|
1
|
Suu-Ire R, Ball S, Ziekah MY, DeMarco J, Kain M, Agyei AS, Epstein JH. Behavioral risk assessment of exposure to wild and domestic animals in response to a Marburg virus disease outbreak, Ghana 2022. One Health 2025; 20:101010. [PMID: 40225191 PMCID: PMC11987680 DOI: 10.1016/j.onehlt.2025.101010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 03/08/2025] [Accepted: 03/08/2025] [Indexed: 04/15/2025] Open
Abstract
In July 2022, Ghana reported its first outbreak of Marburg virus disease (MVD). The source of the outbreak was unknown. In August 2022 we conducted a behavioral risk assessment, surveying 715 participants in three rural communities associated with the presumptive index case: Site 1 in Ashanti Region and Sites 2 and 3 in the Western Region of Ghana. Our primary aim was to characterize exposure to wild and domestic animals, specifically Egyptian rousette bats (ERBs), the natural reservoir for Marburg virus. We focused on two primary routes of potential exposure to ERBs: 1) eating fruit bearing bite marks and 2) entering caves or mines where bats were present. Eating fruit bearing bite marks was common across all sites, but highest at Site 2 in the Western Region. Higher levels of education were negatively correlated with eating fruit bearing bite marks, while having fruit trees present on the participant's home compound increased the odds of this exposure. Residents in Site 3 were significantly more likely to be exposed to bats in caves and mines. Participants across all sites also reported high levels of exposure to bats inside buildings; while ERBs do not typically roost in buildings, this presents a potential risk of exposure to other bat-associated pathogens. One participant at Site 3 reported symptoms consistent with MVD in the previous four months, suggesting the possibility of unrecognized cases that may have been associated with the outbreak. This study identified behaviors within the outbreak regions that could increase the risk of exposure to Marburg virus and other bat-borne pathogens. Serological surveys in these communities would provide important information about the extent of the Marburg outbreak by identifying unreported cases, as well as exposure to other filoviruses.
Collapse
|
|
2
|
Lasso G, Grodus M, Valencia E, DeJesus V, Liang E, Delwel I, Bortz RH, Lupyan D, Ehrlich HY, Castellanos AA, Gazzo A, Wells HL, Wacharapluesadee S, Tremeau-Bravard A, Seetahal JFR, Hughes T, Lee J, Lee MH, Sjodin AR, Geldenhuys M, Mortlock M, Navarrete-Macias I, Gilardi K, Willig MR, Nava AFD, Loh EH, Asrat M, Smiley-Evans T, Magesa WS, Zikankuba S, Wolking D, Suzán G, Ojeda-Flores R, Carrington CVF, Islam A, Epstein JH, Markotter W, Johnson CK, Goldstein T, Han BA, Mazet JAK, Jangra RK, Chandran K, Anthony SJ. Decoding the blueprint of receptor binding by filoviruses through large-scale binding assays and machine learning. Cell Host Microbe 2025; 33:294-313.e11. [PMID: 39818205 PMCID: PMC11825280 DOI: 10.1016/j.chom.2024.12.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 11/06/2024] [Accepted: 12/11/2024] [Indexed: 01/18/2025]
Abstract
Evidence suggests that bats are important hosts of filoviruses, yet the specific species involved remain largely unidentified. Niemann-Pick C1 (NPC1) is an essential entry receptor, with amino acid variations influencing viral susceptibility and species-specific tropism. Herein, we conducted combinatorial binding studies with seven filovirus glycoproteins (GPs) and NPC1 orthologs from 81 bat species. We found that GP-NPC1 binding correlated poorly with phylogeny. By integrating binding assays with machine learning, we identified genetic factors influencing virus-receptor-binding and predicted GP-NPC1-binding avidity for additional filoviruses and bats. Moreover, combining receptor-binding avidities with bat geographic distribution and the locations of previous Ebola outbreaks allowed us to rank bats by their potential as Ebola virus hosts. This study represents a comprehensive investigation of filovirus-receptor binding in bats (1,484 GP-NPC1 pairs, 11 filoviruses, and 135 bats) and describes a multidisciplinary approach to predict susceptible species and guide filovirus host surveillance.
Collapse
Affiliation(s)
- Gorka Lasso
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA.
| | - Michael Grodus
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY 10032, USA
| | - Estefania Valencia
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA
| | - Veronica DeJesus
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA
| | - Eliza Liang
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY 10032, USA
| | - Isabel Delwel
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA
| | - Rob H Bortz
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA
| | | | - Hanna Y Ehrlich
- One Health Institute, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
| | | | - Andrea Gazzo
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Heather L Wells
- Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
| | - Supaporn Wacharapluesadee
- Thai Red Cross Emerging Infectious Diseases Clinical Center, King Chulalongkorn Memorial Hospital, Faculty of Medicine, Chulalongkorn University, Pathumwan, Bangkok 10330, Thailand
| | | | - Janine F R Seetahal
- Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66502, USA
| | - Tom Hughes
- Conservation Medicine, 47000 Sungai Buloh, Selangor, Malaysia; EcoHealth Alliance, New York, NY 10018, USA
| | - Jimmy Lee
- Conservation Medicine, 47000 Sungai Buloh, Selangor, Malaysia; EcoHealth Alliance, New York, NY 10018, USA
| | - Mei-Ho Lee
- Conservation Medicine, 47000 Sungai Buloh, Selangor, Malaysia; EcoHealth Alliance, New York, NY 10018, USA
| | - Anna R Sjodin
- Department of Ecology and Evolutionary Biology, University of Connecticut, Storrs, CT 06269, USA
| | - Marike Geldenhuys
- Centre for Viral Zoonoses, Department of Medical Virology, University of Pretoria, Pretoria 0001, South Africa
| | - Marinda Mortlock
- Centre for Viral Zoonoses, Department of Medical Virology, University of Pretoria, Pretoria 0001, South Africa
| | - Isamara Navarrete-Macias
- Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
| | - Kirsten Gilardi
- One Health Institute, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
| | - Michael R Willig
- Department of Ecology and Evolutionary Biology, University of Connecticut, Storrs, CT 06269, USA; Center for Environmental Sciences and Engineering, Institute of the Environment, University of Connecticut, Storrs, CT 06269, USA
| | - Alessandra F D Nava
- Fundação Oswaldo Cruz-Fiocruz, Instituto Leônidas & Maria Deane, Laboratório de Ecologia de Doenças Transmissíveis na Amazônia - EDTA, Manaus 69.057-070, AM, Brazil
| | - Elisabeth H Loh
- Division of Natural Sciences and Mathematics, Transylvania University, Lexington, KY 40508, USA
| | - Makda Asrat
- Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
| | - Tierra Smiley-Evans
- One Health Institute, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
| | - Walter S Magesa
- College of Veterinary Medicine and Biomedical Sciences, Sokoine University of Agriculture, P.O. Box 3021, Morogoro, Tanzania
| | - Sijali Zikankuba
- College of Veterinary Medicine and Biomedical Sciences, Sokoine University of Agriculture, P.O. Box 3021, Morogoro, Tanzania
| | - David Wolking
- One Health Institute, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
| | - Gerardo Suzán
- Laboratorio de Ecología de Enfermedades y Una Salud, Departamento de Etología, Fauna Silvestre y Animales de Laboratorio, Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autónoma de México, Ciudad de México, 04510, Mexico
| | - Rafael Ojeda-Flores
- Laboratorio de Ecología de Enfermedades y Una Salud, Departamento de Etología, Fauna Silvestre y Animales de Laboratorio, Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autónoma de México, Ciudad de México, 04510, Mexico
| | - Christine V F Carrington
- Department of Preclinical Sciences, Faculty of Medical Sciences, The University of the West Indies, St. Augustine, Republic of Trinidad and Tobago
| | - Ariful Islam
- Gulbali Research Institute, Charles Sturt University, Wagga Wagga, NSW 2678, Australia
| | | | - Wanda Markotter
- Centre for Viral Zoonoses, Department of Medical Virology, University of Pretoria, Pretoria 0001, South Africa
| | - Christine K Johnson
- One Health Institute, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
| | - Tracey Goldstein
- One Health Institute, Colorado State University, Fort Collins, CO 80523, USA
| | - Barbara A Han
- Cary Institute of Ecosystem Studies, Millbrook, NY 12545, USA
| | - Jonna A K Mazet
- One Health Institute, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
| | - Rohit K Jangra
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA; Center for Applied Immunology and Pathological Processes, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA; Center of Excellence for Emerging Viral Threats, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA.
| | - Kartik Chandran
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA.
| | - Simon J Anthony
- Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
| |
Collapse
|
|
3
|
Clifford Astbury C, Demeshko A, Aguilar R, Mapatano MA, Li A, Togño KC, Shi Z, Wang Z, Wu C, Yambayamba MK, Carabin H, Clarke J, De Leon V, Desai S, Gallo-Cajiao E, Lee KM, Sivapragasam K, Wiktorowicz M, Penney TL. Wildlife policy, the food system and One Health: a complex systems analysis of unintended consequences for the prevention of emerging zoonoses in China, the Democratic Republic of the Congo and the Philippines. BMJ Glob Health 2025; 10:e016313. [PMID: 39809527 PMCID: PMC11749200 DOI: 10.1136/bmjgh-2024-016313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 11/29/2024] [Indexed: 01/16/2025] Open
Abstract
INTRODUCTION Evolving human-wildlife interactions have contributed to emerging zoonoses outbreaks, and pandemic prevention policy for wildlife management and conservation requires enhanced consideration from this perspective. However, the risk of unintended consequences is high. In this study, we aimed to assess how unrecognised complexity and system adaptation can lead to policy failure, and how these dynamics may impact zoonotic spillover risk and food system outcomes. METHODOLOGY This study focused on three countries: China, the Democratic Republic of the Congo (DRC) and the Philippines. We combined evidence from a rapid literature review with key informant interviews to develop causal loop diagrams (CLDs), a form of systems map representing causal theory about system factors and interconnections. We analysed these CLDs using the 'fixes that fail' (FTF) systems archetype, a conceptual tool used to understand and communicate how system adaptation can lead to policy failure. In each country, we situated the FTF in the wider system of disease ecology and food system factors to highlight how zoonotic risk and food system outcomes may be impacted. RESULTS We interviewed 104 participants and reviewed 303 documents. In each country, we identified a case of a policy with the potential to become an FTF: wildlife farming in China, the establishment of a new national park in the DRC, and international conservation agenda-setting in the Philippines. In each country, we highlighted context-specific impacts of the FTF on zoonotic spillover risk and key food system outcomes. CONCLUSION Our use of systems thinking highlights how system adaptation may undermine prevention policy aims, with a range of unintended consequences for food systems and human, animal and environmental health. A broader application of systems-informed policy design and evaluation could help identify instruments approporiate for the disruption of system traps and improve policy success. A One Health approach may also increase success by supporting collaboration, communication and trust among actors to imporove collective policy action.
Collapse
Affiliation(s)
- Chloe Clifford Astbury
- Global Food System & Policy Research, York University, Toronto, Ontario, Canada
- Dahdaleh Institute for Global Health Research, York University, Toronto, Ontario, Canada
- Global Strategy Lab, York University, Toronto, Ontario, Canada
| | - Anastassia Demeshko
- Global Food System & Policy Research, York University, Toronto, Ontario, Canada
| | - Russel Aguilar
- Department of Epidemiology and Biostatistics, College of Public Health, University of the Philippines Manila, Manila, Philippines
| | - Mala Ali Mapatano
- School of Public Health, University of Kinshasa, Kinshasa, Democratic Republic of Congo
| | - Angran Li
- Center for Applied Social and Economic Research, New York University Shanghai, Shanghai, China
| | - Kathleen Chelsea Togño
- Department of Epidemiology and Biostatistics, College of Public Health, University of the Philippines Manila, Manila, Philippines
| | - Zhilei Shi
- Zhongnan University of Economics and Law, Wuhan, China
| | - Zhuoyu Wang
- Department of Sociology, Zhejiang University, Hangzhou, China
| | - Cary Wu
- Department of Sociology, York University, Toronto, Ontario, Canada
| | - Marc K Yambayamba
- School of Public Health, University of Kinshasa, Kinshasa, Democratic Republic of Congo
- Section of Epidemiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - Hélène Carabin
- Faculté de médecine vétérinaire, Université de Montréal, Saint-Hyacinthe, Québec, Canada
| | - Janielle Clarke
- Global Food System & Policy Research, York University, Toronto, Ontario, Canada
| | - Valentina De Leon
- Global Food System & Policy Research, York University, Toronto, Ontario, Canada
| | - Shital Desai
- Social and Technological Systems Lab, School of the Arts, Media, Performance & Design, York University, Toronto, Ontario, Canada
| | - Eduardo Gallo-Cajiao
- Department of Human Dimensions of Natural Resources, Warner College of Natural Resources, Colorado State University, Fort Collins, Colorado, USA
| | - Kirsten Melissa Lee
- Global Food System & Policy Research, York University, Toronto, Ontario, Canada
| | | | - Mary Wiktorowicz
- Dahdaleh Institute for Global Health Research, York University, Toronto, Ontario, Canada
- School of Health Policy and Management, Faculty of Health, York University, Toronto, Ontario, Canada
- School of Global Health, Faculty of Health, York Univeristy, Toronto, Ontario, Canada
| | - Tarra L Penney
- Global Food System & Policy Research, York University, Toronto, Ontario, Canada
- Dahdaleh Institute for Global Health Research, York University, Toronto, Ontario, Canada
- Global Strategy Lab, York University, Toronto, Ontario, Canada
- School of Global Health, Faculty of Health, York Univeristy, Toronto, Ontario, Canada
| |
Collapse
|
|
4
|
Munyeku-Bazitama Y, Edidi-Atani F, Takada A. Non-Ebola Filoviruses: Potential Threats to Global Health Security. Viruses 2024; 16:1179. [PMID: 39205153 PMCID: PMC11359311 DOI: 10.3390/v16081179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 07/19/2024] [Accepted: 07/21/2024] [Indexed: 09/04/2024] Open
Abstract
Filoviruses are negative-sense single-stranded RNA viruses often associated with severe and highly lethal hemorrhagic fever in humans and nonhuman primates, with case fatality rates as high as 90%. Of the known filoviruses, Ebola virus (EBOV), the prototype of the genus Orthoebolavirus, has been a major public health concern as it frequently causes outbreaks and was associated with an unprecedented outbreak in several Western African countries in 2013-2016, affecting 28,610 people, 11,308 of whom died. Thereafter, filovirus research mostly focused on EBOV, paying less attention to other equally deadly orthoebolaviruses (Sudan, Bundibugyo, and Taï Forest viruses) and orthomarburgviruses (Marburg and Ravn viruses). Some of these filoviruses have emerged in nonendemic areas, as exemplified by four Marburg disease outbreaks recorded in Guinea, Ghana, Tanzania, and Equatorial Guinea between 2021 and 2023. Similarly, the Sudan virus has reemerged in Uganda 10 years after the last recorded outbreak. Moreover, several novel bat-derived filoviruses have been discovered in the last 15 years (Lloviu virus, Bombali virus, Měnglà virus, and Dehong virus), most of which are poorly characterized but may display a wide host range. These novel viruses have the potential to cause outbreaks in humans. Several gaps are yet to be addressed regarding known and emerging filoviruses. These gaps include the virus ecology and pathogenicity, mechanisms of zoonotic transmission, host range and susceptibility, and the development of specific medical countermeasures. In this review, we summarize the current knowledge on non-Ebola filoviruses (Bombali virus, Bundibugyo virus, Reston virus, Sudan virus, Tai Forest virus, Marburg virus, Ravn virus, Lloviu virus, Měnglà virus, and Dehong virus) and suggest some strategies to accelerate specific countermeasure development.
Collapse
Affiliation(s)
- Yannick Munyeku-Bazitama
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan; (Y.M.-B.); (F.E.-A.)
- Institut National de Recherche Biomédicale, Kinshasa P.O. Box 1197, Democratic Republic of the Congo
- Département de Biologie Médicale, Faculté de Médecine, Université de Kinshasa, Kinshasa P.O. Box 123, Democratic Republic of the Congo
| | - Francois Edidi-Atani
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan; (Y.M.-B.); (F.E.-A.)
- Institut National de Recherche Biomédicale, Kinshasa P.O. Box 1197, Democratic Republic of the Congo
- Département de Biologie Médicale, Faculté de Médecine, Université de Kinshasa, Kinshasa P.O. Box 123, Democratic Republic of the Congo
| | - Ayato Takada
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan; (Y.M.-B.); (F.E.-A.)
- International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
- One Health Research Center, Hokkaido University, Sapporo 001-0020, Japan
- Department of Disease Control, School of Veterinary Medicine, University of Zambia, Lusaka 10101, Zambia
| |
Collapse
|
|
5
|
Sizikova TE, Lebedev VN, Borisevich SV. [Comparative analysis of the taxonomic classification criteria for a number of groups of pathogenic DNA and RNA viruses based on genomic data]. Vopr Virusol 2024; 69:203-218. [PMID: 38996370 DOI: 10.36233/0507-4088-238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Indexed: 07/14/2024]
Abstract
The basis for criteria of the taxonomic classification of DNA and RNA viruses based on data of the genomic sequencing are viewed in this review. The genomic sequences of viruses, which have genome represented by double-stranded DNA (orthopoxviruses as example), positive-sense single-stranded RNA (alphaviruses and flaviviruses as example), non-segmented negative-sense single-stranded RNA (filoviruses as example), segmented negative-sense single-stranded RNA (arenaviruses and phleboviruses as example) are analyzed. The levels of genetic variability that determine the assignment of compared viruses to taxa of various orders are established for each group of viruses.
Collapse
Affiliation(s)
- T E Sizikova
- 48th Central Scientific Research Institute of the Ministry of Defense of the Russian Federation
| | - V N Lebedev
- 48th Central Scientific Research Institute of the Ministry of Defense of the Russian Federation
| | - S V Borisevich
- 48th Central Scientific Research Institute of the Ministry of Defense of the Russian Federation
| |
Collapse
|
|
6
|
Grayo S, Camara A, Doukouré B, Ellis I, Troupin C, Fischer K, Vanhomwegen J, White M, Groschup MH, Diederich S, Tordo N. Geographic Disparities in Domestic Pig Population Exposure to Ebola Viruses, Guinea, 2017-2019. Emerg Infect Dis 2024; 30:681-690. [PMID: 38526081 PMCID: PMC10977825 DOI: 10.3201/eid3004.231034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/26/2024] Open
Abstract
Although pigs are naturally susceptible to Reston virus and experimentally to Ebola virus (EBOV), their role in Orthoebolavirus ecology remains unknown. We tested 888 serum samples collected from pigs in Guinea during 2017-2019 (between the 2013-16 epidemic and its resurgence in 2021) by indirect ELISA against the EBOV nucleoprotein. We identified 2 hotspots of possible pig exposure by IgG titer levels: the northern coast had 48.7% of positive serum samples (37/76), and Forest Guinea, bordering Sierra Leone and Liberia, where the virus emerged and reemerged, had 50% of positive serum samples (98/196). The multitarget Luminex approach confirms ELISA results against Ebola nucleoprotein and highlights cross-reactivities to glycoprotein of EBOV, Reston virus, and Bundibugyo virus. Those results are consistent with previous observations of the circulation of Orthoebolavirus species in pig farming regions in Sierra Leone and Ghana, suggesting potential risk for Ebola virus disease in humans, especially in Forest Guinea.
Collapse
|
|
7
|
Lewis CE, Pinette MM, Lakin SM, Smith G, Fisher M, Moffat E, Embury-Hyatt C, Pickering BS. Experimental Infection of Bundibugyo Virus in Domestic Swine Leads to Viral Shedding with Evidence of Intraspecies Transmission. Transbound Emerg Dis 2024; 2024:5350769. [PMID: 40303058 PMCID: PMC12017203 DOI: 10.1155/2024/5350769] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 10/18/2023] [Accepted: 10/28/2023] [Indexed: 05/02/2025]
Abstract
The Ebolavirus genus contains several of the deadliest zoonotic viruses known. One of these, Bundibugyo virus (BDBV), has been the causative agent of two outbreaks of human disease that have resulted in 211 known cases with a case fatality rate of 33.6%. Although bats are routinely implicated as the possible reservoir species for the ebolaviruses, the source of infection for index cases in almost all outbreaks is unknown with only limited epidemiological evidence directly linking human cases to bats. This lack of evidence leaves open the possibility that maintenance of one or more of these viruses could involve multiple host species or more complex spillover dynamics. Domestic pigs have been found naturally infected with Reston virus (RESTV) and are experimentally susceptible to infection with Ebola virus (EBOV), two other members of the Ebolavirus genus. Infection of pigs resulted in shedding of infectious virus with subsequent transmission to naïve animals being documented, including transmission to humans for RESTV and to nonhuman primates for EBOV. The susceptibility and subsequent viral shedding and pathogenesis of domestic pigs to other ebolaviruses and the potential role this species may play in virus ecology, spillover dynamics, and human public health risk is unknown. For these reasons, we conducted a series of studies aimed at determining the susceptibility of domestic pigs to BDBV thereby demonstrating that pigs are not only susceptible to experimental infection but that the development of productive infection, tissue dissemination, and shedding of infectious virus can also occur while animals remain clinically normal. The role of pigs as a possible interim or amplifying host for ebolaviruses is a concern for both human public health and food security.
Collapse
Affiliation(s)
- Charles E. Lewis
- Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, Iowa, USA
- Interdepartmental Microbiology Program, College of Agriculture and Life Sciences, Iowa State University, Ames, Iowa, USA
| | - Mathieu M. Pinette
- National Centre for Foreign Animal Diseases, Canadian Food Inspection Agency, Winnipeg, Manitoba, Canada
| | - Steven M. Lakin
- Scientific Liaison Services Section, Foreign Animal Disease Diagnostic Laboratory, National Veterinary Services Laboratories, Animal Plant Health Inspection Service, United States Department of Agriculture, Orient Point, New York, USA
| | - Greg Smith
- National Centre for Foreign Animal Diseases, Canadian Food Inspection Agency, Winnipeg, Manitoba, Canada
| | - Mathew Fisher
- National Centre for Foreign Animal Diseases, Canadian Food Inspection Agency, Winnipeg, Manitoba, Canada
| | - Estella Moffat
- National Centre for Foreign Animal Diseases, Canadian Food Inspection Agency, Winnipeg, Manitoba, Canada
| | - Carissa Embury-Hyatt
- National Centre for Foreign Animal Diseases, Canadian Food Inspection Agency, Winnipeg, Manitoba, Canada
| | - Brad S. Pickering
- Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, Iowa, USA
- National Centre for Foreign Animal Diseases, Canadian Food Inspection Agency, Winnipeg, Manitoba, Canada
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Manitoba, Canada
| |
Collapse
|
|
8
|
Lewis CE, Pinette MM, Lakin SM, Smith G, Fisher M, Moffat E, Embury-Hyatt C, Pickering BS. Domestic pigs are susceptible to experimental infection with non-human primate-derived Reston virus without the need for adaptation. Sci Rep 2024; 14:715. [PMID: 38184728 PMCID: PMC10771446 DOI: 10.1038/s41598-024-51280-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 01/03/2024] [Indexed: 01/08/2024] Open
Abstract
Domestic pigs are a critical component of the food supply and one of the most commonly raised production animals. Pork consumption has driven the intensification of pig production expanding into environments conducive to increased emergence and spread of infectious diseases, including the spillover of pathogens into human populations. One of these emerging viruses, Reston virus (RESTV), is an enigma among the Orthoebolavirus genus in that its lack of human pathogenicity is in stark contrast to the high virulence associated with most other ebolaviruses. RESTV is, however, associated with outbreaks of highly lethal hemorrhagic disease in non-human primates (NHP), as well as poorly understood clinical manifestations of mixed virulence and lethality in naturally and experimentally infected domestic pigs. Our results show it is possible for RESTV derived from an NHP to infect domestic pigs resulting in a spectrum of disease, from asymptomatic to severe respiratory distress. Further, we report on the first experimental transmission of RESTV between infected pigs and a co-housed, naïve animal, as well as the first report of the successful use of group oral fluids for the detection of RESTV RNA and virus-specific IgA antibodies.
Collapse
Affiliation(s)
- Charles E Lewis
- Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA, USA
- Interdepartmental Microbiology Program, College of Agriculture and Life Sciences, Iowa State University, Ames, IA, USA
| | - Mathieu M Pinette
- National Centre for Foreign Animal Disease, Canadian Food Inspection Agency, Winnipeg, MB, Canada
| | - Steven M Lakin
- Scientific Liaison Services Section, Foreign Animal Disease Diagnostic Laboratory, National Veterinary Services Laboratories, Animal Plant Health Inspection Service, United States Department of Agriculture, Orient Point, NY, USA
| | - Greg Smith
- National Centre for Foreign Animal Disease, Canadian Food Inspection Agency, Winnipeg, MB, Canada
| | - Mathew Fisher
- National Centre for Foreign Animal Disease, Canadian Food Inspection Agency, Winnipeg, MB, Canada
| | - Estella Moffat
- National Centre for Foreign Animal Disease, Canadian Food Inspection Agency, Winnipeg, MB, Canada
| | - Carissa Embury-Hyatt
- National Centre for Foreign Animal Disease, Canadian Food Inspection Agency, Winnipeg, MB, Canada
| | - Brad S Pickering
- Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA, USA.
- National Centre for Foreign Animal Disease, Canadian Food Inspection Agency, Winnipeg, MB, Canada.
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada.
| |
Collapse
|
|
9
|
Igarashi M, Hirokawa T, Takada A. Structural and Energetic Basis for Differential Binding of Ebola and Marburg Virus Glycoproteins to a Bat-Derived Niemann-Pick C1 Protein. J Infect Dis 2023; 228:S479-S487. [PMID: 37119290 DOI: 10.1093/infdis/jiad120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/14/2023] [Accepted: 04/26/2023] [Indexed: 05/01/2023] Open
Abstract
BACKGROUND Our previous study demonstrated that the fruit bat (Yaeyama flying fox)-derived cell line FBKT1 showed preferential susceptibility to Ebola virus (EBOV), whereas the human cell line HEK293T was similarly susceptible to EBOV and Marburg virus (MARV). This was due to 3 amino acid differences of the endosomal receptor Niemann-Pick C1 (NPC1) between FBKT1 and HEK293T (ie, TET and SGA, respectively, at positions 425-427), as well as 2 amino acid differences at positions 87 and 142 of the viral glycoprotein (GP) between EBOV and MARV. METHODS/RESULTS To understand the contribution of these amino acid differences to interactions between NPC1 and GP, we performed molecular dynamics simulations and binding free energy calculations. The average binding free energies of human NPC1 (hNPC1) and its mutant having TET at positions 425-427 (hNPC1/TET) were similar for the interaction with EBOV GP. In contrast, hNPC1/TET had a weaker interaction with MARV GP than wild-type hNPC1. As expected, substitutions of amino acid residues at 87 or 142 in EBOV and MARV GPs converted the binding affinity to hNPC1/TET. CONCLUSIONS Our data provide structural and energetic insights for understanding potential differences in the GP-NPC1 interaction, which could influence the host tropism of EBOV and MARV.
Collapse
Affiliation(s)
- Manabu Igarashi
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido, Japan
- International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Takatsugu Hirokawa
- Transborder Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Division of Biomedical Science, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Ayato Takada
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido, Japan
- International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido, Japan
- Department of Disease Control, School of Veterinary Medicine, University of Zambia, Lusaka, Zambia
- One Health Research Center, Hokkaido University, Sapporo, Hokkaido, Japan
| |
Collapse
|
|
10
|
Dupuy LC, Spiropoulou CF, Towner JS, Spengler JR, Sullivan NJ, Montgomery JM. Filoviruses: Scientific Gaps and Prototype Pathogen Recommendation. J Infect Dis 2023; 228:S446-S459. [PMID: 37849404 PMCID: PMC11009505 DOI: 10.1093/infdis/jiad362] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2023] Open
Abstract
Viruses in the family Filoviridae, including the commonly known Ebola (EBOV) and Marburg (MARV) viruses, can cause severe hemorrhagic fever in humans and nonhuman primates. Sporadic outbreaks of filovirus disease occur in sub-Saharan Africa with reported case fatality rates ranging from 25% to 90%. The high mortality and increasing frequency and magnitude of recent outbreaks along with the increased potential for spread from rural to urban areas highlight the importance of pandemic preparedness for these viruses. Despite their designation as high-priority pathogens, numerous scientific gaps exist in critical areas. In this review, these gaps and an assessment of potential prototype pathogen candidates are presented for this important virus family.
Collapse
Affiliation(s)
- Lesley C Dupuy
- Virology Branch, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Christina F Spiropoulou
- Viral Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, National Center for Emerging Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Jonathan S Towner
- Viral Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, National Center for Emerging Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Jessica R Spengler
- Viral Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, National Center for Emerging Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Nancy J Sullivan
- National Emerging Infectious Diseases Laboratories, Boston University, Boston, Massachusetts, USA
| | - Joel M Montgomery
- Viral Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, National Center for Emerging Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| |
Collapse
|
|
11
|
Tóth GE, Hume AJ, Suder EL, Zeghbib S, Ábrahám Á, Lanszki Z, Varga Z, Tauber Z, Földes F, Zana B, Scaravelli D, Scicluna MT, Pereswiet-Soltan A, Görföl T, Terregino C, De Benedictis P, Garcia-Dorival I, Alonso C, Jakab F, Mühlberger E, Leopardi S, Kemenesi G. Isolation and genome characterization of Lloviu virus from Italian Schreibers's bats. Sci Rep 2023; 13:11310. [PMID: 37443182 PMCID: PMC10344946 DOI: 10.1038/s41598-023-38364-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 07/06/2023] [Indexed: 07/15/2023] Open
Abstract
Lloviu cuevavirus (LLOV) was the first identified member of Filoviridae family outside the Ebola and Marburgvirus genera. A massive die-off of Schreibers's bats (Miniopterus schreibersii) in the Iberian Peninsula in 2002 led to its initial discovery. Recent studies with recombinant and wild-type LLOV isolates confirmed the zoonotic nature of the virus in vitro. We examined bat samples from Italy for the presence of LLOV in an area outside of the currently known distribution range of the virus. We detected one positive sample from 2020, sequenced the complete coding region of the viral genome and established an infectious isolate of the virus. In addition, we performed the first comprehensive evolutionary analysis of the virus, using the Spanish, Hungarian and the Italian sequences. The most important achievement of this study is the establishment of an additional infectious LLOV isolate from a bat sample using the SuBK12-08 cells, demonstrating that this cell line is highly susceptible to LLOV infection and confirming the previous observation that these bats are effective hosts of the virus in nature. This result further strengthens the role of bats as the natural hosts for zoonotic filoviruses.
Collapse
Affiliation(s)
- Gábor E Tóth
- National Laboratory of Virology, Szentágothai Research Centre, University of Pécs, Pécs, Hungary
- Faculty of Sciences, Institute of Biology, University of Pécs, Pécs, Hungary
| | - Adam J Hume
- Department of Virology, Immunology and Microbiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
- National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA
- Center for Emerging Infectious Diseases Policy and Research, Boston University, Boston, MA, USA
| | - Ellen L Suder
- Department of Virology, Immunology and Microbiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
- National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA
| | - Safia Zeghbib
- National Laboratory of Virology, Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - Ágota Ábrahám
- National Laboratory of Virology, Szentágothai Research Centre, University of Pécs, Pécs, Hungary
- Faculty of Sciences, Institute of Biology, University of Pécs, Pécs, Hungary
| | - Zsófia Lanszki
- National Laboratory of Virology, Szentágothai Research Centre, University of Pécs, Pécs, Hungary
- Faculty of Sciences, Institute of Biology, University of Pécs, Pécs, Hungary
| | - Zsaklin Varga
- National Laboratory of Virology, Szentágothai Research Centre, University of Pécs, Pécs, Hungary
- Faculty of Sciences, Institute of Biology, University of Pécs, Pécs, Hungary
| | - Zsófia Tauber
- National Laboratory of Virology, Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - Fanni Földes
- National Laboratory of Virology, Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - Brigitta Zana
- National Laboratory of Virology, Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - Dino Scaravelli
- ST.E.R.N.A., Forlì, Department of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, Italy
| | - Maria Teresa Scicluna
- UOC Virologia, Istituto Zooprofilattico Sperimentale del Lazio e della Toscana "M. Aleandri", Roma, Italy
| | - Andrea Pereswiet-Soltan
- Institute of Systematics and Evolution of Animals, Polish Academy of Sciences, Kraków, Poland
| | - Tamás Görföl
- National Laboratory of Virology, Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - Calogero Terregino
- OIE Collaborating Centre and National Reference Centre for Infectious Diseases at the Animal-Human Interface, Istituto Zooprofilattico Sperimentale delle Venezie, Legnaro, Italy
| | - Paola De Benedictis
- OIE Collaborating Centre and National Reference Centre for Infectious Diseases at the Animal-Human Interface, Istituto Zooprofilattico Sperimentale delle Venezie, Legnaro, Italy
| | - Isabel Garcia-Dorival
- INIA-CSIC, Centro Nacional Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Madrid, Spain
| | - Covadonga Alonso
- INIA-CSIC, Centro Nacional Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Madrid, Spain
| | - Ferenc Jakab
- National Laboratory of Virology, Szentágothai Research Centre, University of Pécs, Pécs, Hungary
- Faculty of Sciences, Institute of Biology, University of Pécs, Pécs, Hungary
| | - Elke Mühlberger
- Department of Virology, Immunology and Microbiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
- National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA
| | - Stefania Leopardi
- OIE Collaborating Centre and National Reference Centre for Infectious Diseases at the Animal-Human Interface, Istituto Zooprofilattico Sperimentale delle Venezie, Legnaro, Italy
| | - Gábor Kemenesi
- National Laboratory of Virology, Szentágothai Research Centre, University of Pécs, Pécs, Hungary.
- Faculty of Sciences, Institute of Biology, University of Pécs, Pécs, Hungary.
| |
Collapse
|
|
12
|
Lin M, Chen H, Jia L, Yang M, Qiu S, Song H, Wang L, Zheng T. Using a grey relational analysis in an improved Grunow-Finke assessment tool to detect unnatural epidemics. RISK ANALYSIS : AN OFFICIAL PUBLICATION OF THE SOCIETY FOR RISK ANALYSIS 2023; 43:1508-1517. [PMID: 36100578 DOI: 10.1111/risa.14016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
The Grunow-Finke epidemiological assessment tool (GFT) has several limitations in its ability to differentiate between natural and man-made epidemics. Our study aimed to improve the GFT and analyze historical epidemics to validate the model. Using a gray relational analysis (GRA), we improved the GFT by revising the existing standards and adding five new standards. We then removed the artificial weights and final decision threshold. Finally, by using typically unnatural epidemic events as references, we used the GRA to calculate the unnatural probability and obtain assessment results. Using the advanced tool, we conducted retrospective and case analyses to test its performance. In the validation set of 13 historical epidemics, unnatural and natural epidemics were divided into two categories near the unnatural probability of 45%, showing evident differences (p < 0.01) and an assessment accuracy close to 100%. The unnatural probabilities of the Ebola virus disease of 2013 and Middle East Respiratory Syndrome of 2012 were 30.6% and 36.1%, respectively. Our advanced epidemic assessment tool improved the accuracy of the original GFT from approximately 55% to approximately 100% and reduced the impact of human factors on these outcomes effectively.
Collapse
Affiliation(s)
- Mengxuan Lin
- Academy of Military Medical Sciences, Academy of Military Science of Chinese PLA, Beijing, China
| | - Hui Chen
- Department of Infectious Disease Prevention and Control, Center for Disease Control and Prevention of Chinese People's Liberation Army, Beijing, China
| | - Leili Jia
- Department of Infectious Disease Prevention and Control, Center for Disease Control and Prevention of Chinese People's Liberation Army, Beijing, China
| | - Mingjuan Yang
- Department of Infectious Disease Prevention and Control, Center for Disease Control and Prevention of Chinese People's Liberation Army, Beijing, China
| | - Shaofu Qiu
- Department of Infectious Disease Prevention and Control, Center for Disease Control and Prevention of Chinese People's Liberation Army, Beijing, China
| | - Hongbin Song
- Department of Infectious Disease Prevention and Control, Center for Disease Control and Prevention of Chinese People's Liberation Army, Beijing, China
| | - Ligui Wang
- Department of Infectious Disease Prevention and Control, Center for Disease Control and Prevention of Chinese People's Liberation Army, Beijing, China
| | - Tao Zheng
- Academy of Military Medical Sciences, Academy of Military Science of Chinese PLA, Beijing, China
| |
Collapse
|
|
13
|
Su H, van Eerde A, Rimstad E, Bock R, Branza-Nichita N, Yakovlev IA, Clarke JL. Plant-made vaccines against viral diseases in humans and farm animals. FRONTIERS IN PLANT SCIENCE 2023; 14:1170815. [PMID: 37056490 PMCID: PMC10086147 DOI: 10.3389/fpls.2023.1170815] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 03/14/2023] [Indexed: 06/19/2023]
Abstract
Plants provide not only food and feed, but also herbal medicines and various raw materials for industry. Moreover, plants can be green factories producing high value bioproducts such as biopharmaceuticals and vaccines. Advantages of plant-based production platforms include easy scale-up, cost effectiveness, and high safety as plants are not hosts for human and animal pathogens. Plant cells perform many post-translational modifications that are present in humans and animals and can be essential for biological activity of produced recombinant proteins. Stimulated by progress in plant transformation technologies, substantial efforts have been made in both the public and the private sectors to develop plant-based vaccine production platforms. Recent promising examples include plant-made vaccines against COVID-19 and Ebola. The COVIFENZ® COVID-19 vaccine produced in Nicotiana benthamiana has been approved in Canada, and several plant-made influenza vaccines have undergone clinical trials. In this review, we discuss the status of vaccine production in plants and the state of the art in downstream processing according to good manufacturing practice (GMP). We discuss different production approaches, including stable transgenic plants and transient expression technologies, and review selected applications in the area of human and veterinary vaccines. We also highlight specific challenges associated with viral vaccine production for different target organisms, including lower vertebrates (e.g., farmed fish), and discuss future perspectives for the field.
Collapse
Affiliation(s)
- Hang Su
- Division of Biotechnology and Plant Health, NIBIO - Norwegian Institute of Bioeconomy Research, Ås, Norway
| | - André van Eerde
- Division of Biotechnology and Plant Health, NIBIO - Norwegian Institute of Bioeconomy Research, Ås, Norway
| | - Espen Rimstad
- Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Oslo, Norway
| | - Ralph Bock
- Department III, Max Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany
| | - Norica Branza-Nichita
- Department of Viral Glycoproteins, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - Igor A. Yakovlev
- Division of Biotechnology and Plant Health, NIBIO - Norwegian Institute of Bioeconomy Research, Ås, Norway
| | - Jihong Liu Clarke
- Division of Biotechnology and Plant Health, NIBIO - Norwegian Institute of Bioeconomy Research, Ås, Norway
| |
Collapse
|
|
14
|
Widerspick L, Steffen JF, Tappe D, Muñoz-Fontela C. Animal Model Alternatives in Filovirus and Bornavirus Research. Viruses 2023; 15:158. [PMID: 36680198 PMCID: PMC9863967 DOI: 10.3390/v15010158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/02/2023] [Accepted: 01/03/2023] [Indexed: 01/06/2023] Open
Abstract
The order Mononegavirales contains a variety of highly pathogenic viruses that may infect humans, including the families Filoviridae, Bornaviridae, Paramyxoviridae, and Rhabodoviridae. Animal models have historically been important to study virus pathogenicity and to develop medical countermeasures. As these have inherent shortcomings, the rise of microphysiological systems and organoids able to recapitulate hallmarks of the diseases caused by these viruses may have enormous potential to add to or partially replace animal modeling in the future. Indeed, microphysiological systems and organoids are already used in the pharmaceutical R&D pipeline because they are prefigured to overcome the translational gap between model systems and clinical studies. Moreover, they may serve to alleviate ethical concerns related to animal research. In this review, we discuss the value of animal model alternatives in human pathogenic filovirus and bornavirus research. The current animal models and their limitations are presented followed by an overview of existing alternatives, such as organoids and microphysiological systems, which might help answering open research questions.
Collapse
Affiliation(s)
- Lina Widerspick
- Bernhard-Nocht-Institute for Tropical Medicine, 20359 Hamburg, Germany
- German Center for Infection Research (DZIF), Partner Site Hamburg-Luebeck-Borstel-Riems, 38124 Braunschweig, Germany
| | | | - Dennis Tappe
- Bernhard-Nocht-Institute for Tropical Medicine, 20359 Hamburg, Germany
- National Reference Center for Tropical Pathogens, Bernhard-Nocht-Institute for Tropical Medicine, 20359 Hamburg, Germany
| | - César Muñoz-Fontela
- Bernhard-Nocht-Institute for Tropical Medicine, 20359 Hamburg, Germany
- German Center for Infection Research (DZIF), Partner Site Hamburg-Luebeck-Borstel-Riems, 38124 Braunschweig, Germany
| |
Collapse
|
|
15
|
Avatar Mice Underscore the Role of the T Cell-Dendritic Cell Crosstalk in Ebola Virus Disease and Reveal Mechanisms of Protection in Survivors. J Virol 2022; 96:e0057422. [PMID: 36073921 PMCID: PMC9517696 DOI: 10.1128/jvi.00574-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Ebola virus disease (EVD) is a complex infectious disease characterized by high inflammation, multiorgan failure, the dysregulation of innate and adaptive immune responses, and coagulation abnormalities. Evidence accumulated over the last 2 decades indicates that, during fatal EVD, the infection of antigen-presenting cells (APC) and the dysregulation of T cell immunity preclude a successful transition between innate and adaptive immunity, which constitutes a key disease checkpoint. In order to better understand the contribution of the APC-T cell crosstalk to EVD pathophysiology, we have developed avatar mice transplanted with human, donor-specific APCs and T cells. Here, we show that the transplantation of T cells and APCs from Ebola virus (EBOV)-naive individuals into avatar mice results in severe disease and death and that this phenotype is dependent on T cell receptor (TCR)-major histocompatibility complex (MCH) recognition. Conversely, avatar mice were rescued from death induced by EBOV infection after the transplantation of both T cells and plasma from EVD survivors. These results strongly suggest that protection from EBOV reinfection requires both cellular and humoral immune memory responses. IMPORTANCE The crosstalk between dendritic cells and T cells marks the transition between innate and adaptive immune responses, and it constitutes an important checkpoint in EVD. In this study, we present a mouse avatar model in which T cell and dendritic cell interactions from a specific donor can be studied during EVD. Our findings indicate that T cell receptor-major histocompatibility complex-mediated T cell-dendritic cell interactions are associated with disease severity, which mimics the main features of severe EVD in these mice. Resistance to an EBOV challenge in the model was achieved via the transplantation of both survivor T cells and plasma.
Collapse
|
|
16
|
Hume AJ, Heiden B, Olejnik J, Suder EL, Ross S, Scoon WA, Bullitt E, Ericsson M, White MR, Turcinovic J, Thao TTN, Hekman RM, Kaserman JE, Huang J, Alysandratos KD, Toth GE, Jakab F, Kotton DN, Wilson AA, Emili A, Thiel V, Connor JH, Kemenesi G, Cifuentes D, Mühlberger E. Recombinant Lloviu virus as a tool to study viral replication and host responses. PLoS Pathog 2022; 18:e1010268. [PMID: 35120176 PMCID: PMC8849519 DOI: 10.1371/journal.ppat.1010268] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 02/16/2022] [Accepted: 01/11/2022] [Indexed: 01/06/2023] Open
Abstract
Next generation sequencing has revealed the presence of numerous RNA viruses in animal reservoir hosts, including many closely related to known human pathogens. Despite their zoonotic potential, most of these viruses remain understudied due to not yet being cultured. While reverse genetic systems can facilitate virus rescue, this is often hindered by missing viral genome ends. A prime example is Lloviu virus (LLOV), an uncultured filovirus that is closely related to the highly pathogenic Ebola virus. Using minigenome systems, we complemented the missing LLOV genomic ends and identified cis-acting elements required for LLOV replication that were lacking in the published sequence. We leveraged these data to generate recombinant full-length LLOV clones and rescue infectious virus. Similar to other filoviruses, recombinant LLOV (rLLOV) forms filamentous virions and induces the formation of characteristic inclusions in the cytoplasm of the infected cells, as shown by electron microscopy. Known target cells of Ebola virus, including macrophages and hepatocytes, are permissive to rLLOV infection, suggesting that humans could be potential hosts. However, inflammatory responses in human macrophages, a hallmark of Ebola virus disease, are not induced by rLLOV. Additional tropism testing identified pneumocytes as capable of robust rLLOV and Ebola virus infection. We also used rLLOV to test antivirals targeting multiple facets of the replication cycle. Rescue of uncultured viruses of pathogenic concern represents a valuable tool in our arsenal for pandemic preparedness. Due to increasing utilization of high-throughput sequencing technologies, RNA sequences of many unknown viruses have been discovered in bats and other animal species. Research on the pathogenic potential of these viruses is hampered by incomplete viral genome sequences and difficulties in isolating infectious virus from the animal hosts. One example of these potentially zoonotic pathogens is Lloviu virus (LLOV), a filovirus which is closely related to Ebola virus. Here we applied molecular virological approaches, including minigenome assays, to complement the incomplete LLOV genome ends with sequences from related viruses and identify cis-acting elements required for LLOV replication and transcription that were missing in the published LLOV sequence. The resulting full-length clones were used to generate infectious recombinant LLOV. We used this virus for electron microscopic analyses, infection studies in human cells, host response analysis, and antiviral drug testing. Our results provide new insights into the pathogenic potential of LLOV and delineate a roadmap for studying uncultured viruses.
Collapse
Affiliation(s)
- Adam J. Hume
- Department of Microbiology, Boston University School of Medicine; Boston, Massachusetts, United States of America
- National Emerging Infectious Diseases Laboratories, Boston University; Boston, Massachusetts, United States of America
- * E-mail: (AJH); (EM)
| | - Baylee Heiden
- Department of Microbiology, Boston University School of Medicine; Boston, Massachusetts, United States of America
- National Emerging Infectious Diseases Laboratories, Boston University; Boston, Massachusetts, United States of America
| | - Judith Olejnik
- Department of Microbiology, Boston University School of Medicine; Boston, Massachusetts, United States of America
- National Emerging Infectious Diseases Laboratories, Boston University; Boston, Massachusetts, United States of America
| | - Ellen L. Suder
- Department of Microbiology, Boston University School of Medicine; Boston, Massachusetts, United States of America
- National Emerging Infectious Diseases Laboratories, Boston University; Boston, Massachusetts, United States of America
| | - Stephen Ross
- Department of Microbiology, Boston University School of Medicine; Boston, Massachusetts, United States of America
- National Emerging Infectious Diseases Laboratories, Boston University; Boston, Massachusetts, United States of America
- Department of Biochemistry, Boston University School of Medicine; Boston, Massachusetts, United States of America
| | - Whitney A. Scoon
- Department of Microbiology, Boston University School of Medicine; Boston, Massachusetts, United States of America
- National Emerging Infectious Diseases Laboratories, Boston University; Boston, Massachusetts, United States of America
| | - Esther Bullitt
- Department of Physiology & Biophysics, Boston University School of Medicine; Boston, Massachusetts, United States of America
| | - Maria Ericsson
- Department of Cell Biology, Harvard Medical School; Boston, Massachusetts, United States of America
| | - Mitchell R. White
- Department of Microbiology, Boston University School of Medicine; Boston, Massachusetts, United States of America
- National Emerging Infectious Diseases Laboratories, Boston University; Boston, Massachusetts, United States of America
| | - Jacquelyn Turcinovic
- Department of Microbiology, Boston University School of Medicine; Boston, Massachusetts, United States of America
- National Emerging Infectious Diseases Laboratories, Boston University; Boston, Massachusetts, United States of America
- Program in Bioinformatics, Boston University; Boston, Massachusetts, United States of America
| | - Tran T. N. Thao
- Institute of Virology and Immunology (IVI); Bern, Switzerland
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern; Bern, Switzerland
| | - Ryan M. Hekman
- Department of Biochemistry, Boston University School of Medicine; Boston, Massachusetts, United States of America
- Center for Network Systems Biology, Boston University; Boston, Massachusetts, United States of America
| | - Joseph E. Kaserman
- Center for Regenerative Medicine of Boston University and Boston Medical Center; Boston, Massachusetts, United States of America
- The Pulmonary Center and Department of Medicine, Boston University School of Medicine; Boston, Massachusetts, United States of America
| | - Jessie Huang
- Center for Regenerative Medicine of Boston University and Boston Medical Center; Boston, Massachusetts, United States of America
- The Pulmonary Center and Department of Medicine, Boston University School of Medicine; Boston, Massachusetts, United States of America
| | - Konstantinos-Dionysios Alysandratos
- Center for Regenerative Medicine of Boston University and Boston Medical Center; Boston, Massachusetts, United States of America
- The Pulmonary Center and Department of Medicine, Boston University School of Medicine; Boston, Massachusetts, United States of America
| | - Gabor E. Toth
- Institute of Biology, Faculty of Sciences, University of Pécs, Pécs, Hungary
- Szentágothai Research Centre, University of Pécs; Pécs, Hungary
| | - Ferenc Jakab
- Institute of Biology, Faculty of Sciences, University of Pécs, Pécs, Hungary
- Szentágothai Research Centre, University of Pécs; Pécs, Hungary
| | - Darrell N. Kotton
- Center for Regenerative Medicine of Boston University and Boston Medical Center; Boston, Massachusetts, United States of America
- The Pulmonary Center and Department of Medicine, Boston University School of Medicine; Boston, Massachusetts, United States of America
- Department of Pathology & Laboratory Medicine, Boston University School of Medicine, Boston Medical Center; Boston, Massachusetts, United States of America
| | - Andrew A. Wilson
- Center for Regenerative Medicine of Boston University and Boston Medical Center; Boston, Massachusetts, United States of America
- The Pulmonary Center and Department of Medicine, Boston University School of Medicine; Boston, Massachusetts, United States of America
| | - Andrew Emili
- Department of Biochemistry, Boston University School of Medicine; Boston, Massachusetts, United States of America
- Center for Network Systems Biology, Boston University; Boston, Massachusetts, United States of America
- Department of Biology, Boston University; Boston, Massachusetts, United States of America
| | - Volker Thiel
- Institute of Virology and Immunology (IVI); Bern, Switzerland
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern; Bern, Switzerland
| | - John H. Connor
- Department of Microbiology, Boston University School of Medicine; Boston, Massachusetts, United States of America
- National Emerging Infectious Diseases Laboratories, Boston University; Boston, Massachusetts, United States of America
| | - Gabor Kemenesi
- Institute of Biology, Faculty of Sciences, University of Pécs, Pécs, Hungary
- Szentágothai Research Centre, University of Pécs; Pécs, Hungary
| | - Daniel Cifuentes
- Department of Biochemistry, Boston University School of Medicine; Boston, Massachusetts, United States of America
| | - Elke Mühlberger
- Department of Microbiology, Boston University School of Medicine; Boston, Massachusetts, United States of America
- National Emerging Infectious Diseases Laboratories, Boston University; Boston, Massachusetts, United States of America
- * E-mail: (AJH); (EM)
| |
Collapse
|
|
17
|
Yamaoka S, Ebihara H. Pathogenicity and Virulence of Ebolaviruses with Species- and Variant-specificity. Virulence 2021; 12:885-901. [PMID: 33734027 PMCID: PMC7993122 DOI: 10.1080/21505594.2021.1898169] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 02/10/2021] [Accepted: 02/19/2021] [Indexed: 01/05/2023] Open
Abstract
Ebola virus (EBOV), belonging to the species Zaire ebolavirus in the genus Ebolavirus, causes a severe febrile illness in humans with case fatality rates (CFRs) up to 90%. While there have been six virus species classified, which each have a single type virus in the genus Ebolavirus, CFRs of ebolavirus infections vary among viruses belonging to each distinct species. In this review, we aim to define the ebolavirus species-specific virulence on the basis of currently available laboratory and experimental findings. In addition, this review will also cover the variant-specific virulence of EBOV by referring to the unique biological and pathogenic characteristics of EBOV variant Makona, a new EBOV variant isolated from the 2013-2016 EBOV disease outbreak in West Africa. A better definition of species-specific and variant-specific virulence of ebolaviruses will facilitate our comprehensive knowledge on genus Ebolavirus biology, leading to the development of therapeutics against well-focused pathogenic mechanisms of each Ebola disease.
Collapse
Affiliation(s)
- Satoko Yamaoka
- Department of Molecular Medicine, Mayo Clinic, Rochester, USA
| | - Hideki Ebihara
- Department of Molecular Medicine, Mayo Clinic, Rochester, USA
| |
Collapse
|
|
18
|
Bhattacharyya S. Mechanisms of Immune Evasion by Ebola Virus. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1313:15-22. [PMID: 34661889 DOI: 10.1007/978-3-030-67452-6_2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
Abstract
The 2013-2016 Ebola virus epidemic in West Africa, which also spread to the USA, UK and Europe, was the largest reported outbreak till date (World Health Organization. 2016. https://apps.who.int/iris/bitstream/handle/10665/208883/ebolasitrep_10Jun2016_eng.pdf;jsessionid=8B7D74BC9D82D2BE1B110BAFFAD3A6E6?sequence=1 ). The recent Ebola outbreak in the Democratic Republic of the Congo has raised immense global concern on this severe and often fatal infection. Although sporadic, the severity and lethality of Ebola virus disease outbreaks has led to extensive research worldwide on this virus. Vaccine (World Health Organization. 2016. https://www.who.int/en/news-room/detail/23-12-2016-final-trial-results-confirm-ebola-vaccine-provides-high-protection-against-disease ; Henao-Restrepo et al. Lancet 389:505-518, 2017) and drug (Hayden. Nature, 557, 475-476, 2018; Dyall et al. J Infect Dis 218(suppl_5), S672-S678, 2018) development efforts against Ebola virus are research hotspots, and a few approved therapeutics are currently available (Centers for Disease Control and Prevention. 2021. https://www.cdc.gov/vhf/ebola/clinicians/vaccine/index.html; Centers for Disease Control and Prevention. 2021. https://www.cdc.gov/vhf/ebola/treatment/index.html). Ebola virus has evolved several mechanisms of host immune evasion, which facilitate its replication and pathogenesis. This chapter describes the Ebola virus morphology, genome, entry, replication, pathogenesis and viral proteins involved in host immune evasion. Further understanding of the underlying molecular mechanisms of immune evasion may facilitate development of additional novel and sustainable strategies against this deadly virus.
Collapse
Affiliation(s)
- Suchita Bhattacharyya
- Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, UK.
| |
Collapse
|
|
19
|
Brockhurst JK, Villano JS. The Role of Animal Research in Pandemic Responses. Comp Med 2021; 71:359-368. [PMID: 34610857 PMCID: PMC8594262 DOI: 10.30802/aalas-cm-21-000062] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/12/2021] [Accepted: 09/06/2021] [Indexed: 12/21/2022]
Abstract
The significant advances made by the global scientific community during the COVID-19 pandemic, exemplified by the development of multiple SARS-CoV-2 vaccines in less than 1 y, were made possible in part because of animal research. Historically, animals have been used to study the characterization, treatment, and prevention of most of the major infectious disease outbreaks that humans have faced. From the advent of modern 'germ theory' prior to the 1918 Spanish Flu pandemic through the more recent Ebola and Zika virus outbreaks, research that uses animals has revealed or supported key discoveries in disease pathogenesis and therapy development, helping to save lives during crises. Here we summarize the role of animal research in past pandemic and epidemic response efforts, as well as current and future considerations for animal research in the context of infectious disease research.
Collapse
Affiliation(s)
- Jacqueline K Brockhurst
- Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jason S Villano
- Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| |
Collapse
|
|
20
|
Glud HA, George S, Skovgaard K, Larsen LE. Zoonotic and reverse zoonotic transmission of viruses between humans and pigs. APMIS 2021; 129:675-693. [PMID: 34586648 PMCID: PMC9297979 DOI: 10.1111/apm.13178] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 08/28/2021] [Indexed: 12/30/2022]
Abstract
Humans and pigs share a close contact relationship, similar biological traits, and one of the highest estimated number of viruses compared to other mammalian species. The contribution and directionality of viral exchange between humans and pigs remain unclear for some of these viruses, but their transmission routes are important to characterize in order to prevent outbreaks of disease in both host species. This review collects and assesses the evidence to determine the likely transmission route of 27 viruses between humans and pigs.
Collapse
Affiliation(s)
- Helena Aagaard Glud
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Sophie George
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Kerstin Skovgaard
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Lars Erik Larsen
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
|
21
|
Plant-based vaccine research development against viral diseases with emphasis on Ebola virus disease: A review study. Curr Opin Pharmacol 2021; 60:261-267. [PMID: 34481336 DOI: 10.1016/j.coph.2021.08.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 07/30/2021] [Accepted: 08/03/2021] [Indexed: 11/21/2022]
Abstract
Ebola virus infection results in the fast onset of severe acute haemorrhagic fever with high mortality. The Ebola virus is labelled as a category A pathogen. Vaccines against the Ebola virus (EBOV) are essential for everyone, and an expansion in the arena of vaccine synthesis; especially, plant-based vaccine development has drawn attention. To express the heterologous protein for plant-based vectors, both RNA and DNA viruses have been adapted. Among the different approaches of plant-based vaccine technologies, the agroinfiltration method, which was initially established to investigate plant-virus interactions, has been considered an effective method to produce monoclonal antibodies against EBOV. The effectiveness of plants as bioreactors of vaccine/monoclonal antibodies development could be well-thought-out to attend the obligatory mandate. The review confers recent progress in the production of plant-based vaccines and antibody treatments against the Ebola virus disease, thereby alleviating public health alarms associated with EBOV.
Collapse
|
|
22
|
Schiffman Z, Liu G, Cao W, Zhu W, Emeterio K, Qiu X, Banadyga L. The Ferret as a Model for Filovirus Pathogenesis and Countermeasure Evaluation. ILAR J 2021; 61:62-71. [PMID: 33951727 DOI: 10.1093/ilar/ilab011] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 12/04/2020] [Accepted: 01/14/2021] [Indexed: 11/13/2022] Open
Abstract
The domestic ferret (Mustela putorius furo) has long been a popular animal model for evaluating viral pathogenesis and transmission as well as the efficacy of candidate countermeasures. Without question, the ferret has been most widely implemented for modeling respiratory viruses, particularly influenza viruses; however, in recent years, it has gained attention as a novel animal model for characterizing filovirus infections. Although ferrets appear resistant to infection and disease caused by Marburg and Ravn viruses, they are highly susceptible to lethal disease caused by Ebola, Sudan, Bundibugyo, and Reston viruses. Notably, unlike the immunocompetent rodent models of filovirus infection, ferrets are susceptible to lethal disease caused by wild-type viruses, and they recapitulate many aspects of human filovirus disease, including systemic virus replication, coagulation abnormalities, and a dysregulated immune response. Along with the stringency with which they reproduce Ebola disease, their relatively small size and availability make ferrets an attractive choice for countermeasure evaluation and pathogenesis modeling. Indeed, they are so far the only small animal model available for Bundibugyo virus. Nevertheless, ferrets do have their limitations, including the lack of commercially available reagents to dissect host responses and their unproven predictive value in therapeutic evaluation. Although the use of the ferret model in ebolavirus research has been consistent over the last few years, its widespread use and utility remains to be fully proven. This review provides a comprehensive overview of the ferret models of filovirus infection and perspective on their ongoing use in pathogenesis modeling and countermeasure evaluation.
Collapse
Affiliation(s)
- Zachary Schiffman
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Manitoba, Canada.,Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
| | - Guodong Liu
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
| | - Wenguang Cao
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
| | - Wenjun Zhu
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
| | - Karla Emeterio
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Manitoba, Canada.,Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
| | - Xiangguo Qiu
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
| | - Logan Banadyga
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
| |
Collapse
|
|
23
|
Dixit D, Masumbuko Claude K, Kjaldgaard L, Hawkes MT. Review of Ebola virus disease in children - how far have we come? Paediatr Int Child Health 2021; 41:12-27. [PMID: 32894024 DOI: 10.1080/20469047.2020.1805260] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Ebola virus (EBOV) causes an extremely contagious viral haemorrhagic fever associated with high mortality. While, historically, children have represented a small number of total cases of Ebolavirus disease (EVD), in recent outbreaks up to a quarter of cases have been in children. They pose unique challenges in clinical management and infection prevention and control. In this review of paediatric EVD, the epidemiology of past EVD outbreaks with specific focus on children is discussed, the clinical manifestations and laboratory findings are described and key developments in clinical management including specific topics such as viral persistence and breastfeeding while considering unique psychosocial and anthropological considerations for paediatric care including of survivors and orphans and the stigma they face are discussed. In addition to summarising the literature, perspectives based on the authors' experience of EVD outbreaks in the Democratic Republic of the Congo (DRC) are described.Abbreviations: ARDS: acute respiratory distress syndrome; aOR: adjusted odds ratio; ALT: alanine transferase; ALIMA: Alliance for International Medical Action; AST: aspartate transaminase; BUN: blood urea nitrogen; CNS: central nervous system; CUBE: chambre d'urgence biosécurisée pour épidémie; COVID-19: coronavirus disease 2019; Ct: cycle threshold; DRC: Democratic Republic of Congo; ETC: ebola treatment centre; ETU: ebola treatment unit; EBOV: ebola virus; EVD: ebolavirus disease; FEAST: fluid expansion as supportive therapy; GP: glycoprotein; IV: intravenous; MEURI: monitored emergency use of unregistered interventions; NETEC: National Ebola Training and Education Centre; NP: nucleoprotein; ORS: oral rehydration solution; PALM: Pamoja Tulinde Maisha; PREVAIL: Partnership for Research on Ebola Virus in Liberia; PPE: personal protective equipment; PCR: polymerase chain reaction; PEP: post-exposure prophylaxis; RDTs: rapid diagnostic tests; RT: reverse transcriptase; RNA: ribonucleic acid; UNICEF: United Nations International Children's Emergency Fund; USA: United States of America; WHO: World Health Organization.
Collapse
Affiliation(s)
- Devika Dixit
- Department of Medicine and Pediatrics. Division of Infectious Diseases, University of Saskatchewan, Saskatoon, SK, Canada
| | | | | | - Michael T Hawkes
- Department of Pediatrics. Division of Infectious Diseases, University of Alberta, Edmonton, Alberta, Canada.,School of Public Health, University of Alberta, Edmonton, Canada.,Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Canada.,Stollery Science Laboratory, Edmonton, Alberta, Canada.,Women and Children's Health Research Institute, Edmonton, Alberta, Canada
| |
Collapse
|
|
24
|
Christy MP, Uekusa Y, Gerwick L, Gerwick WH. Natural Products with Potential to Treat RNA Virus Pathogens Including SARS-CoV-2. JOURNAL OF NATURAL PRODUCTS 2021; 84:161-182. [PMID: 33352046 PMCID: PMC7771248 DOI: 10.1021/acs.jnatprod.0c00968] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Indexed: 05/03/2023]
Abstract
Three families of RNA viruses, the Coronaviridae, Flaviviridae, and Filoviridae, collectively have great potential to cause epidemic disease in human populations. The current SARS-CoV-2 (Coronaviridae) responsible for the COVID-19 pandemic underscores the lack of effective medications currently available to treat these classes of viral pathogens. Similarly, the Flaviviridae, which includes such viruses as Dengue, West Nile, and Zika, and the Filoviridae, with the Ebola-type viruses, as examples, all lack effective therapeutics. In this review, we present fundamental information concerning the biology of these three virus families, including their genomic makeup, mode of infection of human cells, and key proteins that may offer targeted therapies. Further, we present the natural products and their derivatives that have documented activities to these viral and host proteins, offering hope for future mechanism-based antiviral therapeutics. By arranging these potential protein targets and their natural product inhibitors by target type across these three families of virus, new insights are developed, and crossover treatment strategies are suggested. Hence, natural products, as is the case for other therapeutic areas, continue to be a promising source of structurally diverse new anti-RNA virus therapeutics.
Collapse
Affiliation(s)
- Mitchell P. Christy
- Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92093, United States
| | - Yoshinori Uekusa
- Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92093, United States
- Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan
| | - Lena Gerwick
- Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92093, United States
| | - William H. Gerwick
- Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92093, United States
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093, United States
| |
Collapse
|
|
25
|
Schiffman Z, Yan F, He S, Tierney K, Zhu W, Emeterio K, Zhang H, Banadyga L, Qiu X. Taï Forest Virus Does Not Cause Lethal Disease in Ferrets. Microorganisms 2021; 9:microorganisms9020213. [PMID: 33494199 PMCID: PMC7909818 DOI: 10.3390/microorganisms9020213] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/14/2021] [Accepted: 01/15/2021] [Indexed: 11/25/2022] Open
Abstract
Filoviruses are zoonotic, negative-sense RNA viruses, most of which are capable of causing severe disease in humans and nonhuman primates, often with high case fatality rates. Among these viruses, those belonging to the Ebolavirus genus—particularly Ebola virus, Sudan virus, and Bundibugyo virus—represent some of the most pathogenic to humans. Taï Forest virus (TAFV) is thought to be among the least pathogenic ebolaviruses; however, only a single non-fatal case has been documented in humans, in 1994. With the recent success of the ferret as a lethal model for a number of ebolaviruses, we set out to evaluate its suitability as a model for TAFV. Our results demonstrate that, unlike other ebolaviruses, TAFV infection in ferrets does not result in lethal disease. None of the intramuscularly inoculated animals demonstrated any overt signs of disease, whereas the intranasally inoculated animals exhibited mild to moderate weight loss during the early stage of infection but recovered quickly. Low levels of viral RNA were detected in the blood and tissues of several animals, particularly the intranasally inoculated animals, and all animals mounted a humoral immune response, with high titers of GP-specific IgG detectable as early as 14 days post-infection. These data provide additional insight into the pathogenesis of TAFV.
Collapse
Affiliation(s)
- Zachary Schiffman
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9, Canada; (Z.S.); (K.E.); (H.Z.)
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; (S.H.); (K.T.); (W.Z.); (X.Q.)
| | - Feihu Yan
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun 130122, China;
| | - Shihua He
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; (S.H.); (K.T.); (W.Z.); (X.Q.)
| | - Kevin Tierney
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; (S.H.); (K.T.); (W.Z.); (X.Q.)
| | - Wenjun Zhu
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; (S.H.); (K.T.); (W.Z.); (X.Q.)
| | - Karla Emeterio
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9, Canada; (Z.S.); (K.E.); (H.Z.)
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; (S.H.); (K.T.); (W.Z.); (X.Q.)
| | - Huajun Zhang
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9, Canada; (Z.S.); (K.E.); (H.Z.)
| | - Logan Banadyga
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; (S.H.); (K.T.); (W.Z.); (X.Q.)
- Correspondence:
| | - Xiangguo Qiu
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; (S.H.); (K.T.); (W.Z.); (X.Q.)
| |
Collapse
|
|
26
|
Reston virus causes severe respiratory disease in young domestic pigs. Proc Natl Acad Sci U S A 2020; 118:2015657118. [PMID: 33443221 DOI: 10.1073/pnas.2015657118] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Reston virus (RESTV), an ebolavirus, causes clinical disease in macaques but has yet only been associated with rare asymptomatic infections in humans. Its 2008 emergence in pigs in the Philippines raised concerns about food safety, pathogenicity, and zoonotic potential, questions that are still unanswered. Until today, the virulence of RESTV for pigs has remained elusive, with unclear pathogenicity in naturally infected animals and only one experimental study demonstrating susceptibility and evidence for shedding but no disease. Here we show that combined oropharyngeal and nasal infection of young (3- to 7-wk-old) Yorkshire cross pigs with RESTV resulted in severe respiratory disease, with most animals reaching humane endpoint within a week. RESTV-infected pigs developed severe cyanosis, tachypnea, and acute interstitial pneumonia, with RESTV shedding from oronasal mucosal membranes. Our studies indicate that RESTV should be considered a livestock pathogen with zoonotic potential.
Collapse
|
|
27
|
Kalvatchev N, Sirakov I. Respiratory viruses crossing the species barrier and emergence of new human coronavirus infectious disease. BIOTECHNOL BIOTEC EQ 2020. [DOI: 10.1080/13102818.2020.1843539] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Affiliation(s)
- Nikolay Kalvatchev
- Department of Medical Microbiology, Faculty of Medicine, Medical University of Sofia, Sofia, Bulgaria
| | - Ivo Sirakov
- Department of Medical Microbiology, Faculty of Medicine, Medical University of Sofia, Sofia, Bulgaria
| |
Collapse
|
|
28
|
Mitchell J, Dean K, Haas C. Ebola Virus Dose Response Model for Aerosolized Exposures: Insights from Primate Data. RISK ANALYSIS : AN OFFICIAL PUBLICATION OF THE SOCIETY FOR RISK ANALYSIS 2020; 40:2390-2398. [PMID: 32638435 DOI: 10.1111/risa.13551] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 03/21/2020] [Accepted: 06/01/2020] [Indexed: 06/11/2023]
Abstract
This study develops dose-response models for Ebolavirus using previously published data sets from the open literature. Two such articles were identified in which three different species of nonhuman primates were challenged by aerosolized Ebolavirus in order to study pathology and clinical disease progression. Dose groups were combined and pooled across each study in order to facilitate modeling. The endpoint of each experiment was death. The exponential and exact beta-Poisson models were fit to the data using maximum likelihood estimation. The exact beta-Poisson was deemed the recommended model because it more closely approximated the probability of response at low doses though both models provided a good fit. Although transmission is generally considered to be dominated by person-to-person contact, aerosolization is a possible route of exposure. If possible, this route of exposure could be particularly concerning for persons in occupational roles managing contaminated liquid wastes from patients being treated for Ebola infection and the wastewater community responsible for disinfection. Therefore, this study produces a necessary mathematical relationship between exposure dose and risk of death for the inhalation route of exposure that can support quantitative microbial risk assessment aimed at informing risk mitigation strategies including personal protection policies against occupational exposures.
Collapse
Affiliation(s)
- Jade Mitchell
- Department of Biosystems and Agricultural Engineering, Michigan State University, East Lansing, MI, USA
| | - Kara Dean
- Department of Biosystems and Agricultural Engineering, Michigan State University, East Lansing, MI, USA
| | - Charles Haas
- Department of Civil, Architectural and Environmental Engineering, Drexel University, Philadelphia, PA, USA
| |
Collapse
|
|
29
|
To B or Not to B: Mechanisms of Protection Conferred by rVSV-EBOV-GP and the Roles of Innate and Adaptive Immunity. Microorganisms 2020; 8:microorganisms8101473. [PMID: 32992829 PMCID: PMC7600878 DOI: 10.3390/microorganisms8101473] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 09/22/2020] [Accepted: 09/23/2020] [Indexed: 12/28/2022] Open
Abstract
Zaire Ebola virus (EBOV) is a member of the Filoviridae family of negative sense, single-stranded RNA viruses. EBOV infection causes Ebola virus disease (EVD), characterized by coagulopathy, lymphopenia, and multi-organ failure, which can culminate in death. In 2019, the FDA approved the first vaccine against EBOV, a recombinant live-attenuated viral vector wherein the G protein of vesicular stomatitis virus is replaced with the glycoprotein (GP) of EBOV (rVSV-EBOV-GP, Ervebo® by Merck). This vaccine demonstrates high efficacy in nonhuman primates by providing prophylactic, rapid, and post-exposure protection. In humans, rVSV-EBOV-GP demonstrated 100% protection in several phase III clinical trials in over 10,000 individuals during the 2013–2016 West Africa epidemic. As of 2020, over 218,000 doses of rVSV-EBOV-GP have been administered to individuals with high risk of EBOV exposure. Despite licensure and robust preclinical studies, the mechanisms of rVSV-EBOV-GP-mediated protection are not fully understood. Such knowledge is crucial for understanding vaccine-mediated correlates of protection from EVD and to aid the further design and development of therapeutics against filoviruses. Here, we summarize the current literature regarding the host response to vaccination and EBOV exposure, and evidence regarding innate and adaptive immune mechanisms involved in rVSV-EBOV-GP-mediated protection, with a focus on the host transcriptional response. Current data strongly suggest a protective synergy between rapid innate and humoral immunity.
Collapse
|
|
30
|
Di Paola N, Sanchez-Lockhart M, Zeng X, Kuhn JH, Palacios G. Viral genomics in Ebola virus research. Nat Rev Microbiol 2020; 18:365-378. [PMID: 32367066 PMCID: PMC7223634 DOI: 10.1038/s41579-020-0354-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/09/2020] [Indexed: 12/20/2022]
Abstract
Filoviruses such as Ebola virus continue to pose a substantial health risk to humans. Advances in the sequencing and functional characterization of both pathogen and host genomes have provided a wealth of knowledge to clinicians, epidemiologists and public health responders during outbreaks of high-consequence viral disease. Here, we describe how genomics has been historically used to investigate Ebola virus disease outbreaks and how new technologies allow for rapid, large-scale data generation at the point of care. We highlight how genomics extends beyond consensus-level sequencing of the virus to include intra-host viral transcriptomics and the characterization of host responses in acute and persistently infected patients. Similar genomics techniques can also be applied to the characterization of non-human primate animal models and to known natural reservoirs of filoviruses, and metagenomic sequencing can be the key to the discovery of novel filoviruses. Finally, we outline the importance of reverse genetics systems that can swiftly characterize filoviruses as soon as their genome sequences are available.
Collapse
Affiliation(s)
- Nicholas Di Paola
- United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, USA
| | - Mariano Sanchez-Lockhart
- United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, USA
| | - Xiankun Zeng
- United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, USA
| | - Jens H Kuhn
- Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA
| | - Gustavo Palacios
- United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, USA.
| |
Collapse
|
|
31
|
Takadate Y, Kondoh T, Igarashi M, Maruyama J, Manzoor R, Ogawa H, Kajihara M, Furuyama W, Sato M, Miyamoto H, Yoshida R, Hill TE, Freiberg AN, Feldmann H, Marzi A, Takada A. Niemann-Pick C1 Heterogeneity of Bat Cells Controls Filovirus Tropism. Cell Rep 2020; 30:308-319.e5. [PMID: 31940478 PMCID: PMC11075117 DOI: 10.1016/j.celrep.2019.12.042] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 09/15/2019] [Accepted: 12/12/2019] [Indexed: 11/18/2022] Open
Abstract
Fruit bats are suspected to be natural hosts of filoviruses, including Ebola virus (EBOV) and Marburg virus (MARV). Interestingly, however, previous studies suggest that these viruses have different tropisms depending on the bat species. Here, we show a molecular basis underlying the host-range restriction of filoviruses. We find that bat-derived cell lines FBKT1 and ZFBK13-76E show preferential susceptibility to EBOV and MARV, respectively, whereas the other bat cell lines tested are similarly infected with both viruses. In FBKT1 and ZFBK13-76E, unique amino acid (aa) sequences are found in the Niemann-Pick C1 (NPC1) protein, one of the cellular receptors interacting with the filovirus glycoprotein (GP). These aa residues, as well as a few aa differences between EBOV and MARV GPs, are crucial for the differential susceptibility to filoviruses. Taken together, our findings indicate that the heterogeneity of bat NPC1 orthologs is an important factor controlling filovirus species-specific host tropism.
Collapse
Affiliation(s)
- Yoshihiro Takadate
- Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
| | - Tatsunari Kondoh
- Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
| | - Manabu Igarashi
- Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan; Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo 001-0020, Japan
| | - Junki Maruyama
- Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
| | - Rashid Manzoor
- Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
| | - Hirohito Ogawa
- Hokudai Center for Zoonosis Control in Zambia, School of Veterinary Medicine, University of Zambia, Lusaka 10101, Zambia; Department of Disease Control, School of Veterinary Medicine, University of Zambia, Lusaka 10101, Zambia
| | - Masahiro Kajihara
- Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
| | - Wakako Furuyama
- Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA
| | - Masahiro Sato
- Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
| | - Hiroko Miyamoto
- Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
| | - Reiko Yoshida
- Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
| | - Terence E Hill
- Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Alexander N Freiberg
- Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Heinz Feldmann
- Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA
| | - Andrea Marzi
- Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA
| | - Ayato Takada
- Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan; Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo 001-0020, Japan; Department of Disease Control, School of Veterinary Medicine, University of Zambia, Lusaka 10101, Zambia.
| |
Collapse
|
|
32
|
Escudero-Pérez B, Ruibal P, Rottstegge M, Lüdtke A, Port JR, Hartmann K, Gómez-Medina S, Müller-Guhl J, Nelson EV, Krasemann S, Rodríguez E, Muñoz-Fontela C. Comparative pathogenesis of Ebola virus and Reston virus infection in humanized mice. JCI Insight 2019; 4:126070. [PMID: 31550241 PMCID: PMC6948759 DOI: 10.1172/jci.insight.126070] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 09/19/2019] [Indexed: 01/14/2023] Open
Abstract
Filoviruses of the genus Ebolavirus include 6 species with marked differences in their ability to cause disease in humans. From the highly virulent Ebola virus to the seemingly nonpathogenic Reston virus, case fatality rates can range between 0% and 90%. In order to understand the molecular basis of these differences, it is imperative to establish disease models that recapitulate human disease as faithfully as possible. Nonhuman primates (NHPs) are the gold-standard models for filovirus pathogenesis, but comparative studies are skewed by the fact that Reston virus infection can be lethal for NHPs. Here we used HLA-A2-transgenic, NOD-scid-IL-2γ receptor-knockout (NSG-A2) mice reconstituted with human hematopoiesis to compare Ebola virus and Reston virus pathogenesis in a human-like environment. While markedly less pathogenic than Ebola virus, Reston virus killed 20% of infected mice, a finding that was linked to exacerbated inflammation and viral replication in the liver. In addition, the case fatality ratios of different Ebolavirus species in humans were recapitulated in the humanized mice. Our findings point to humanized mice as a putative model to test the pathogenicity of newly discovered filoviruses, and suggest that further investigations on Reston virus pathogenesis in humans are warranted.
Collapse
Affiliation(s)
- Beatriz Escudero-Pérez
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.,German Center for Infection Research (DZIF), Partner Site Hamburg, Hamburg, Germany
| | - Paula Ruibal
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Monika Rottstegge
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.,German Center for Infection Research (DZIF), Partner Site Hamburg, Hamburg, Germany
| | - Anja Lüdtke
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Julia R Port
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.,German Center for Infection Research (DZIF), Partner Site Hamburg, Hamburg, Germany
| | - Kristin Hartmann
- Institute for Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sergio Gómez-Medina
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.,German Center for Infection Research (DZIF), Partner Site Hamburg, Hamburg, Germany
| | - Jürgen Müller-Guhl
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.,Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Emily V Nelson
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.,German Center for Infection Research (DZIF), Partner Site Hamburg, Hamburg, Germany
| | - Susanne Krasemann
- Institute for Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Estefanía Rodríguez
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - César Muñoz-Fontela
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.,German Center for Infection Research (DZIF), Partner Site Hamburg, Hamburg, Germany
| |
Collapse
|
|
33
|
Dovih P, Laing ED, Chen Y, Low DHW, Ansil BR, Yang X, Shi Z, Broder CC, Smith GJD, Linster M, Ramakrishnan U, Mendenhall IH. Filovirus-reactive antibodies in humans and bats in Northeast India imply zoonotic spillover. PLoS Negl Trop Dis 2019; 13:e0007733. [PMID: 31671094 PMCID: PMC6822707 DOI: 10.1371/journal.pntd.0007733] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 08/26/2019] [Indexed: 11/26/2022] Open
Abstract
Bats are reservoirs for several zoonotic pathogens, including filoviruses. Recent work highlights the diversity of bat borne filoviruses in Asia. High risk activities at the bat-human interface pose the threat of zoonotic virus transmission. We present evidence for prior exposure of bat harvesters and two resident fruit bat species to filovirus surface glycoproteins by screening sera in a multiplexed serological assay. Antibodies reactive to two antigenically distinct filoviruses were detected in human sera and to three individual filoviruses in bats in remote Northeast India. Sera obtained from Eonycteris spelaea bats showed similar patterns of cross-reactivity as human samples, suggesting them as the species responsible for the spillover. In contrast, sera from Rousettus leschenaultii bats reacted to two different virus glycoproteins. Our results indicate circulation of several filoviruses in bats and the possibility for filovirus transmission from bats to humans. Focused virus surveillance at human-wildlife interfaces enables proactive detection of potentially epidemic pathogens. Filoviruses, including ebolaviruses and marburgviruses, are pathogens with epidemic potential. They were previously detected in bats and have caused disease outbreaks in humans with a high case fatality rate. Here, we tested sera obtained from bats and humans at a high-risk interface for the presence of filovirus reactive antibodies. Human participants were engaged in annual bat hunts, possibly exposing them to bat-borne viruses. We report the exposure of humans to filoviruses that were likely derived from the two sampled bat species. The bats contain antibodies raised to presumably three distinct filoviruses. Our findings suggest bats in South Asia act as a reservoir host of a diverse range of filoviruses and filovirus spillover occurs through human exposure to these bats.
Collapse
Affiliation(s)
- Pilot Dovih
- National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India
- Sastra University, School of Chemistry and Biotechnology, Thanjavur, Tamil Nadu, India
| | - Eric D. Laing
- Uniformed Services University of the Health Sciences, Department of Microbiology and Immunology, Bethesda, Maryland, United States of America
| | - Yihui Chen
- Duke-National University of Singapore Medical School, Programme in Emerging Infectious Diseases, Singapore
| | - Dolyce H. W. Low
- Duke-National University of Singapore Medical School, Programme in Emerging Infectious Diseases, Singapore
- National University of Singapore, Graduate School for Integrative Sciences and Engineering, Singapore
| | - B. R. Ansil
- National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India
- Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Xinglou Yang
- Wuhan Institute of Virology, Department of Emerging Infectious Diseases, Wuhan, China
| | - Zhengli Shi
- Wuhan Institute of Virology, Department of Emerging Infectious Diseases, Wuhan, China
| | - Christopher C. Broder
- Uniformed Services University of the Health Sciences, Department of Microbiology and Immunology, Bethesda, Maryland, United States of America
| | - Gavin J. D. Smith
- Duke-National University of Singapore Medical School, Programme in Emerging Infectious Diseases, Singapore
| | - Martin Linster
- Duke-National University of Singapore Medical School, Programme in Emerging Infectious Diseases, Singapore
| | - Uma Ramakrishnan
- National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India
| | - Ian H. Mendenhall
- Duke-National University of Singapore Medical School, Programme in Emerging Infectious Diseases, Singapore
- * E-mail:
| |
Collapse
|
|
34
|
Abstract
Objective There have been five documented outbreaks of Ebola Reston virus (RESTV) in animals epidemiologically linked to the Philippines. This assessment was conducted to determine the risk of RESTV occurring in humans in the Philippines and its potential pathogenicity in humans. Methods The World Health Organization Rapid Risk Assessment of Acute Public Health Events Manual was used for the assessment. A literature review was done and a risk assessment matrix was used for the risk characterization of the outbreaks in the Philippines. The risk assessment was conducted by the Philippines Field Epidemiology Training Program. Results The risk of RESTV occurring in humans in the Philippines and its potential pathogenicity in humans were both assessed as moderate. Animals involved in RESTV outbreaks in the Philippines were non-human primates and domestic pigs. The presence of RESTV in pigs poses a possibility of genetic evolution of the virus. Although RESTV has been identified in humans, there was no death or illness attributed to the infection. The Philippines Inter-agency Committee on Zoonoses oversees collaboration between the animal and human health sectors for the prevention and control of zoonoses. However, there is no surveillance of risk animals or previously affected farms to monitor and facilitate early identification of cases. Discussion The moderate risk of RESTV recurring among humans in the Philippines and its potential pathogenicity in humans reinforces the need for early detection, surveillance and continued studies of RESTV pathogenesis and its health consequences. The One Health approach, with the involvement and coordination of public health, veterinary services and the community, is essential in the detection, control and management of zoonosis.
Collapse
|
|
35
|
Kämper L, Zierke L, Schmidt ML, Müller A, Wendt L, Brandt J, Hartmann E, Braun S, Holzerland J, Groseth A, Hoenen T. Assessment of the function and intergenus-compatibility of Ebola and Lloviu virus proteins. J Gen Virol 2019; 100:760-772. [DOI: 10.1099/jgv.0.001261] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Affiliation(s)
- Lennart Kämper
- 1 Institute for Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Greifswald – Insel Riems, Germany
| | - Lukas Zierke
- 1 Institute for Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Greifswald – Insel Riems, Germany
| | - Marie Luisa Schmidt
- 1 Institute for Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Greifswald – Insel Riems, Germany
| | - Andreas Müller
- 1 Institute for Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Greifswald – Insel Riems, Germany
| | - Lisa Wendt
- 1 Institute for Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Greifswald – Insel Riems, Germany
| | - Janine Brandt
- 1 Institute for Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Greifswald – Insel Riems, Germany
| | - Eric Hartmann
- 1 Institute for Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Greifswald – Insel Riems, Germany
| | - Stefanie Braun
- 1 Institute for Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Greifswald – Insel Riems, Germany
| | - Julia Holzerland
- 2 Junior Research Group Arenavirus Biology, Friedrich-Loeffler-Institut, Greifswald – Insel Riems, Germany
| | - Allison Groseth
- 2 Junior Research Group Arenavirus Biology, Friedrich-Loeffler-Institut, Greifswald – Insel Riems, Germany
| | - Thomas Hoenen
- 1 Institute for Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Greifswald – Insel Riems, Germany
| |
Collapse
|
|
36
|
Martell HJ, Masterson SG, McGreig JE, Michaelis M, Wass MN. Is the Bombali virus pathogenic in humans? Bioinformatics 2019; 35:3553-3558. [DOI: 10.1093/bioinformatics/btz267] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 03/14/2019] [Accepted: 04/15/2019] [Indexed: 11/13/2022] Open
Abstract
Abstract
Motivation
The potential of the Bombali virus, a novel Ebolavirus, to cause disease in humans remains unknown. We have previously identified potential determinants of Ebolavirus pathogenicity in humans by analysing the amino acid positions that are differentially conserved (specificity determining positions; SDPs) between human pathogenic Ebolaviruses and the non-pathogenic Reston virus. Here, we include the many Ebolavirus genome sequences that have since become available into our analysis and investigate the amino acid sequence of the Bombali virus proteins at the SDPs that discriminate between human pathogenic and non-human pathogenic Ebolaviruses.
Results
The use of 1408 Ebolavirus genomes (196 in the original analysis) resulted in a set of 166 SDPs (reduced from 180), 146 (88%) of which were retained from the original analysis. This indicates the robustness of our approach and refines the set of SDPs that distinguish human pathogenic Ebolaviruses from Reston virus. At SDPs, Bombali virus shared the majority of amino acids with the human pathogenic Ebolaviruses (63.25%). However, for two SDPs in VP24 (M136L, R139S) that have been proposed to be critical for the lack of Reston virus human pathogenicity because they alter the VP24-karyopherin interaction, the Bombali virus amino acids match those of Reston virus. Thus, Bombali virus may not be pathogenic in humans. Supporting this, no Bombali virus-associated disease outbreaks have been reported, although Bombali virus was isolated from fruit bats cohabitating in close contact with humans, and anti-Ebolavirus antibodies that may indicate contact with Bombali virus have been detected in humans.
Availability and implementation
Data files are available from https://github.com/wasslab/EbolavirusSDPsBioinformatics2019.
Supplementary information
Supplementary data are available at Bioinformatics online.
Collapse
Affiliation(s)
- Henry J Martell
- Industrial Biotechnology Centre and School of Biosciences, University of Kent, Canterbury, Kent, UK
| | - Stuart G Masterson
- Industrial Biotechnology Centre and School of Biosciences, University of Kent, Canterbury, Kent, UK
| | - Jake E McGreig
- Industrial Biotechnology Centre and School of Biosciences, University of Kent, Canterbury, Kent, UK
| | - Martin Michaelis
- Industrial Biotechnology Centre and School of Biosciences, University of Kent, Canterbury, Kent, UK
| | - Mark N Wass
- Industrial Biotechnology Centre and School of Biosciences, University of Kent, Canterbury, Kent, UK
| |
Collapse
|
|
37
|
Yan F, He S, Banadyga L, Zhu W, Zhang H, Rahim MN, Collignon B, Senthilkumaran C, Embury-Hyatt C, Qiu X. Characterization of Reston virus infection in ferrets. Antiviral Res 2019; 165:1-10. [PMID: 30836107 DOI: 10.1016/j.antiviral.2019.03.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Revised: 02/28/2019] [Accepted: 03/01/2019] [Indexed: 12/22/2022]
Abstract
Among the five currently recognized type viruses within the genus Ebolavirus, Reston virus (RESTV) is not known to cause disease in humans, although asymptomatic infections have been confirmed in the past. Intriguingly, despite the absence of pathogenicity in humans, RESTV is highly lethal to nonhuman primates and has been isolated from domestic pigs co-infected with other viruses in the Philippines and China. Whether infection in these animals can support the eventual emergence of a human-pathogenic RESTV remains unclear and requires further investigation. Unfortunately, there is currently no lethal small animal model available to investigate RESTV pathogenicity or pan-ebolavirus therapeutics. Here we show that wild type RESTV is uniformly lethal in ferrets. In this study, ferrets were challenged with 1260 TCID50 of wild type RESTV either intramuscularly or intranasally and monitored for clinical signs, survival, virus replication, alteration in serum biochemistry and blood cell counts. Irrespective of the route of challenge, viremia occurred in all ferrets on day 5 post-infection, and all animals succumbed to infection between days 9 and 11. Additionally, several similarities were observed between this model and the other ferret models of filovirus infection, including substantial decreases in lymphocyte and platelet counts and abnormalities in serum biochemistry indicating hepatic injury. The ferret model represents the first uniformly lethal model for RESTV infection, and it will undoubtedly prove useful for evaluating virus pathogenicity as well as pan-ebolavirus countermeasures.
Collapse
Affiliation(s)
- Feihu Yan
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada; Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada; Key Laboratory of Jilin Province for Zoonosis Prevention and Control in Key Lab, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, Jilin, China
| | - Shihua He
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
| | - Logan Banadyga
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
| | - Wenjun Zhu
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
| | - Huajun Zhang
- Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Md Niaz Rahim
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada; Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Brad Collignon
- Canadian Food Inspection Agency, National Centre for Foreign Animal Disease, Winnipeg, Manitoba, Canada
| | - Chandrika Senthilkumaran
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
| | - Carissa Embury-Hyatt
- Canadian Food Inspection Agency, National Centre for Foreign Animal Disease, Winnipeg, Manitoba, Canada
| | - Xiangguo Qiu
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada; Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada.
| |
Collapse
|
|
38
|
Rahim MN, Zhang Z, He S, Zhu W, Banadyga L, Safronetz D, Qiu X. Postexposure Protective Efficacy of T-705 (Favipiravir) Against Sudan Virus Infection in Guinea Pigs. J Infect Dis 2018; 218:S649-S657. [PMID: 29982696 PMCID: PMC6249569 DOI: 10.1093/infdis/jiy303] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Filoviruses such as Ebola virus (EBOV), Marburg virus (MARV), and Sudan virus (SUDV) cause deadly viral hemorrhagic fever in humans, with high case-fatality rates; however, no licensed therapeutic agent or vaccine has been clinically approved to treat or prevent infection. T-705 (favipiravir) is a novel antiviral drug that has been approved for the treatment of influenza in Japan. T-705 exhibits broad-spectrum antiviral activity against different viruses, including MARV and EBOV, and here, we are the first to report the in vitro and in vivo antiviral activity of T-705 against SUDV. T-705 treatment reduced SUDV replication in Vero E6 cells. Subcutaneous administration of T-705, beginning 1-4 days after infection and continuing for 7 days, significantly protected SUDV-infected guinea pigs, with a survival rate of 83%-100%. Viral RNA replication and infectious virus production were also significantly reduced in the blood, spleen, liver, lungs, and kidney. Moreover, early administration of low-dose T-705 and late administration (at 5 days after infection) of higher-dose T-705 also showed partial protection. Overall, our study is the first to demonstrate the antiviral activity of T-705 against SUDV, suggesting that T-705 may be a potential drug candidate for use during outbreaks.
Collapse
Affiliation(s)
- Md N Rahim
- Special Pathogens Program, National Microbiology laboratory, Public Health Agency of Canada
- Department of Medical Microbiology, University of Manitoba, Winnipeg, Canada
| | - Zirui Zhang
- Special Pathogens Program, National Microbiology laboratory, Public Health Agency of Canada
- Department of Medical Microbiology, University of Manitoba, Winnipeg, Canada
| | - Shihua He
- Special Pathogens Program, National Microbiology laboratory, Public Health Agency of Canada
| | - Wenjun Zhu
- Special Pathogens Program, National Microbiology laboratory, Public Health Agency of Canada
- Department of Medical Microbiology, University of Manitoba, Winnipeg, Canada
| | - Logan Banadyga
- Special Pathogens Program, National Microbiology laboratory, Public Health Agency of Canada
- Department of Medical Microbiology, University of Manitoba, Winnipeg, Canada
| | - David Safronetz
- Special Pathogens Program, National Microbiology laboratory, Public Health Agency of Canada
- Department of Medical Microbiology, University of Manitoba, Winnipeg, Canada
| | - Xiangguo Qiu
- Special Pathogens Program, National Microbiology laboratory, Public Health Agency of Canada
- Department of Medical Microbiology, University of Manitoba, Winnipeg, Canada
| |
Collapse
|
|
39
|
Goldstein T, Anthony SJ, Gbakima A, Bird BH, Bangura J, Tremeau-Bravard A, Belaganahalli MN, Wells HL, Dhanota JK, Liang E, Grodus M, Jangra RK, DeJesus VA, Lasso G, Smith BR, Jambai A, Kamara BO, Kamara S, Bangura W, Monagin C, Shapira S, Johnson CK, Saylors K, Rubin EM, Chandran K, Lipkin WI, Mazet JAK. The discovery of Bombali virus adds further support for bats as hosts of ebolaviruses. Nat Microbiol 2018; 3:1084-1089. [PMID: 30150734 PMCID: PMC6557442 DOI: 10.1038/s41564-018-0227-2] [Citation(s) in RCA: 234] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 07/25/2018] [Indexed: 11/08/2022]
Abstract
Here we describe the complete genome of a new ebolavirus, Bombali virus (BOMV) detected in free-tailed bats in Sierra Leone (little free-tailed (Chaerephon pumilus) and Angolan free-tailed (Mops condylurus)). The bats were found roosting inside houses, indicating the potential for human transmission. We show that the viral glycoprotein can mediate entry into human cells. However, further studies are required to investigate whether exposure has actually occurred or if BOMV is pathogenic in humans.
Collapse
Affiliation(s)
- Tracey Goldstein
- One Health Institute & Karen C. Drayer Wildlife Health Center, School of Veterinary Medicine, University of California, Davis, CA, USA.
| | - Simon J Anthony
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, USA.
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
- EcoHealth Alliance, New York, NY, USA.
| | - Aiah Gbakima
- Metabiota, Inc. Sierra Leone, Freetown, Sierra Leone
| | - Brian H Bird
- One Health Institute & Karen C. Drayer Wildlife Health Center, School of Veterinary Medicine, University of California, Davis, CA, USA
| | - James Bangura
- Metabiota, Inc. Sierra Leone, Freetown, Sierra Leone
| | - Alexandre Tremeau-Bravard
- One Health Institute & Karen C. Drayer Wildlife Health Center, School of Veterinary Medicine, University of California, Davis, CA, USA
| | - Manjunatha N Belaganahalli
- One Health Institute & Karen C. Drayer Wildlife Health Center, School of Veterinary Medicine, University of California, Davis, CA, USA
| | - Heather L Wells
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Jasjeet K Dhanota
- One Health Institute & Karen C. Drayer Wildlife Health Center, School of Veterinary Medicine, University of California, Davis, CA, USA
| | - Eliza Liang
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, USA
- EcoHealth Alliance, New York, NY, USA
| | - Michael Grodus
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Rohit K Jangra
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY, USA
| | - Veronica A DeJesus
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY, USA
| | - Gorka Lasso
- Department of Systems Biology, Irving Cancer Research Center, Columbia University, New York, NY, USA
| | - Brett R Smith
- One Health Institute & Karen C. Drayer Wildlife Health Center, School of Veterinary Medicine, University of California, Davis, CA, USA
| | - Amara Jambai
- Ministry of Health and Sanitation, Freetown, Sierra Leone
| | | | - Sorie Kamara
- Livestock and Veterinary Services Division, Ministry of Agriculture, Forestry and Food Security, Freetown, Sierra Leone
| | - William Bangura
- Forestry and Wildlife Division, Ministry of Agriculture, Forestry and Food Security, Freetown, Sierra Leone
| | - Corina Monagin
- One Health Institute & Karen C. Drayer Wildlife Health Center, School of Veterinary Medicine, University of California, Davis, CA, USA
- Metabiota, Inc., San Francisco, CA, USA
| | - Sagi Shapira
- Department of Systems Biology, Irving Cancer Research Center, Columbia University, New York, NY, USA
- Department of Microbiology & Immunology, Columbia University, New York, NY, USA
| | - Christine K Johnson
- One Health Institute & Karen C. Drayer Wildlife Health Center, School of Veterinary Medicine, University of California, Davis, CA, USA
| | | | | | - Kartik Chandran
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY, USA
| | - W Ian Lipkin
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, USA
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Jonna A K Mazet
- One Health Institute & Karen C. Drayer Wildlife Health Center, School of Veterinary Medicine, University of California, Davis, CA, USA
| |
Collapse
|
|
40
|
Cross RW, Fenton KA, Geisbert TW. Small animal models of filovirus disease: recent advances and future directions. Expert Opin Drug Discov 2018; 13:1027-1040. [DOI: 10.1080/17460441.2018.1527827] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- Robert W. Cross
- Galveston National Laboratory, The University of Texas Medical Branch, Galveston, TX, USA
- Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX, USA
| | - Karla A. Fenton
- Galveston National Laboratory, The University of Texas Medical Branch, Galveston, TX, USA
- Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX, USA
| | - Thomas W. Geisbert
- Galveston National Laboratory, The University of Texas Medical Branch, Galveston, TX, USA
- Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX, USA
| |
Collapse
|
|
41
|
Abstract
The West African Ebola virus (EBOV) epidemic has fast-tracked countermeasures for this rare, emerging zoonotic pathogen. Until 2013-2014, most EBOV vaccine candidates were stalled between the preclinical and clinical milestones on the path to licensure, because of funding problems, lack of interest from pharmaceutical companies, and competing priorities in public health. The unprecedented and devastating epidemic propelled vaccine candidates toward clinical trials that were initiated near the end of the active response to the outbreak. Those trials did not have a major impact on the epidemic but provided invaluable data on vaccine safety, immunogenicity, and, to a limited degree, even efficacy in humans. There are plenty of lessons to learn from these trials, some of which are addressed in this review. Better preparation is essential to executing an effective response to EBOV in the future; yet, the first indications of waning interest are already noticeable.
Collapse
Affiliation(s)
- Heinz Feldmann
- Laboratory of Virology, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 59840, USA;
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Manitoba 93E 0J9, Canada
| | - Friederike Feldmann
- Rocky Mountain Veterinary Branch, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 59840, USA
| | - Andrea Marzi
- Laboratory of Virology, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 59840, USA;
| |
Collapse
|
|
42
|
Manhart WA, Pacheco JR, Hume AJ, Cressey TN, Deflubé LR, Mühlberger E. A Chimeric Lloviu Virus Minigenome System Reveals that the Bat-Derived Filovirus Replicates More Similarly to Ebolaviruses than Marburgviruses. Cell Rep 2018; 24:2573-2580.e4. [PMID: 30184492 PMCID: PMC6159894 DOI: 10.1016/j.celrep.2018.08.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 07/12/2018] [Accepted: 08/06/2018] [Indexed: 12/31/2022] Open
Abstract
Recently, traces of zoonotic viruses have been discovered in bats and other species around the world, but despite repeated attempts, full viral genomes have not been rescued. The absence of critical genetic sequences from these viruses and the difficulties to isolate infectious virus from specimens prevent research on their pathogenic potential for humans. One example of these zoonotic pathogens is Lloviu virus (LLOV), a filovirus that is closely related to Ebola virus. Here, we established LLOV minigenome systems based on sequence complementation from other filoviruses. Our results show that the LLOV replication and transcription mechanisms are, in general, more similar to ebolaviruses than to marburgviruses. We also show that a single nucleotide at the 3' genome end determines species specificity of the LLOV polymerase. The data obtained here will be instrumental for the rescue of infectious LLOV clones for pathogenesis studies.
Collapse
Affiliation(s)
- Whitney A Manhart
- Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA; National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, MA 02118, USA
| | - Jennifer R Pacheco
- Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA; National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, MA 02118, USA
| | - Adam J Hume
- Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA; National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, MA 02118, USA
| | - Tessa N Cressey
- Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA; National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, MA 02118, USA
| | - Laure R Deflubé
- Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA; National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, MA 02118, USA
| | - Elke Mühlberger
- Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA; National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, MA 02118, USA.
| |
Collapse
|
|
43
|
Filovirus – Auslöser von hämorrhagischem Fieber. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2018; 61:894-907. [DOI: 10.1007/s00103-018-2757-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
|
|
44
|
Identification of a small molecule inhibitor of Ebola virus genome replication and transcription using in silico screening. Antiviral Res 2018; 156:46-54. [PMID: 29870771 PMCID: PMC6371959 DOI: 10.1016/j.antiviral.2018.06.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 05/16/2018] [Accepted: 06/01/2018] [Indexed: 02/02/2023]
Abstract
Ebola virus (EBOV) causes a severe haemorrhagic fever in humans and has a mortality rate over 50%. With no licensed drug treatments available, EBOV poses a significant threat. Investigations into possible therapeutics have been severely hampered by the classification of EBOV as a BSL4 pathogen. Here, we describe a drug discovery pathway combining in silico screening of compounds predicted to bind to a hydrophobic pocket on the nucleoprotein (NP); with a robust and rapid EBOV minigenome assay for inhibitor validation at BSL2. One compound (MCCB4) was efficacious (EC50 4.8 μM), exhibited low cytotoxicity (CC50 > 100 μM) and was specific, with no effect on either a T7 RNA polymerase driven firefly luciferase or a Bunyamwera virus minigenome. Further investigations revealed that this small molecule inhibitor was able to outcompete established replication complexes, an essential aspect for a potential EBOV treatment.
An EBOV drug discovery pathway which is performed at BSL2 and successfully identifies SMIs. MCCB4 is a SMI of EBOV which is effective, specific and not cytotoxic. The effect of MCCB4 was demonstrated in two cell types. MCCB4 is able to outcompete established EBOV replication complexes. SAR analysis was performed with 2nd generation compounds.
Collapse
|
|
45
|
Abstract
The Filoviridae are a family of negative-strand RNA viruses that include several important human pathogens. Ebola virus (EBOV) and Marburg virus are well-known filoviruses which cause life-threatening viral hemorrhagic fever in human and nonhuman primates. In addition to severe pathogenesis, filoviruses also exhibit a propensity for human-to-human transmission by close contact, posing challenges to containment and crisis management. Past outbreaks, in particular the recent West African EBOV epidemic, have been responsible for thousands of deaths and vaulted the filoviruses into public consciousness. Both national and international health agencies continue to regard potential filovirus outbreaks as critical threats to global public health. To develop effective countermeasures, a basic understanding of filovirus biology is needed. This review encompasses the epidemiology, ecology, molecular biology, and evolution of the filoviruses.
Collapse
Affiliation(s)
- Jackson Emanuel
- Laboratory of Virology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, United States
| | - Andrea Marzi
- Laboratory of Virology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, United States
| | - Heinz Feldmann
- Laboratory of Virology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, United States.
| |
Collapse
|
|
46
|
Singh RK, Dhama K, Malik YS, Ramakrishnan MA, Karthik K, Khandia R, Tiwari R, Munjal A, Saminathan M, Sachan S, Desingu PA, Kattoor JJ, Iqbal HMN, Joshi SK. Ebola virus - epidemiology, diagnosis, and control: threat to humans, lessons learnt, and preparedness plans - an update on its 40 year's journey. Vet Q 2017; 37:98-135. [PMID: 28317453 DOI: 10.1080/01652176.2017.1309474] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2016] [Accepted: 03/17/2017] [Indexed: 02/08/2023] Open
Abstract
Ebola virus (EBOV) is an extremely contagious pathogen and causes lethal hemorrhagic fever disease in man and animals. The recently occurred Ebola virus disease (EVD) outbreaks in the West African countries have categorized it as an international health concern. For the virus maintenance and transmission, the non-human primates and reservoir hosts like fruit bats have played a vital role. For curbing the disease timely, we need effective therapeutics/prophylactics, however, in the absence of any approved vaccine, timely diagnosis and monitoring of EBOV remains of utmost importance. The technologically advanced vaccines like a viral-vectored vaccine, DNA vaccine and virus-like particles are underway for testing against EBOV. In the absence of any effective control measure, the adaptation of high standards of biosecurity measures, strict sanitary and hygienic practices, strengthening of surveillance and monitoring systems, imposing appropriate quarantine checks and vigilance on trade, transport, and movement of visitors from EVD endemic countries remains the answer of choice for tackling the EBOV spread. Herein, we converse with the current scenario of EBOV giving due emphasis on animal and veterinary perspectives along with advances in diagnosis and control strategies to be adopted, lessons learned from the recent outbreaks and the global preparedness plans. To retrieve the evolutionary information, we have analyzed a total of 56 genome sequences of various EBOV species submitted between 1976 and 2016 in public databases.
Collapse
Affiliation(s)
- Raj Kumar Singh
- a ICAR-Indian Veterinary Research Institute , Bareilly , India
| | - Kuldeep Dhama
- b Division of Pathology, ICAR-Indian Veterinary Research Institute , Bareilly , India
| | - Yashpal Singh Malik
- c Division of Biological Standardization, ICAR-Indian Veterinary Research Institute , Bareilly , India
| | | | - Kumaragurubaran Karthik
- e Divison of Bacteriology and Mycology, ICAR-Indian Veterinary Research Institute , Bareilly , India
| | - Rekha Khandia
- f Department of Biochemistry and Genetics , Barkatullah University , Bhopal , India
| | - Ruchi Tiwari
- g Department of Veterinary Microbiology and Immunology , College of Veterinary Sciences, Deen Dayal Upadhayay Pashu Chikitsa Vigyan Vishwavidyalay Evum Go-Anusandhan Sansthan (DUVASU) , Mathura , India
| | - Ashok Munjal
- f Department of Biochemistry and Genetics , Barkatullah University , Bhopal , India
| | - Mani Saminathan
- b Division of Pathology, ICAR-Indian Veterinary Research Institute , Bareilly , India
| | - Swati Sachan
- h Immunology Section, ICAR-Indian Veterinary Research Institute , Bareilly , India
| | | | - Jobin Jose Kattoor
- c Division of Biological Standardization, ICAR-Indian Veterinary Research Institute , Bareilly , India
| | - Hafiz M N Iqbal
- i School of Engineering and Science, Tecnologico de Monterrey , Monterrey , Mexico
| | - Sunil Kumar Joshi
- j Cellular Immunology Lab , Frank Reidy Research Center for Bioelectrics , School of Medical Diagnostics & Translational Sciences, Old Dominion University , Norfolk , VA , USA
| |
Collapse
|
|
47
|
Agnandji ST, Fernandes JF, Bache EB, Obiang Mba RM, Brosnahan JS, Kabwende L, Pitzinger P, Staarink P, Massinga-Loembe M, Krähling V, Biedenkopf N, Fehling SK, Strecker T, Clark DJ, Staines HM, Hooper JW, Silvera P, Moorthy V, Kieny MP, Adegnika AA, Grobusch MP, Becker S, Ramharter M, Mordmüller B, Lell B, VEBCON Consortium, Krishna S, Kremsner PG. Safety and immunogenicity of rVSVΔG-ZEBOV-GP Ebola vaccine in adults and children in Lambaréné, Gabon: A phase I randomised trial. PLoS Med 2017; 14:e1002402. [PMID: 28985239 PMCID: PMC5630143 DOI: 10.1371/journal.pmed.1002402] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 09/07/2017] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND The rVSVΔG-ZEBOV-GP vaccine prevented Ebola virus disease when used at 2 × 107 plaque-forming units (PFU) in a trial in Guinea. This study provides further safety and immunogenicity data. METHODS AND FINDINGS A randomised, open-label phase I trial in Lambaréné, Gabon, studied 5 single intramuscular vaccine doses of 3 × 103, 3 × 104, 3 × 105, 3 × 106, or 2 × 107 PFU in 115 adults and a dose of 2 × 107 PFU in 20 adolescents and 20 children. The primary objective was safety and tolerability 28 days post-injection. Immunogenicity, viraemia, and shedding post-vaccination were evaluated as secondary objectives. In adults, mild-to-moderate adverse events were frequent, but there were no serious or severe adverse events related to vaccination. Before vaccination, Zaire Ebola virus (ZEBOV)-glycoprotein (GP)-specific and ZEBOV antibodies were detected in 11% and 27% of adults, respectively. In adults, 74%-100% of individuals who received a dose 3 × 104, 3 × 105, 3 × 106, or 2 × 107 PFU had a ≥4.0-fold increase in geometric mean titres (GMTs) of ZEBOV-GP-specific antibodies at day 28, reaching GMTs of 489 (95% CI: 264-908), 556 (95% CI: 280-1,101), 1,245 (95% CI: 899-1,724), and 1,503 (95% CI: 931-2,426), respectively. Twenty-two percent of adults had a ≥4-fold increase of ZEBOV antibodies, with GMTs at day 28 of 1,015 (647-1,591), 1,887 (1,154-3,085), 1,445 (1,013-2,062), and 3,958 (2,249-6,967) for the same doses, respectively. These antibodies persisted up to day 180 for doses ≥3 × 105 PFU. Adults with antibodies before vaccination had higher GMTs throughout. Neutralising antibodies were detected in more than 50% of participants at doses ≥3 × 105 PFU. As in adults, no serious or severe adverse events related to vaccine occurred in adolescents or children. At day 2, vaccine RNA titres were higher for adolescents and children than adults. At day 7, 78% of adolescents and 35% of children had recombinant vesicular stomatitis virus RNA detectable in saliva. The vaccine induced high GMTs of ZEBOV-GP-specific antibodies at day 28 in adolescents, 1,428 (95% CI: 1,025-1,989), and children, 1,620 (95% CI: 806-3,259), and in both groups antibody titres increased up to day 180. The absence of a control group, lack of stratification for baseline antibody status, and imbalances in male/female ratio are the main limitations of this study. CONCLUSIONS Our data confirm the acceptable safety and immunogenicity profile of the 2 × 107 PFU dose in adults and support consideration of lower doses for paediatric populations and those who request boosting. TRIAL REGISTRATION Pan African Clinical Trials Registry PACTR201411000919191.
Collapse
Affiliation(s)
- Selidji T. Agnandji
- Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon
- Institut für Tropenmedizin, Universitätsklinikum Tübingen, Tübingen, Germany
- German Centre for Infection Research (DZIF) partner sites Universitätsklinikum Tübingen and Gießen-Marburg-Langen, Germany
| | - José F. Fernandes
- Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon
- Institut für Tropenmedizin, Universitätsklinikum Tübingen, Tübingen, Germany
| | | | | | - Jessica S. Brosnahan
- Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon
- Institut für Tropenmedizin, Universitätsklinikum Tübingen, Tübingen, Germany
- German Centre for Infection Research (DZIF) partner sites Universitätsklinikum Tübingen and Gießen-Marburg-Langen, Germany
| | - Lumeka Kabwende
- Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon
| | - Paul Pitzinger
- Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon
- Institut für Tropenmedizin, Universitätsklinikum Tübingen, Tübingen, Germany
- Bernhard Nocht Hospital for Tropical Diseases, Bernhard Nocht Institute for Tropical Medicine and University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Pieter Staarink
- Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon
- Center of Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Division of Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands
| | | | - Verena Krähling
- German Centre for Infection Research (DZIF) partner sites Universitätsklinikum Tübingen and Gießen-Marburg-Langen, Germany
- Institute for Virology, Philipps-Universität Marburg, Marburg, Germany
| | - Nadine Biedenkopf
- Institute for Virology, Philipps-Universität Marburg, Marburg, Germany
| | | | - Thomas Strecker
- Institute for Virology, Philipps-Universität Marburg, Marburg, Germany
| | - David J. Clark
- Centre for Diagnostics and Antimicrobial Resistance, Institute for Infection & Immunity, St. George’s, University of London, London, United Kingdom
| | - Henry M. Staines
- Centre for Diagnostics and Antimicrobial Resistance, Institute for Infection & Immunity, St. George’s, University of London, London, United Kingdom
| | - Jay W. Hooper
- US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America
| | - Peter Silvera
- US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America
| | | | | | - Akim A. Adegnika
- Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon
- Institut für Tropenmedizin, Universitätsklinikum Tübingen, Tübingen, Germany
- German Centre for Infection Research (DZIF) partner sites Universitätsklinikum Tübingen and Gießen-Marburg-Langen, Germany
- Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands
| | - Martin P. Grobusch
- Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon
- Institut für Tropenmedizin, Universitätsklinikum Tübingen, Tübingen, Germany
- Center of Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Division of Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands
| | - Stephan Becker
- German Centre for Infection Research (DZIF) partner sites Universitätsklinikum Tübingen and Gießen-Marburg-Langen, Germany
- Institute for Virology, Philipps-Universität Marburg, Marburg, Germany
| | - Michael Ramharter
- Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon
- Institut für Tropenmedizin, Universitätsklinikum Tübingen, Tübingen, Germany
- Bernhard Nocht Hospital for Tropical Diseases, Bernhard Nocht Institute for Tropical Medicine and University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Benjamin Mordmüller
- Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon
- Institut für Tropenmedizin, Universitätsklinikum Tübingen, Tübingen, Germany
- German Centre for Infection Research (DZIF) partner sites Universitätsklinikum Tübingen and Gießen-Marburg-Langen, Germany
| | - Bertrand Lell
- Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon
- Institut für Tropenmedizin, Universitätsklinikum Tübingen, Tübingen, Germany
- German Centre for Infection Research (DZIF) partner sites Universitätsklinikum Tübingen and Gießen-Marburg-Langen, Germany
| | | | - Sanjeev Krishna
- Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon
- Institut für Tropenmedizin, Universitätsklinikum Tübingen, Tübingen, Germany
- Centre for Diagnostics and Antimicrobial Resistance, Institute for Infection & Immunity, St. George’s, University of London, London, United Kingdom
- St. George’s University Hospitals NHS Foundation Trust, London, United Kingdom
- * E-mail: (SK); (PGK)
| | - Peter G. Kremsner
- Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon
- Institut für Tropenmedizin, Universitätsklinikum Tübingen, Tübingen, Germany
- German Centre for Infection Research (DZIF) partner sites Universitätsklinikum Tübingen and Gießen-Marburg-Langen, Germany
- * E-mail: (SK); (PGK)
| |
Collapse
|
|
48
|
Hengjan Y, Iida K, Doysabas KCC, Phichitrasilp T, Ohmori Y, Hondo E. Diurnal behavior and activity budget of the golden-crowned flying fox (Acerodon jubatus) in the Subic bay forest reserve area, the Philippines. J Vet Med Sci 2017; 79:1667-1674. [PMID: 28804092 PMCID: PMC5658557 DOI: 10.1292/jvms.17-0329] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Acerodon jubatus (the Golden-Crowned flying fox) is an endemic species
in the Philippines, which was suspected to be a host of the Reston strain of the Ebola
virus. As nocturnal animals, the flying foxes spend daytime at the roosting site, which
they use for self-maintenance and reproduction. To understand the variation in diurnal
behavior and time allocation for various activities in the Golden-Crowned flying fox, we
investigated their daytime behavior and activity budget using instantaneous scan sampling
and all occurrence focal sampling. Data collection was performed from 07:00 to 18:00 hr
during January 8–17, 2017. The most frequent activity was sleeping (76.3%). The remaining
activities were wing flapping (5.0%), self-grooming (4.2%), hanging relaxation (3.4%),
wing spread (2.9%), movement (2.4%), mating/courtship (2.4%), aggression (1.9%), hanging
alert (1.2%), excretion (0.1%) and scent marks (0.05%). The frequency of sleeping, wing
flapping, self-grooming, hanging relaxation, aggression, mating/courtship and movement
behaviors changed with the time of the day. Females allocated more time for resting than
males, while males spent more time on the activities that helped enhance their mating
opportunities, for example, movement, sexual activity and territorial behavior.
Collapse
Affiliation(s)
- Yupadee Hengjan
- Laboratory of Animal Morphology, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan
| | - Keisuke Iida
- Laboratory of Animal Morphology, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan
| | - Karla Cristine C Doysabas
- Laboratory of Animal Morphology, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan
| | - Thanmaporn Phichitrasilp
- Department of Veterinary Technology, Faculty of Veterinary Technology, Kasetsart University, Bangkok 10900, Thailand
| | - Yasushige Ohmori
- Laboratory of Animal Morphology, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan
| | - Eiichi Hondo
- Laboratory of Animal Morphology, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan
| |
Collapse
|
|
49
|
Ebola Virus Delta Peptide Is a Viroporin. J Virol 2017; 91:JVI.00438-17. [PMID: 28539454 DOI: 10.1128/jvi.00438-17] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Accepted: 05/18/2017] [Indexed: 12/16/2022] Open
Abstract
The Ebola virus (EBOV) genome encodes a partly conserved 40-residue nonstructural polypeptide, called the delta peptide, that is produced in abundance during Ebola virus disease (EVD). The function of the delta peptide is unknown, but sequence analysis has suggested that delta peptide could be a viroporin, belonging to a diverse family of membrane-permeabilizing small polypeptides involved in replication and pathogenesis of numerous viruses. Full-length and conserved C-terminal delta peptide fragments permeabilize the plasma membranes of nucleated cells of rodent, dog, monkey, and human origin; increase ion permeability across confluent cell monolayers; and permeabilize synthetic lipid bilayers. Permeabilization activity is completely dependent on the disulfide bond between the two conserved cysteines. The conserved C-terminal portion of the peptide is biochemically stable in human serum, and most serum-stable fragments have full activity. Taken together, the evidence strongly suggests that Ebola virus delta peptide is a viroporin and that it may be a novel, targetable aspect of Ebola virus disease pathology.IMPORTANCE During the unparalleled West African outbreak of Ebola virus disease (EVD) that began in late 2013, the lack of effective countermeasures resulted in chains of serial infection and a high mortality rate among infected patients. A better understanding of disease pathology is desperately needed to develop better countermeasures. We show here that the Ebola virus delta peptide, a conserved nonstructural protein produced in large quantities by infected cells, has the characteristics of a viroporin. This information suggests a critical role for the delta peptide in Ebola virus disease pathology and as a possible target for novel countermeasures.
Collapse
|
|
50
|
Olejnik J, Forero A, Deflubé LR, Hume AJ, Manhart WA, Nishida A, Marzi A, Katze MG, Ebihara H, Rasmussen AL, Mühlberger E. Ebolaviruses Associated with Differential Pathogenicity Induce Distinct Host Responses in Human Macrophages. J Virol 2017; 91:e00179-17. [PMID: 28331091 PMCID: PMC5432886 DOI: 10.1128/jvi.00179-17] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 03/08/2017] [Indexed: 11/20/2022] Open
Abstract
Ebola virus (EBOV) and Reston virus (RESTV) are members of the Ebolavirus genus which greatly differ in their pathogenicity. While EBOV causes a severe disease in humans characterized by a dysregulated inflammatory response and elevated cytokine and chemokine production, there are no reported disease-associated human cases of RESTV infection, suggesting that RESTV is nonpathogenic for humans. The underlying mechanisms determining the pathogenicity of different ebolavirus species are not yet known. In this study, we dissected the host response to EBOV and RESTV infection in primary human monocyte-derived macrophages (MDMs). As expected, EBOV infection led to a profound proinflammatory response, including strong induction of type I and type III interferons (IFNs). In contrast, RESTV-infected macrophages remained surprisingly silent. Early activation of IFN regulatory factor 3 (IRF3) and NF-κB was observed in EBOV-infected, but not in RESTV-infected, MDMs. In concordance with previous results, MDMs treated with inactivated EBOV and Ebola virus-like particles (VLPs) induced NF-κB activation mediated by Toll-like receptor 4 (TLR4) in a glycoprotein (GP)-dependent manner. This was not the case in cells exposed to live RESTV, inactivated RESTV, or VLPs containing RESTV GP, indicating that RESTV GP does not trigger TLR4 signaling. Our results suggest that the lack of immune activation in RESTV-infected MDMs contributes to lower pathogenicity by preventing the cytokine storm observed in EBOV infection. We further demonstrate that inhibition of TLR4 signaling abolishes EBOV GP-mediated NF-κB activation. This finding indicates that limiting the excessive TLR4-mediated proinflammatory response in EBOV infection should be considered as a potential supportive treatment option for EBOV disease.IMPORTANCE Emerging infectious diseases are a major public health concern, as exemplified by the recent devastating Ebola virus (EBOV) outbreak. Different ebolavirus species are associated with widely varying pathogenicity in humans, ranging from asymptomatic infections for Reston virus (RESTV) to severe disease with fatal outcomes for EBOV. In this comparative study of EBOV- and RESTV-infected human macrophages, we identified key differences in host cell responses. Consistent with previous data, EBOV infection is associated with a proinflammatory signature triggered by the surface glycoprotein (GP), which can be inhibited by blocking TLR4 signaling. In contrast, infection with RESTV failed to stimulate a strong host response in infected macrophages due to the inability of RESTV GP to stimulate TLR4. We propose that disparate proinflammatory host signatures contribute to the differences in pathogenicity reported for ebolavirus species and suggest that proinflammatory pathways represent an intriguing target for the development of novel therapeutics.
Collapse
Affiliation(s)
- Judith Olejnik
- Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA
- National Emerging Infectious Diseases Laboratories, Boston University, Boston, Massachusetts, USA
| | - Adriana Forero
- Department of Microbiology, University of Washington, Seattle, Washington, USA
| | - Laure R Deflubé
- Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA
- National Emerging Infectious Diseases Laboratories, Boston University, Boston, Massachusetts, USA
| | - Adam J Hume
- Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA
- National Emerging Infectious Diseases Laboratories, Boston University, Boston, Massachusetts, USA
| | - Whitney A Manhart
- Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA
- National Emerging Infectious Diseases Laboratories, Boston University, Boston, Massachusetts, USA
| | - Andrew Nishida
- Department of Microbiology, University of Washington, Seattle, Washington, USA
| | - Andrea Marzi
- Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana, USA
| | - Michael G Katze
- Department of Microbiology, University of Washington, Seattle, Washington, USA
| | - Hideki Ebihara
- Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana, USA
| | - Angela L Rasmussen
- Department of Microbiology, University of Washington, Seattle, Washington, USA
| | - Elke Mühlberger
- Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA
- National Emerging Infectious Diseases Laboratories, Boston University, Boston, Massachusetts, USA
| |
Collapse
|