at different time periods. Cochran’s Q test is further applied to test the spatial heterogeneity of the LF epidemics. A linear random-effect regression model is adopted to quantify the association between R and state rainfall with various lag terms. Our estimated Rs for 2017-18 (1.33 with 95% CI 1.29-1.37) was significantly higher than those for 2016-17 (1.23 with 95% CI: (1.22, 1.24)) and 2018-19 (ranged from 1.08 to 1.36). We report spatial heterogeneity in the Rs for epidemics in different Nigerian regions. We find that a one-unit (mm) increase in average monthly rainfall over the past 7 months could cause a 0.62% (95% CI 0.20%-1.05%)) rise in R. There is significant spatial heterogeneity in the LF epidemics in different Nigerian regions. We report clear evidence of rainfall impacts on LF epidemics in Nigeria and quantify the impact.

KEYWORDS: Lassa fever; Nigeria; modelling analysis; rainfall; reproduction number; spatial heterogeneity

PMID: 31918780 DOI: 10.1017/S0950268819002267

Keywords: Lassa fever; Nigeria.

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#Sequelae of #Lassa Fever: Postviral #Cerebellar #Ataxia (Open Forum Infect Dis., abstract)

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

Open Forum Infect Dis. 2019 Dec 3;6(12):ofz512. doi: 10.1093/ofid/ofz512. eCollection 2019 Dec.

Sequelae of Lassa Fever: Postviral Cerebellar Ataxia.

Ezeomah C1,2, Adoga A3, Ihekweazu C4, Paessler S1,2, Cisneros I1,2,5, Tomori O6, Walker D1,7.

Author information: 1 Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA. 2 Galveston National Laboratory, Institute of Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, USA. 3 Department of Otorhinolaryngology, Head and Neck Surgery, Jos University Teaching Hospital, University of Jos, Jos, Nigeria. 4 Nigerian Center for Disease Control, Federal Ministry of Health, Abuja, Nigeria. 5 Center for Addiction Research, University of Texas Medical Branch, Galveston, Texas, USA. 6 National Lassa Fever Steering Committee, Federal Ministry of Health, Abuja, Nigeria. 7 Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, USA.

 

Abstract

Lassa fever is a zoonotic disease endemic in some West African countries. It is exported to countries in America, Asia, and Europe. Antivirals against Lassa fever are important to provide a cure in patients with the disease and provide protection against it. In addition, due to the potential utilization of Lassa virus as a bioterrorism agent, vaccines against the disease can be utilized as a counterterrorism measure. Developing antiviral compounds and vaccines against the disease requires understanding of the pathogenesis of Lassa fever and its disease course, including the signs, symptoms, complications, and sequelae. An important sequela of Lassa fever is ataxia. A few cases of postviral ataxia following Lassa fever have been described in the literature. This review focuses on highlighting these cases, the gaps in scientific knowledge where further research is needed, and possible ways of diagnosing postviral ataxia after Lassa fever in resource-limited settings.

© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

KEYWORDS: Lassa fever; ataxia; neurodegenerative disorder; postviral; sequelae of Lassa fever

PMID: 31879673 PMCID: PMC6923636 DOI: 10.1093/ofid/ofz512

Keywords: Lassa fever; Cerebellar ataxia.

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The #antifungal #isavuconazole inhibits the entry of #lassa virus by targeting the stable signal peptide-GP2 subunit interface of lassa virus glycoprotein (Antiviral Res., abstract)

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

Antiviral Res. 2019 Dec 23:104701. doi: 10.1016/j.antiviral.2019.104701. [Epub ahead of print]

The antifungal isavuconazole inhibits the entry of lassa virus by targeting the stable signal peptide-GP2 subunit interface of lassa virus glycoprotein.

Zhang X1, Tang K1, Guo Y2.

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 & Peking Union Medical College, Beijing, China. 2 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 & Peking Union Medical College, Beijing, China. Electronic address: yingguo6@imm.ac.cn.

 

Abstract

Lassa virus (LASV) is the causative agent of Lassa hemorrhagic fever in humans, and the limited therapeutic treatment for Lassa fever poses significant threat to public health in West Africa. Using an HIV based pseudovirus platform, we identified isavuconazole, a triazole antifungal for systemic use, as a LASV entry inhibitor with an EC50 of 1.2 μM. Isavuconazole inhibits Lassa virus entry by blocking the pH dependent viral fusion mediated by the Lassa virus surface glycoprotein. Fragment replacement mutational study indicated that isavuconazole targets the stable signal peptide (SSP)-membrane fusion subunit (GP2) interface of Lassa glycoprotein. Further mutational study of the SSP-GP2 region of LASV glycoprotein revealed that S27 in the N-terminal transmembrane region of SSP and V431, F434 and V435 in the transmembrane domain of GP2 affect anti-LASV activity of isavuconazole. Isavuconazole also displays antiviral activity to five New World (NW) mammarenaviruses that cause hemorrhagic fever. This study facilitates the potential repurposing of isavuconazole for therapeutic intervention against human-pathogenic arenaviruses, and provides the basis for further structural optimization of arenavirus fusion inhibitors based on the predicted structural characteristics of the unique SSP-GP2 interface.

Copyright © 2019. Published by Elsevier B.V.

KEYWORDS: Arenavirus; Drug repurposing; Entry inhibitor; Glycoprotein; Isavuconazole; Lassa virus

PMID: 31877348 DOI: 10.1016/j.antiviral.2019.104701

Keywords: Antivirals; Mammarenavirus; Lassa fever; Isavuconazole.

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Delayed-onset #paraparesis in #Lassa fever: A case report (Int J Infect Dis., abstract)

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

Int J Infect Dis. 2019 Dec 19. pii: S1201-9712(19)30495-3. doi: 10.1016/j.ijid.2019.12.022. [Epub ahead of print]

Delayed-onset paraparesis in Lassa fever: A case report.

Duvignaud A1, Doutchi M2, Abejegah C3, Etafo I4, Jaspard M5, Serra B6, Tricaud E7, Levy-Marchal C8, Anglaret X9, Ahmed LA10, Adedosu AN11, Malvy D12, Ayodeji OO13.

Author information: 1 Inserm U1219, University of Bordeaux, 146 Rue Léo Saignat, 33076 Bordeaux, France; Department of Infectious Diseases and Tropical Medicine, Division of Tropical Medicine and Clinical International Health, CHU de Bordeaux, Hôpital Pellegrin, Place Amélie Raba Léon, 33076 Bordeaux, France; Programme PAC-CI/ANRS Research Site, CHU de Treichville, 18 BP 1954 Abidjan 18, Abidjan, Côte d’Ivoire. Electronic address: alex.duvignaud@gmail.com. 2 The Alliance for International Medical Action, Route de l’Aéroport, Rue NG 96 BP: 15530, Dakar, Senegal; Department of Infectious Diseases, Centre Hospitalier National de Zinder, Zinder, Niger. Electronic address: m.doutchi@yahoo.fr. 3 Infection Control and Research Centre, Community Health Department, Federal Medical Centre Owo, Michael Adekun Ajasin Road, PMB 1053, Owo, Ondo State, Nigeria. Electronic address: cabejegah2007@gmail.com. 4 Infection Control and Research Centre, Community Health Department, Federal Medical Centre Owo, Michael Adekun Ajasin Road, PMB 1053, Owo, Ondo State, Nigeria. Electronic address: eziunorijeoma2014@yahoo.com. 5 Inserm U1219, University of Bordeaux, 146 Rue Léo Saignat, 33076 Bordeaux, France; Programme PAC-CI/ANRS Research Site, CHU de Treichville, 18 BP 1954 Abidjan 18, Abidjan, Côte d’Ivoire; The Alliance for International Medical Action, Route de l’Aéroport, Rue NG 96 BP: 15530, Dakar, Senegal. Electronic address: marie.jaspard@coral.alima.ngo. 6 Inserm U1219, University of Bordeaux, 146 Rue Léo Saignat, 33076 Bordeaux, France; Programme PAC-CI/ANRS Research Site, CHU de Treichville, 18 BP 1954 Abidjan 18, Abidjan, Côte d’Ivoire; The Alliance for International Medical Action, Route de l’Aéroport, Rue NG 96 BP: 15530, Dakar, Senegal. Electronic address: beatrice.serra33@gmail.com. 7 Imagerie médicale du 109, Rue de Messei, Flers, France. Electronic address: elise.tricaud@gmail.com. 8 The Alliance for International Medical Action, Route de l’Aéroport, Rue NG 96 BP: 15530, Dakar, Senegal. Electronic address: claire.levy-marchal@coral.alima.ngo. 9 Inserm U1219, University of Bordeaux, 146 Rue Léo Saignat, 33076 Bordeaux, France; Programme PAC-CI/ANRS Research Site, CHU de Treichville, 18 BP 1954 Abidjan 18, Abidjan, Côte d’Ivoire. Electronic address: Xavier.Anglaret@u-bordeaux.fr. 10 Department of Family Medicine, Federal Medical Centre Owo, Michael Adekun Ajasin Road, PMB 1053, Owo, Ondo State, Nigeria. Electronic address: akahmed2@yahoo.co.uk. 11 Viral Hemorrhagic Fever Laboratory, Federal Medical Centre Owo, Michael Adekun Ajasin Road, PMB 1053, Owo, Ondo State, Nigeria. Electronic address: nelsonadedosu@gmail.com. 12 Inserm U1219, University of Bordeaux, 146 Rue Léo Saignat, 33076 Bordeaux, France; Department of Infectious Diseases and Tropical Medicine, Division of Tropical Medicine and Clinical International Health, CHU de Bordeaux, Hôpital Pellegrin, Place Amélie Raba Léon, 33076 Bordeaux, France; Programme PAC-CI/ANRS Research Site, CHU de Treichville, 18 BP 1954 Abidjan 18, Abidjan, Côte d’Ivoire. Electronic address: denis.malvy@chu-bordeaux.fr. 13 Infection Control and Research Centre, Community Health Department, Federal Medical Centre Owo, Michael Adekun Ajasin Road, PMB 1053, Owo, Ondo State, Nigeria. Electronic address: femiayodeji@yahoo.com.

 

Abstract

Lassa fever (LF) is an endemic viral hemorrhagic fever in West Africa. Among the serious complications of the disease are neurological manifestations whose spectrum is incompletely known. Here we report the case of a 61-year-old man who developed a delayed-onset paraparesis a few weeks after getting infected with Lassa virus thereby suggesting a possible association between LF and spinal cord disorders.

Copyright © 2019. Published by Elsevier Ltd.

KEYWORDS: Acute Kidney Injury; Central Nervous System; Lassa fever; Myelitis; Nigeria; Paraparesis

PMID: 31866549 DOI: 10.1016/j.ijid.2019.12.022

Keywords: Lassa fever; Paraparesis; Neurology.

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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.

 

Abstract

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.

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A cell-based, infectious-free, #platform to identify #inhibitors of #lassa virus #ribonucleoprotein (vRNP) activity (Antiviral Res., abstract)

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

Antiviral Res. 2019 Nov 28:104667. doi: 10.1016/j.antiviral.2019.104667. [Epub ahead of print]

A cell-based, infectious-free, platform to identify inhibitors of lassa virus ribonucleoprotein (vRNP) activity.

Cubitt B1, Ortiz-Riano E2, Cheng BY2, Kim YJ1, Yeh CD3, Chen CZ3, Southall NOE3, Zheng W3, Martinez-Sobrido L2, de la Torre JC4.

Author information: 1 Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, 92037, USA. 2 Department of Microbiology and Immunology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY, 14642, USA. 3 National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20892, USA. 4 Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, 92037, USA. Electronic address: juanct@scripps.edu.

 

Abstract

The mammarenavirus Lassa (LASV) is highly prevalent in West Africa where it infects several hundred thousand individuals annually resulting in a high number of Lassa fever (LF) cases, a febrile disease associated with high morbidity and significant mortality. Mounting evidence indicates that the worldwide-distributed prototypic mammarenavirus lymphocytic choriomeningitis virus (LCMV) is a neglected human pathogen of clinical significance. There are not Food and Drug Administration (FDA) licensed vaccines and current anti-mammarenavirus therapy is limited to an off-label use of ribavirin that is only partially effective and can cause significant side effects. Therefore, there is an unmet need for novel antiviral drugs to combat LASV. This task would be facilitated by the implementation of high throughput screens (HTS) to identify inhibitors of the activity of the virus ribonucleoprotein (vRNP) responsible for directing virus RNA genome replication and gene transcription. The use of live LASV for this purpose is jeopardized by the requirement of biosafety level 4 (BSL4) containment. We have developed a virus-free cell platform, where expression levels of reporter genes serve as accurate surrogates of vRNP activity, to develop cell-based assays compatible with HTS to identify inhibitors of LASV and LCMV mammarenavirus vRNP activities.

Copyright © 2019. Published by Elsevier B.V.

PMID: 31786250 DOI: 10.1016/j.antiviral.2019.104667

Keywords: Mammarenavirus; Lassa fever; Ribavirin.

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#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.

 

Abstract

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.

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