220 results on '"David Safronetz"'
Search Results
2. Characterizing changes in transcriptome and kinome responses in testicular cells during infection by Ebola virus
- Author
-
Andrew L. Webb, Brayden G. Schindell, Geoff Soule, Abu B. Siddik, Bernard Abrenica, Harram Memon, Ruey-Chyi Su, David Safronetz, and Jason Kindrachuk
- Subjects
Infectious and parasitic diseases ,RC109-216 ,Biology (General) ,QH301-705.5 - Abstract
Abstract Ebola virus (EBOV) is able to persist and actively replicate in the reproductive tract of male disease survivors months or years after recovery from Ebola virus disease (EVD)1. Persistent EBOV infections are usually asymptomatic and can be transmitted sexually, but the host and viral factors that mediate these infections have not been characterized2,3. We investigated the interaction between host and viral factors during EBOV infection of the blood testis barrier (BTB), with a focus on Sertoli cells as a potential reservoir for viral persistence. We assessed viral replication kinetics and host responses of mouse testicular Leydig cells and Sertoli cells infected with EBOV Makona (i.e. infectious EBOV) and collected samples up to 28 days post-infection. Viral replication was apparent in both cell lines, but intracellular early viral loads were much higher in Leydig cells compared to Sertoli cells. We used RNAseq analysis to characterize transcriptomic responses of Leydig cells and Sertoli cells to EBOV infection over time. Further investigation of early interactions between host cells and EBOV was performed using virus-like particles (EBOV trVLP) and assays of phosphorylation-based cell signaling. Our findings indicate that virus-treated Sertoli cells responded more rapidly and robustly than Leydig cells, and with a particular emphasis on detection of, and response to, external stimuli. We discuss how the roles played by Sertoli cells in immune privilege and spermatogenesis may affect their initial and continued response to EBOV infection in a manner that could facilitate asymptomatic persistence.
- Published
- 2024
- Full Text
- View/download PDF
3. The rVSV-EBOV vaccine provides limited cross-protection against Sudan virus in guinea pigs
- Author
-
Wenguang Cao, Shihua He, Guodong Liu, Helene Schulz, Karla Emeterio, Michael Chan, Kevin Tierney, Kim Azaransky, Geoff Soule, Nikesh Tailor, Abdjeleel Salawudeen, Rick Nichols, Joan Fusco, David Safronetz, and Logan Banadyga
- Subjects
Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Recombinant vesicular stomatitis viruses (rVSVs) engineered to express heterologous viral glycoproteins have proven to be remarkably effective vaccines. Indeed, rVSV-EBOV, which expresses the Ebola virus (EBOV) glycoprotein, recently received clinical approval in the United States and Europe for its ability to prevent EBOV disease. Analogous rVSV vaccines expressing glycoproteins of different human-pathogenic filoviruses have also demonstrated efficacy in pre-clinical evaluations, yet these vaccines have not progressed far beyond research laboratories. In the wake of the most recent outbreak of Sudan virus (SUDV) in Uganda, the need for proven countermeasures was made even more acute. Here we demonstrate that an rVSV-based vaccine expressing the SUDV glycoprotein (rVSV-SUDV) generates a potent humoral immune response that protects guinea pigs from SUDV disease and death. Although the cross-protection generated by rVSV vaccines for different filoviruses is thought to be limited, we wondered whether rVSV-EBOV might also provide protection against SUDV, which is closely related to EBOV. Surprisingly, nearly 60% of guinea pigs that were vaccinated with rVSV-EBOV and challenged with SUDV survived, suggesting that rVSV-EBOV offers limited protection against SUDV, at least in the guinea pig model. These results were confirmed by a back-challenge experiment in which animals that had been vaccinated with rVSV-EBOV and survived EBOV challenge were inoculated with SUDV and survived. Whether these data are applicable to efficacy in humans is unknown, and they should therefore be interpreted cautiously. Nevertheless, this study confirms the potency of the rVSV-SUDV vaccine and highlights the potential for rVSV-EBOV to elicit a cross-protective immune response.
- Published
- 2023
- Full Text
- View/download PDF
4. Bivalent vaccines effectively protect mice against influenza A and respiratory syncytial viruses
- Author
-
Sathya N. Thulasi Raman, Adrian Zetner, Anwar M. Hashem, Devina Patel, Jianguo Wu, Caroline Gravel, Jun Gao, Wanyue Zhang, Annabelle Pfeifle, Levi Tamming, Karan Parikh, Jingxin Cao, Roger Tam, David Safronetz, Wangxue Chen, Michael J.W. Johnston, Lisheng Wang, Simon Sauve, Michael Rosu-Myles, Gary Van Domselaar, and Xuguang Li
- Subjects
Adenovirus ,influenza ,RSV ,pre-fusion stabilized F ,HA-stem ,RSV T-cell epitopes ,Infectious and parasitic diseases ,RC109-216 ,Microbiology ,QR1-502 - Abstract
ABSTRACTInfluenza and Respiratory Syncytial virus (RSV) infections together contribute significantly to the burden of acute lower respiratory tract infections. Despite the disease burden, no approved RSV vaccine is available. While approved vaccines are available for influenza, seasonal vaccination is required to maintain protection. In addition to both being respiratory viruses, they follow a common seasonality, which warrants the necessity for a concerted vaccination approach. Here, we designed bivalent vaccines by utilizing highly conserved sequences, targeting both influenza A and RSV, as either a chimeric antigen or individual antigens separated by a ribosome skipping sequence. These vaccines were found to be effective in protecting the animals from challenge by either virus, with mechanisms of protection being substantially interrogated in this communication.
- Published
- 2023
- Full Text
- View/download PDF
5. Mucosal Vaccination with a Newcastle Disease Virus-Vectored Vaccine Reduces Viral Loads in SARS-CoV-2-Infected Cynomolgus Macaques
- Author
-
Bryce M. Warner, Mable Chan, Nikesh Tailor, Robert Vendramelli, Jonathan Audet, Courtney Meilleur, Thang Truong, Lauren Garnett, Marnie Willman, Geoff Soule, Kevin Tierney, Alixandra Albietz, Estella Moffat, Rick Higgins, Lisa A. Santry, Alexander Leacy, Phuc H. Pham, Jacob G. E. Yates, Yanlong Pei, David Safronetz, James E. Strong, Leonardo Susta, Carissa Embury-Hyatt, Sarah K. Wootton, and Darwyn Kobasa
- Subjects
Newcastle disease virus ,SARS-CoV-2 ,COVID-19 ,vaccine ,cynomolgus macaque ,Medicine - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged following an outbreak of unexplained viral illness in China in late 2019. Since then, it has spread globally causing a pandemic that has resulted in millions of deaths and has had enormous economic and social consequences. The emergence of SARS-CoV-2 saw the rapid and widespread development of a number of vaccine candidates worldwide, and this never-before-seen pace of vaccine development led to several candidates progressing immediately through clinical trials. Many countries have now approved vaccines for emergency use, with large-scale vaccination programs ongoing. Despite these successes, there remains a need for ongoing pre-clinical and clinical development of vaccine candidates against SARS-CoV-2, as well as vaccines that can elicit strong mucosal immune responses. Here, we report on the efficacy of a Newcastle disease virus-vectored vaccine candidate expressing SARS-CoV-2 spike protein (NDV-FLS) administered to cynomolgus macaques. Macaques given two doses of the vaccine via respiratory immunization developed robust immune responses and had reduced viral RNA levels in nasal swabs and in the lower airway. Our data indicate that NDV-FLS administered mucosally provides significant protection against SARS-CoV-2 infection, resulting in reduced viral burden and disease manifestation, and should be considered as a viable candidate for clinical development.
- Published
- 2024
- Full Text
- View/download PDF
6. Bivalent VSV Vectors Mediate Rapid and Potent Protection from Andes Virus Challenge in Hamsters
- Author
-
Joshua Marceau, David Safronetz, Cynthia Martellaro, Andrea Marzi, Kyle Rosenke, and Heinz Feldmann
- Subjects
Orthohantavirus ,Andes virus ,VSV ,vaccine ,Syrian hamster ,emergency vaccination ,Microbiology ,QR1-502 - Abstract
Orthohantaviruses may cause hemorrhagic fever with renal syndrome or hantavirus cardiopulmonary syndrome. Andes virus (ANDV) is the only orthohantavirus associated with human–human transmission. Therefore, emergency vaccination would be a valuable public health measure to combat ANDV-derived infection clusters. Here, we utilized a promising vesicular stomatitis virus (VSV)-based vaccine to advance the approach for emergency applications. We compared monovalent and bivalent VSV vectors containing the Ebola virus (EBOV), glycoprotein (GP), and ANDV glycoprotein precursor (GPC) for protective efficacy in pre-, peri- and post-exposure immunization by the intraperitoneal and intranasal routes. Inclusion of the EBOV GP was based on its favorable immune cell targeting and the strong innate responses elicited by the VSV-EBOV vaccine. Our data indicates no difference of ANDV GPC expressing VSV vectors in pre-exposure immunization independent of route, but a potential benefit of the bivalent VSVs following peri- and post-exposure intraperitoneal vaccination.
- Published
- 2024
- Full Text
- View/download PDF
7. Experimental Infection of North American Deer Mice with Clade I and II Monkeypox Virus Isolates
- Author
-
Yvon Deschambault, Levi Klassen, Geoff Soule, Kevin Tierney, Kimberly Azaransky, Angela Sloan, and David Safronetz
- Subjects
mpox ,monkeypox ,MPXV ,viruses ,deer mouse ,experimental infection ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Abstract
The global spread of monkeypox virus has raised concerns over the establishment of novel enzootic reservoirs in expanded geographic regions. We demonstrate that although deer mice are permissive to experimental infection with clade I and II monkeypox viruses, the infection is short-lived and has limited capability for active transmission.
- Published
- 2023
- Full Text
- View/download PDF
8. Experimental Infection of Peromyscus Species Rodents with Sin Nombre Virus
- Author
-
Kaye Quizon, Kimberly Holloway, Mahmood Iranpour, Bryce M. Warner, Yvon Deschambault, Geoff Soule, Kevin Tierney, Darwyn Kobasa, Angela Sloan, and David Safronetz
- Subjects
Sin Nombre virus ,viruses ,Peromyscus ,Peromyscus leucopus ,Peromyscus maniculatus ,rodents ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Abstract
We demonstrate that 6 distinct Peromyscus rodent species are permissive to experimental infection with Sin Nombre orthohantavirus (SNV). Viral RNA and SNV antibodies were detected in members of all 6 species. P. leucopus mice demonstrated markedly higher viral and antibody titers than P. maniculatus mice, the established primary hosts for SNV.
- Published
- 2022
- Full Text
- View/download PDF
9. AAV-monoclonal antibody expression protects mice from Ebola virus without impeding the endogenous antibody response to heterologous challenge
- Author
-
Laura P. van Lieshout, Amira D. Rghei, Wenguang Cao, Shihua He, Geoff Soule, Wenjun Zhu, Sylvia P. Thomas, Debra Sorensen, Kathy Frost, Kevin Tierney, Brad Thompson, Stephanie Booth, David Safronetz, Raveendra R. Kulkarni, Byram W. Bridle, Xiangguo Qiu, Logan Banadyga, and Sarah K. Wootton
- Subjects
adeno-associated virus (AAV) ,Ebola ,vectored immunoprophylaxis ,immunotherapy ,monoclonal antibody ,AAV6.2FF ,Genetics ,QH426-470 ,Cytology ,QH573-671 - Abstract
Filoviruses cause severe hemorrhagic fever with case fatality rates as high as 90%. Filovirus-specific monoclonal antibodies (mAbs) confer protection in nonhuman primates as late as 5 days after challenge, and FDA-approved mAbs REGN-EB3 and mAb114 have demonstrated efficacy against Ebola virus (EBOV) infection in humans. Vectorized antibody expression mediated by adeno-associated virus (AAV) can generate protective and sustained concentrations of therapeutic mAbs in animal models for a variety of infectious diseases, including EBOV. Here we demonstrate that AAV6.2FF-mediated expression of murine IgG2a EBOV mAbs, 2G4 and 5D2, protects from mouse-adapted (MA)-EBOV infection with none of the surviving mice developing anti-VP40 antibodies above background. Protective serum concentrations of AAV6.2FF-2G4/AAV6.2FF-5D2 did not alter endogenous antibody responses to heterologous virus infection. AAV-mediated expression of EBOV mAbs 100 and 114, and pan-ebolavirus mAbs, FVM04, ADI-15878, and CA45, as human IgG1 antibodies conferred protection against MA-EBOV at low serum concentrations, with minimum protective serum levels as low as 2 μg/mL. Vectorized expression of murine IgG2a or human IgG1 mAbs led to sustained expression in the serum of mice for >400 days or for the lifetime of the animal, respectively. AAV6.2FF-mediated mAb expression offers an alternative to recombinant antibody administration in scenarios where long-term protection is preferable to passive immunization.
- Published
- 2022
- Full Text
- View/download PDF
10. The Nucleocapsid Proteins of SARS-CoV-2 and Its Close Relative Bat Coronavirus RaTG13 Are Capable of Inhibiting PKR- and RNase L-Mediated Antiviral Pathways
- Author
-
Kyle LeBlanc, Jessie Lynch, Christine Layne, Robert Vendramelli, Angela Sloan, Nikesh Tailor, Yvon Deschambault, Fushun Zhang, Darwyn Kobasa, David Safronetz, Yan Xiang, and Jingxin Cao
- Subjects
G3BP1 ,PKR ,RNase L ,RaTG13 ,SARS-CoV-2 nucleocapsid ,double-stranded RNA virus ,Microbiology ,QR1-502 - Abstract
ABSTRACT Coronaviruses (CoVs), including severe acute respiratory syndrome CoV (SARS-CoV), Middle East respiratory syndrome CoV (MERS-CoV), and SARS-CoV-2, produce double-stranded RNA (dsRNA) that activates antiviral pathways such as PKR and OAS/RNase L. To successfully replicate in hosts, viruses must evade such antiviral pathways. Currently, the mechanism of how SARS-CoV-2 antagonizes dsRNA-activated antiviral pathways is unknown. In this study, we demonstrate that the SARS-CoV-2 nucleocapsid (N) protein, the most abundant viral structural protein, is capable of binding to dsRNA and phosphorylated PKR, inhibiting both the PKR and OAS/RNase L pathways. The N protein of the bat coronavirus (bat-CoV) RaTG13, the closest relative of SARS-CoV-2, has a similar ability to inhibit the human PKR and RNase L antiviral pathways. Via mutagenic analysis, we found that the C-terminal domain (CTD) of the N protein is sufficient for binding dsRNA and inhibiting RNase L activity. Interestingly, while the CTD is also sufficient for binding phosphorylated PKR, the inhibition of PKR antiviral activity requires not only the CTD but also the central linker region (LKR). Thus, our findings demonstrate that the SARS-CoV-2 N protein is capable of antagonizing the two critical antiviral pathways activated by viral dsRNA and that its inhibition of PKR activities requires more than dsRNA binding mediated by the CTD. IMPORTANCE The high transmissibility of SARS-CoV-2 is an important viral factor defining the coronavirus disease 2019 (COVID-19) pandemic. To transmit efficiently, SARS-CoV-2 must be capable of disarming the innate immune response of its host efficiently. Here, we describe that the nucleocapsid protein of SARS-CoV-2 is capable of inhibiting two critical innate antiviral pathways, PKR and OAS/RNase L. Moreover, the counterpart of the closest animal coronavirus relative of SARS-CoV-2, bat-CoV RaTG13, can also inhibit human PKR and OAS/RNase L antiviral activities. Thus, the importance of our discovery for understanding the COVID-19 pandemic is 2-fold. First, the ability of SARS-CoV-2 N to inhibit innate antiviral activity is likely a factor contributing to the transmissibility and pathogenicity of the virus. Second, the bat relative of SARS-CoV-2 has the capacity to inhibit human innate immunity, which thus likely contributed to the establishment of infection in humans. The findings described in this study are valuable for developing novel antivirals and vaccines.
- Published
- 2023
- Full Text
- View/download PDF
11. Universal antibody targeting the highly conserved fusion peptide provides cross-protection in mice
- Author
-
Abenaya Muralidharan, Caroline Gravel, Greg Harris, Anwar M. Hashem, Wanyue Zhang, David Safronetz, Gary Van Domselaar, Florian Krammer, Simon Sauve, Michael Rosu-Myles, Lisheng Wang, Wangxue Chen, and Xuguang Li
- Subjects
influenza ,universal antibody ,uni-1 ,antibody-dependent cellular cytotoxicity (adcc) ,cross-protection ,Immunologic diseases. Allergy ,RC581-607 ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Influenza is a major public health concern causing millions of hospitalizations every year. The current vaccines need annual updating based on prediction of likely strains in the upcoming season. However, mismatches between vaccines and the actual circulating viruses can occur, reducing vaccine effectiveness significantly because of the remarkably high rate of mutation in the viral glycoprotein, hemagglutinin (HA). Clearly, it would be of great interest to determine the potential role of universally conserved epitopes in inducing protective immunity. Here, an antibody against the 14-aa fusion peptide sequence at the N-terminus of the HA2 subunit (Uni-1) was investigated for its ability to elicit antibody-dependent cellular cytotoxicity (ADCC) in vitro and cross-protection against lethal infection in animals. Uni-1, known to neutralize influenza type A (IAV) in vitro, was found to induce strong ADCC against diverse influenza viruses, including human and avian IAVs and both lineages of type B (IBV). The ADCC effects against human IAVs by Uni-1 was comparable to ADCC induced by well-characterized antibodies, F10 and FI6V3. Importantly, mice treated with Uni-1 were protected against lethal challenge of IAV and IBV. These results revealed the versatile effector functions of this universal antibody against markedly diverse strains of both IAV and IBV.
- Published
- 2022
- Full Text
- View/download PDF
12. Polyclonal alpaca antibodies protect against hantavirus pulmonary syndrome in a lethal Syrian hamster model
- Author
-
Patrycja Sroga, Angela Sloan, Bryce M. Warner, Kevin Tierney, Jocelyne Lew, Guodong Liu, Michael Chan, Yvon Deschambault, Derek R. Stein, Geoff Soule, Logan Banadyga, Darryl Falzarano, and David Safronetz
- Subjects
Medicine ,Science - Abstract
Abstract The use of antibody-based therapies for the treatment of high consequence viral pathogens has gained interest over the last fifteen years. Here, we sought to evaluate the use of unique camelid-based IgG antibodies to prevent lethal hantavirus pulmonary syndrome (HPS) in Syrian hamsters. Using purified, polyclonal IgG antibodies generated in DNA-immunized alpacas, we demonstrate that post-exposure treatments reduced viral burdens and organ-specific pathology associated with lethal HPS. Antibody treated animals did not exhibit signs of disease and were completely protected. The unique structures and properties, particularly the reduced size, distinct paratope formation and increased solubility of camelid antibodies, in combination with this study support further pre-clinical evaluation of heavy-chain only antibodies for treatment of severe respiratory diseases, including HPS.
- Published
- 2021
- Full Text
- View/download PDF
13. An introduction to the Marburg virus vaccine consortium, MARVAC
- Author
-
Robert W. Cross, Ira M. Longini, Stephan Becker, Karin Bok, David Boucher, Miles W. Carroll, Janet V. Díaz, William E. Dowling, Ruxandra Draghia-Akli, James T. Duworko, John M. Dye, Michael A. Egan, Patricia Fast, Amy Finan, Courtney Finch, Thomas R. Fleming, Joan Fusco, Thomas W. Geisbert, Anthony Griffiths, Stephan Günther, Lisa E. Hensley, Anna Honko, Ruth Hunegnaw, Jocelyn Jakubik, Julie Ledgerwood, Kerstin Luhn, Demetrius Matassov, Jeffrey Meshulam, Emily V. Nelson, Christopher L. Parks, Roxana Rustomjee, David Safronetz, Lauren M. Schwartz, Dean Smith, Paul Smock, Ydrissa Sow, Christina F. Spiropoulou, Nancy J. Sullivan, Kelly L. Warfield, Daniel Wolfe, Courtney Woolsey, Roland Zahn, Ana María Henao-Restrepo, César Muñoz-Fontela, and Andrea Marzi
- Subjects
Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
The emergence of Marburg virus (MARV) in Guinea and Ghana triggered the assembly of the MARV vaccine “MARVAC” consortium representing leaders in the field of vaccine research and development aiming to facilitate a rapid response to this infectious disease threat. Here, we discuss current progress, challenges, and future directions for MARV vaccines.
- Published
- 2022
14. Ebola Virus IgG Seroprevalence in Southern Mali
- Author
-
Sidy Bane, Kyle Rosenke, Ousmane Maiga, Friederike Feldmann, Kimberly Meade-White, Julie Callison, David Safronetz, Nafomon Sogoba, and Heinz Feldmann
- Subjects
Ebola virus ,ebolaviruses ,filoviruses ,serology ,viruses ,zoonoses ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Abstract
Mali had 2 reported introductions of Ebola virus (EBOV) during the 2013–2016 West Africa epidemic. Previously, no evidence for EBOV circulation was reported in Mali. We performed an EBOV serosurvey study in southern Mali. We found low seroprevalence in the population, indicating local exposure to EBOV or closely related ebola viruses.
- Published
- 2021
- Full Text
- View/download PDF
15. SARS-CoV-2 infection and transmission in the North American deer mouse
- Author
-
Bryan D. Griffin, Mable Chan, Nikesh Tailor, Emelissa J. Mendoza, Anders Leung, Bryce M. Warner, Ana T. Duggan, Estella Moffat, Shihua He, Lauren Garnett, Kaylie N. Tran, Logan Banadyga, Alixandra Albietz, Kevin Tierney, Jonathan Audet, Alexander Bello, Robert Vendramelli, Amrit S. Boese, Lisa Fernando, L. Robbin Lindsay, Claire M. Jardine, Heidi Wood, Guillaume Poliquin, James E. Strong, Michael Drebot, David Safronetz, Carissa Embury-Hyatt, and Darwyn Kobasa
- Subjects
Science - Abstract
Deer mice are natural hosts for a number of human pathogens. Here, Griffin et al. report that intranasal exposure of the North American deer mouse to SARS-CoV-2 results in virus replication and shedding, despite causing only mild or asymptomatic illness. Additionally, infected deer mice can transmit SARS-CoV-2 to naïve deer mice.
- Published
- 2021
- Full Text
- View/download PDF
16. Japanese encephalitis virus persists in the human reproductive epithelium and porcine reproductive tissues.
- Author
-
Subash Chapagain, Prince Pal Singh, Khanh Le, David Safronetz, Heidi Wood, and Uladzimir Karniychuk
- Subjects
Arctic medicine. Tropical medicine ,RC955-962 ,Public aspects of medicine ,RA1-1270 - Abstract
Japanese encephalitis virus (JEV) is the emerging and geographically expanding flavivirus and the major causative agent of encephalitis in humans in Asia. There are risks of JEV introduction into the Americas given a large population of amplifying hosts-pigs and wild boars, and insect vectors-Culex mosquitoes. There are emerging concerns about vector-free ways of flavivirus transmission, for example sexual and transplacental Zika virus transmissions, which may change flavivirus epidemiology and expand the geographical range to territories with no insect vectors. It is unknown whether JEV has tropism in the female lower reproductive tract and the potential for sexual transmission in humans. While clinical outcomes of transplacental JEV infection are described in humans and pigs, cellular targets and tissue tropism in the upper reproductive tract are also unknown. Here, we studied JEV infection phenotypes and host transcriptional responses in human reproductive epithelial cells. We found that JEV caused persistent infection and cytopathology in the vaginal epithelium, endometrial epithelium, and trophoblast. Human vaginal epithelial cells infected with JEV had altered transcriptional responses associated with inflammation and disruption of epithelial barrier function. Also, using pigs-the native amplifying host for JEV, we confirmed JEV tropism in the female lower and upper reproductive tracts. We discovered that JEV persists in the vaginal mucosa for at least 28 days and pigs shed the virus in vaginal secretions. We also found JEV persistence in the endometrium and placenta with transplacental and fetal infections. Altogether, we discovered that JEV targets the vaginal epithelium and has the potential for sexual transmission in humans. We also contributed to a better understanding of JEV pathogenesis during transplacental infection. Further studies are needed to better understand the interactions of JEV with reproductive tissues, how persistent infection affects female reproductive functions, and the risks for non-vector transmission.
- Published
- 2022
- Full Text
- View/download PDF
17. An Outbred Guinea Pig Disease Model for Lassa Fever Using a Host-Adapted Clade III Nigerian Lassa Virus
- Author
-
Yvon Deschambault, Geoff Soule, Levi Klassen, Angela Sloan, Jonathan Audet, Kim Azaransky, Abdulmajid S. Musa, Adama Ahmad, Afolabi M. Akinpelu, Nwando Mba, Derek R. Stein, Marc Ranson, Muhamad Almiski, Kevin Tierney, Gabor Fischer, Mable Chan, and David Safronetz
- Subjects
Lassa virus ,disease modelling ,medical countermeasures ,infectious diseases ,Microbiology ,QR1-502 - Abstract
Nigeria experiences annual outbreaks of Lassa fever (LF) with high case numbers. At least three clades of Lassa virus (LASV) have been documented in Nigeria, though recent outbreaks are most often associated with clade II or clade III viruses. Using a recently isolated clade III LASV from a case of LF in Nigeria in 2018, we developed and characterized a guinea pig adapted virus capable of causing lethal disease in commercially available Hartley guinea pigs. Uniform lethality was observed after four passages of the virus and was associated with only two dominant genomic changes. The adapted virus was highly virulent with a median lethal dose of 10 median tissue culture infectious doses. Disease was characterized by several hallmarks of LF in similar models including high fever, thrombocytopenia, coagulation disorders, and increased inflammatory immune mediators. High viral loads were noted in all solid organ specimens analyzed. Histological abnormalities were most striking in the lungs and livers of terminal animals and included interstitial inflammation, edema, and steatosis. Overall, this model represents a convenient small animal model for a clade III Nigeria LASV with which evaluation of specific prophylactic vaccines and medical countermeasures can be conducted.
- Published
- 2023
- Full Text
- View/download PDF
18. Hantavirus Cardiopulmonary Syndrome in Canada
- Author
-
Bryce M. Warner, Sebastian Dowhanik, Jonathan Audet, Allen Grolla, Daryl Dick, James E. Strong, Darwyn Kobasa, L. Robbin Lindsay, Gary Kobinger, Heinz Feldmann, Harvey Artsob, Michael A. Drebot, and David Safronetz
- Subjects
hantavirus cardiopulmonary syndrome ,hantavirus pulmonary syndrome hantavirus ,Sin Nombre virus ,Canada ,viruses ,hantavirus ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Abstract
Hantavirus cardiopulmonary syndrome (HCPS) is a severe respiratory disease caused by Sin Nombre virus in North America (SNV). As of January 1, 2020, SNV has caused 143 laboratory-confirmed cases of HCPS in Canada. We review critical aspects of SNV virus epidemiology and the ecology, biology, and genetics of HCPS in Canada.
- Published
- 2020
- Full Text
- View/download PDF
19. Dysregulation of Ephrin receptor and PPAR signaling pathways in neural progenitor cells infected by Zika virus
- Author
-
Sathya N. Thulasi Raman, Elyse Latreille, Jun Gao, Wanyue Zhang, Jianguo Wu, Marsha S. Russell, Lisa Walrond, Terry Cyr, Jessie R. Lavoie, David Safronetz, Jingxin Cao, Simon Sauve, Aaron Farnsworth, Wangxue Chen, Pei-Yong Shi, Youchun Wang, Lisheng Wang, Michael Rosu-Myles, and Xuguang Li
- Subjects
Neural progenitor cells ,ZIKV ,Ephrin signaling ,PPAR signaling ,proteomics ,ingenuity pathway analysis ,Infectious and parasitic diseases ,RC109-216 ,Microbiology ,QR1-502 - Abstract
ABSTRACTZika virus (ZIKV) infection is a serious public threat with cases reported in about 70 countries and territories. One of the most serious consequences of ZIKV infection is congenital microcephaly in babies. Congenital microcephaly has been suggested to result from infection of neural progenitor cells (NPCs) in the developing fetal brain. However, the molecular and cellular mechanisms underlying microcephaly development remains to be fully elucidated. In this study, we employed quantitative proteomics to determine protein expression profile that occur during viral replication in NPCs. Bioinformatics analysis of the protein expression changes resulted in the identification of a wide range of cell signaling pathways. Specifically, pathways involved in neurogenesis and embryonic development were markedly altered, along with those associated with cell cycle, apoptosis, lipid metabolism and oxidative stress. Notably, the differential regulation of Ephrin Receptor and PPAR signaling pathways, as revealed by quantitative proteomics and validated by qPCR array, underscores the need to explore these pathways in disease development. Collectively, these results indicate that ZIKV-induced pathogenesis involves complex virus-host reactions; the findings reported here could help shed light on the mechanisms underlying ZIKV-induced microcephaly and ZIKV replication in NPCs.
- Published
- 2020
- Full Text
- View/download PDF
20. DNA Based Vaccine Expressing SARS-CoV-2 Spike-CD40L Fusion Protein Confers Protection Against Challenge in a Syrian Hamster Model
- Author
-
Levi A. Tamming, Diana Duque, Anh Tran, Wanyue Zhang, Annabelle Pfeifle, Emmanuel Laryea, Jianguo Wu, Sathya N. Thulasi Raman, Caroline Gravel, Marsha S. Russell, Anwar M. Hashem, Reem M. Alsulaiman, Rowa Y. Alhabbab, Jun Gao, David Safronetz, Jingxin Cao, Lisheng Wang, Wangxue Chen, Michael J. W. Johnston, Simon Sauve, Michael Rosu-Myles, and Xuguang Li
- Subjects
SARS-CoV-2 ,coronavirus ,vaccination ,DNA ,antibody response ,pathology ,Immunologic diseases. Allergy ,RC581-607 - Abstract
SARS-CoV-2 infections present a tremendous threat to public health. Safe and efficacious vaccines are the most effective means in preventing the infections. A variety of vaccines have demonstrated excellent efficacy and safety around the globe. Yet, development of alternative forms of vaccines remains beneficial, particularly those with simpler production processes, less stringent storage conditions, and the capability of being used in heterologous prime/boost regimens which have shown improved efficacy against many diseases. Here we reported a novel DNA vaccine comprised of the SARS-CoV-2 spike protein fused with CD40 ligand (CD40L) serving as both a targeting ligand and molecular adjuvant. A single intramuscular injection in Syrian hamsters induced significant neutralizing antibodies 3-weeks after vaccination, with a boost substantially improving immune responses. Moreover, the vaccine also reduced weight loss and suppressed viral replication in the lungs and nasal turbinates of challenged animals. Finally, the incorporation of CD40L into the DNA vaccine was shown to reduce lung pathology more effectively than the DNA vaccine devoid of CD40L. These results collectively indicate that this DNA vaccine candidate could be further explored because of its efficacy and known safety profile.
- Published
- 2022
- Full Text
- View/download PDF
21. Host parameters and mode of infection influence outcome in SARS-CoV-2-infected hamsters
- Author
-
Bryan D. Griffin, Bryce M. Warner, Mable Chan, Emelissa Valcourt, Nikesh Tailor, Logan Banadyga, Anders Leung, Shihua He, Amrit S. Boese, Jonathan Audet, Wenguang Cao, Estella Moffat, Lauren Garnett, Kevin Tierney, Kaylie N. Tran, Alixandra Albietz, Kathy Manguiat, Geoff Soule, Alexander Bello, Robert Vendramelli, Jessica Lin, Yvon Deschambault, Wenjun Zhu, Heidi Wood, Samira Mubareka, David Safronetz, James E. Strong, Carissa Embury-Hyatt, and Darwyn Kobasa
- Subjects
Cellular physiology ,Microbiology ,Virology ,Science - Abstract
Summary: The golden hamster model of SARS-CoV-2 infection recapitulates key characteristics of COVID-19. In this work we examined the influence of the route of exposure, sex, and age on SARS-CoV-2 pathogenesis in hamsters. We report that delivery of SARS-CoV-2 by a low- versus high-volume intranasal or intragastric route results in comparable viral titers in the lung and viral shedding. However, low-volume intranasal exposure results in milder weight loss, whereas intragastric exposure leads to a diminished capacity to regain body weight. Male hamsters, and particularly older male hamsters, display an impaired capacity to recover from illness and delayed viral clearance. These factors were found to influence the nature of the host inflammatory cytokine response but had a minimal effect on the quality and durability of the humoral immune response and susceptibility to re-infection. These data further elucidate key factors that impact pre-clinical challenge studies carried out in the hamster model of COVID-19.
- Published
- 2021
- Full Text
- View/download PDF
22. Intranasal vaccination with a Newcastle disease virus-vectored vaccine protects hamsters from SARS-CoV-2 infection and disease
- Author
-
Bryce M. Warner, Lisa A. Santry, Alexander Leacy, Mable Chan, Phuc H. Pham, Robert Vendramelli, Yanlong Pei, Nikesh Tailor, Emelissa Valcourt, Anders Leung, Shihua He, Bryan D. Griffin, Jonathan Audet, Marnie Willman, Kevin Tierney, Alixandra Albietz, Kathy L. Frost, Jacob G.E. Yates, Robert C. Mould, Lily Chan, Yeganeh Mehrani, Jason P. Knapp, Jessica A. Minott, Logan Banadyga, David Safronetz, Heidi Wood, Stephanie Booth, Pierre P. Major, Byram W. Bridle, Leonardo Susta, Darwyn Kobasa, and Sarah K. Wootton
- Subjects
Immune respons ,Virology ,Science - Abstract
Summary: The pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19). Worldwide efforts are being made to develop vaccines to mitigate this pandemic. We engineered two recombinant Newcastle disease virus (NDV) vectors expressing either the full-length SARS-CoV-2 spike protein (NDV-FLS) or a version with a 19 amino acid deletion at the carboxy terminus (NDV-Δ19S). Hamsters receiving two doses (prime-boost) of NDV-FLS developed a robust SARS-CoV-2-neutralizing antibody response, with elimination of infectious virus in the lungs and minimal lung pathology at five days post-challenge. Single-dose vaccination with NDV-FLS significantly reduced SARS-CoV-2 replication in the lungs but only mildly decreased lung inflammation. NDV-Δ19S-treated hamsters had a moderate decrease in SARS-CoV-2 titers in lungs and presented with severe microscopic lesions, suggesting that truncation of the spike protein was a less effective strategy. In summary, NDV-vectored vaccines represent a viable option for protection against COVID-19.
- Published
- 2021
- Full Text
- View/download PDF
23. Synthetic vaccine affords full protection to mice against lethal challenge of influenza B virus of both genetic lineages
- Author
-
Caroline Gravel, Abenaya Muralidharan, Amparo Duran, Adrian Zetner, Annabelle Pfeifle, Wanyue Zhang, Anwar Hashem, Levi Tamming, Aaron Farnsworth, Hugues Loemba, Wangxue Chen, Florian Krammer, David Safronetz, Jingxin Cao, Lisheng Wang, Simon Sauve, Michael Rosu-Myles, Gary Van Domselaar, and Xuguang Li
- Subjects
Immunology ,immune response ,Virology ,Science - Abstract
Summary: A quarter of all seasonal influenza cases are caused by type B influenza virus (IBV) that also dominates periodically. Here, we investigated a recombinant adenovirus vaccine carrying a synthetic HA2 representing the consensus sequence of all IBV hemagglutinins. The vaccine fully protected mice from lethal challenges by IBV of both genetic lineages, demonstrating its breadth of protection. The protection was not mediated by neutralizing antibodies but robust antibody-dependent cellular cytotoxicity and cell-mediated immune responses. Complete protection of the animals required the entire codon-optimized HA2 sequence that elicited a balanced immune response, whereas truncated vaccines without either the fusion peptide or the transmembrane domain reduced the efficacy of protection. Finally, the vaccines did not demonstrate any sign of disease exacerbation following lung pathology and morbidity monitoring. Collectively, these data suggest that it could be worth further exploring this prototype universal vaccine because of its considerable efficacy, safety, and breadth of protection.
- Published
- 2021
- Full Text
- View/download PDF
24. Differential pathogenesis of closely related 2018 Nigerian outbreak clade III Lassa virus isolates.
- Author
-
Derek R Stein, Bryce M Warner, Jonathan Audet, Geoff Soule, Vinayakumar Siragam, Patrycja Sroga, Bryan D Griffin, Anders Leung, Allen Grolla, Kevin Tierney, Alix Albietz, Darwyn Kobasa, Abdulmajid S Musa, Adama Ahmad, Afolabi M Akinpelu, Nwando Mba, Rebecca Rosenke, Dana P Scott, Greg Saturday, Chikwe Ihekweazu, and David Safronetz
- Subjects
Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
Nigeria continues to experience ever increasing annual outbreaks of Lassa fever (LF). The World Health Organization has recently declared Lassa virus (LASV) as a priority pathogen for accelerated research leading to a renewed international effort to develop relevant animal models of disease and effective countermeasures to reduce LF morbidity and mortality in endemic West African countries. A limiting factor in evaluating medical countermeasures against LF is a lack of well characterized animal models outside of those based on infection with LASV strain Josiah originating form Sierra Leone, circa 1976. Here we genetically characterize five recent LASV isolates collected from the 2018 outbreak in Nigeria. Three isolates were further evaluated in vivo and despite being closely related and from the same spatial / geographic region of Nigeria, only one of the three isolates proved lethal in strain 13 guinea pigs and non-human primates (NHP). Additionally, this isolate exhibited atypical pathogenesis characteristics in the NHP model, most notably respiratory failure, not commonly described in hemorrhagic cases of LF. These results suggest that there is considerable phenotypic heterogeneity in LASV infections in Nigeria, which leads to a multitude of pathogenesis characteristics that could account for differences between subclinical and lethal LF infections. Most importantly, the development of disease models using currently circulating LASV strains in West Africa are critical for the evaluation of potential vaccines and medical countermeasures.
- Published
- 2021
- Full Text
- View/download PDF
25. Single Immunization of a Vaccine Vectored by a Novel Recombinant Vaccinia Virus Affords Effective Protection Against Respiratory Syncytial Virus Infection in Cotton Rats
- Author
-
Marsha S. Russell, Sathya N. Thulasi Raman, Caroline Gravel, Wanyue Zhang, Annabelle Pfeifle, Wangxue Chen, Gary Van Domselaar, David Safronetz, Michael Johnston, Simon Sauve, Lisheng Wang, Michael Rosu-Myles, Jingxin Cao, and Xuguang Li
- Subjects
vaccine ,antibodies ,vaccinia ,virus ,vector ,respiratory syncytial virus ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Respiratory syncytial virus (RSV) is a leading cause of respiratory infections worldwide and disease management measures are hampered by the lack of a safe and effective vaccine against the infection. We constructed a novel recombinant RSV vaccine candidate based on a deletion mutant vaccinia virus platform, in that the host range genes E3L and K3L were deleted (designated as VACVΔE3LΔK3L) and a poxvirus K3L ortholog gene was used as a marker for the rapid and efficient selection of recombinant viruses. The safety of the modified vaccinia virus was investigated by intranasal administration of BALB/c mice with the modified vaccinia vector using a dose known to be lethal in the wild-type Western Reserve. Only a minor loss of body weight by less than 5% and mild pulmonary inflammation were observed, both of which were transient in nature following nasal administration of the high-dose modified vaccinia virus. In addition, the viruses were cleared from the lung in 2 days with no viral invasions of the brain and other vital organs. These results suggest that the virulence of the virus has been essentially abolished. We then investigated the efficiency of the vector for the delivery of vaccines against RSV through comparison with another RSV vaccine delivered by the widely used Modified Vaccinia virus Ankara (MVA) backbone. In the cotton rats, we found a single intramuscular administration of VACVΔE3LΔK3L-vectored vaccine elicited immune responses and protection at a level comparable to the MVA-vectored vaccine against RSV infection. The distinct features of this novel VACV vector, such as an E3L deletion for attenuation and a K3L ortholog for positive selection and high efficiency for vaccine delivery, could provide unique advantages to the application of VACV as a platform for vaccine development.
- Published
- 2021
- Full Text
- View/download PDF
26. Evaluating Temperature Sensitivity of Vesicular Stomatitis Virus–Based Vaccines
- Author
-
Derek R. Stein, Patrycja Sroga, Bryce M. Warner, Yvon Deschambault, Guillaume Poliquin, and David Safronetz
- Subjects
Viral hemorrhagic fever ,Ebola virus ,Lassa virus ,vaccine stability ,vaccines ,viruses ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Abstract
Use of the vesicular stomatitis virus (VSV)–based Ebola virus vaccine during outbreaks and the potential use of a similar VSV-based Lassa virus vaccine has raised questions about the vaccines’ stability should the cold chain fail. We demonstrated that current cold chain conditions might tolerate significant variances without affecting efficacy.
- Published
- 2019
- Full Text
- View/download PDF
27. Persistent Zika virus infection in porcine conceptuses is associated with elevated in utero cortisol levels
- Author
-
Ivan Trus, Joseph Darbellay, Yanyun Huang, Matthew Gilmour, David Safronetz, Volker Gerdts, and Uladzimir Karniychuk
- Subjects
Zika virus ,cortisol ,pig ,fetus ,placenta ,11β-HSD ,HPA axis ,Infectious and parasitic diseases ,RC109-216 - Published
- 2018
- Full Text
- View/download PDF
28. Simulated sunlight decreases the viability of SARS-CoV-2 in mucus
- Author
-
Angela Sloan, Todd Cutts, Bryan D. Griffin, Samantha Kasloff, Zachary Schiffman, Mable Chan, Jonathan Audet, Anders Leung, Darwyn Kobasa, Derek R. Stein, David Safronetz, and Guillaume Poliquin
- Subjects
Medicine ,Science - Abstract
The novel coronavirus, SARS-CoV-2, has spread into a pandemic since its emergence in Wuhan, China in December of 2019. This has been facilitated by its high transmissibility within the human population and its ability to remain viable on inanimate surfaces for an extended period. To address the latter, we examined the effect of simulated sunlight on the viability of SARS-CoV-2 spiked into tissue culture medium or mucus. The study revealed that inactivation took 37 minutes in medium and 107 minutes in mucus. These times-to-inactivation were unexpected since they are longer than have been observed in other studies. From this work, we demonstrate that sunlight represents an effective decontamination method but the speed of decontamination is variable based on the underlying matrix. This information has an important impact on the development of infection prevention and control protocols to reduce the spread of this deadly pathogen.
- Published
- 2021
29. Lassa viral dynamics in non-human primates treated with favipiravir or ribavirin.
- Author
-
Guillaume Lingas, Kyle Rosenke, David Safronetz, and Jérémie Guedj
- Subjects
Biology (General) ,QH301-705.5 - Abstract
Lassa fever is an haemorrhagic fever caused by Lassa virus (LASV). There is no vaccine approved against LASV and the only recommended antiviral treatment relies on ribavirin, despite limited evidence of efficacy. Recently, the nucleotide analogue favipiravir showed a high antiviral efficacy, with 100% survival obtained in an otherwise fully lethal non-human primate (NHP) model of Lassa fever. However the mechanism of action of the drug is not known and the absence of pharmacokinetic data limits the translation of these results to the human setting. Here we aimed to better understand the antiviral effect of favipiravir by developping the first mathematical model recapitulating Lassa viral dynamics and treatment. We analyzed the viral dynamics in 24 NHPs left untreated or treated with ribavirin or favipiravir, and we put the results in perspective with those obtained with the same drugs in the context of Ebola infection. Our model estimates favipiravir EC50 in vivo to 2.89 μg.mL-1, which is much lower than what was found against Ebola virus. The main mechanism of action of favipiravir was to decrease virus infectivity, with an efficacy of 91% at the highest dose. Based on our knowledge acquired on the drug pharmacokinetics in humans, our model predicts that favipiravir doses larger than 1200 mg twice a day should have the capability to strongly reduce the production infectious virus and provide a milestone towards a future use in humans.
- Published
- 2021
- Full Text
- View/download PDF
30. Oral Vaccination With Recombinant Vesicular Stomatitis Virus Expressing Sin Nombre Virus Glycoprotein Prevents Sin Nombre Virus Transmission in Deer Mice
- Author
-
Bryce M. Warner, Rohit K. Jangra, Bryan D. Griffin, Derek R. Stein, Darwyn Kobasa, Kartik Chandran, Gary P. Kobinger, and David Safronetz
- Subjects
sin nombre virus ,hantavirus ,hantavirus cardiopulmonary syndrome ,deer mice ,Peromyscus maniculatus ,Microbiology ,QR1-502 - Abstract
Sin Nombre virus (SNV) is the major cause of hantavirus cardiopulmonary syndrome (HCPS) in North America, a severe respiratory disease with a high fatality rate. SNV is carried by Peromyscus maniculatus, or deer mice, and human infection occurs following inhalation of aerosolized virus in mouse excreta or secreta, often in peri-domestic settings. Currently there are no FDA approved vaccines or therapeutics for SNV or any other hantaviruses, therefore prevention of infection is an important means of reducing the disease burden of HCPS. One approach for preventing HCPS cases is to prevent the spread of the virus amongst the rodent reservoir population through bait vaccination. However, bait style vaccines for rodent-borne viruses have not been employed in the field, unlike those targeting larger species. Here we utilized a recombinant vesicular stomatitis virus expressing SNV glycoprotein precursor (rVSVΔG/SNVGPC) in an attempt to prevent SNV transmission. Vaccination of deer mice with rVSVΔG/SNVGPC was able to reduce viral RNA copy numbers in the blood and lungs of directly infected animals. More importantly, vaccination, either intramuscularly or orally, significantly reduced the number of transmission events in a SNV transmission model compared with control animals. This provides a proof-of-concept in which oral vaccination of deer mice results in protection against acquiring the virus following direct contact with infected deer mice. Further development of bait style vaccines for SNV or other rodent-borne viruses could provide an effective means of reducing disease burden.
- Published
- 2020
- Full Text
- View/download PDF
31. Susceptibility of Chicken Embryos, Sheep, Cattle, Pigs, and Chickens to Zika Virus Infection
- Author
-
Aruna Ambagala, Thang Truong, Colleen Cottam-Birt, Yohannes Berhane, Volker Gerdts, Uladzimir Karniychuk, David Safronetz, and Shawn Babiuk
- Subjects
Zika virus ,embryo ,tissue tropism ,susceptibility ,chicken ,Veterinary medicine ,SF600-1100 - Abstract
The susceptibility of sheep, cattle, pigs, chickens and chicken embryos to Zika virus infection was evaluated by experimental inoculation with Zika virus Thailand strain isolated from a Canadian traveler in 2013. The inoculated animals did not develop any clinical signs of disease nor evidence of Zika virus replication in peripheral blood, cerebrospinal fluid and tissues including brain and spinal cord assessed by real-time RT-PCR. Sera were also negative for Zika virus antibodies by Zika virus neutralization assays as well as Zika virus immunoperoxidase staining of Zika infected Vero cells. Chicken embryos were inoculated by different routes including yolk sac (4 day old embryos), chorioallantoic membrane (8 day old embryos), amniotic fluid (8 day old embryos) and intravenous routes (12 day old embryos). Virus replication in chicken embryos was observed in the brain and body tissues following intravenous (IV), yolk sac (YS), chorioallantoic membrane (CAM), and amniotic fluid (AF) inoculation routes. The highest mortality was observed in embryos inoculated via yolk sac. The dead embryos showed diffuse muscular hemorrhages. The yolk sac inoculated chicken embryos showed delayed hatching and displayed neurological signs immediately after hatching. These studies demonstrate that 8 week old sheep, 6 month old cattle, 4 week old pigs, and 4 week old chickens are not susceptible to Zika virus infection when inoculated experimentally and therefore unlikely to pose a risk as Zika virus reservoirs. However, chicken embryos are highly susceptible to Zika virus resulting in clinical disease of chicks after hatching. This study demonstrates that Zika virus has a tropism for embryonic tissue and that chicken embryos can be used as a model to study Zika virus replication and pathogenesis.
- Published
- 2020
- Full Text
- View/download PDF
32. Use of Favipiravir to Treat Lassa Virus Infection in Macaques
- Author
-
Kyle Rosenke, Heinz Feldmann, Jonna B. Westover, Patrick William Hanley, Cynthia Martellaro, Friederike Feldmann, Greg Saturday, Jamie Lovaglio, Dana P. Scott, Yousuke Furuta, Takashi Komeno, Brian B. Gowen, and David Safronetz
- Subjects
Lassa virus ,antiviral ,favipiravir ,treatment ,viruses ,macaques ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Abstract
Lassa virus, the cause of Lassa fever in humans, is endemic to West Africa. Treatment of Lassa fever is primarily supportive, although ribavirin has shown limited efficacy if administered early during infection. We tested favipiravir in Lassa virus–viremic macaques and found that 300 mg/kg daily for 2 weeks successfully treated infection.
- Published
- 2018
- Full Text
- View/download PDF
33. Subclinical in utero Zika virus infection is associated with interferon alpha sequelae and sex-specific molecular brain pathology in asymptomatic porcine offspring.
- Author
-
Ivan Trus, Daniel Udenze, Brian Cox, Nathalie Berube, Rebecca E Nordquist, Franz Josef van der Staay, Yanyun Huang, Gary Kobinger, David Safronetz, Volker Gerdts, and Uladzimir Karniychuk
- Subjects
Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
Zika virus (ZIKV) infection during human pregnancy may lead to severe fetal pathology and debilitating impairments in offspring. However, the majority of infections are subclinical and not associated with evident birth defects. Potentially detrimental life-long health outcomes in asymptomatic offspring evoke high concerns. Thus, animal models addressing sequelae in offspring may provide valuable information. To induce subclinical infection, we inoculated selected porcine fetuses at the mid-stage of development. Inoculation resulted in trans-fetal virus spread and persistent infection in the placenta and fetal membranes for two months. Offspring did not show congenital Zika syndrome (e.g., microcephaly, brain calcifications, congenital clubfoot, arthrogryposis, seizures) or other visible birth defects. However, a month after birth, a portion of offspring exhibited excessive interferon alpha (IFN-α) levels in blood plasma in a regular environment. Most affected offspring also showed dramatic IFN-α shutdown during social stress providing the first evidence for the cumulative impact of prenatal ZIKV exposure and postnatal environmental insult. Other eleven cytokines tested before and after stress were not altered suggesting the specific IFN-α pathology. While brains from offspring did not have histopathology, lesions, and ZIKV, the whole genome expression analysis of the prefrontal cortex revealed profound sex-specific transcriptional changes that most probably was the result of subclinical in utero infection. RNA-seq analysis in the placenta persistently infected with ZIKV provided independent support for the sex-specific pattern of in utero-acquired transcriptional responses. Collectively, our results provide strong evidence that two hallmarks of fetal ZIKV infection, altered type I IFN response and molecular brain pathology can persist after birth in offspring in the absence of congenital Zika syndrome.
- Published
- 2019
- Full Text
- View/download PDF
34. Zika Virus Causes Persistent Infection in Porcine Conceptuses and may Impair Health in Offspring
- Author
-
Joseph Darbellay, Brian Cox, Kenneth Lai, Mario Delgado-Ortega, Colette Wheler, Donald Wilson, Stewart Walker, Gregory Starrak, Duncan Hockley, Yanyun Huang, George Mutwiri, Andrew Potter, Matthew Gilmour, David Safronetz, Volker Gerdts, and Uladzimir Karniychuk
- Subjects
Zika virus ,Fetus ,Offspring ,Persistent infection ,Behavior ,Pig ,Medicine ,Medicine (General) ,R5-920 - Abstract
Outcomes of Zika virus (ZIKV) infection in pregnant women vary from the birth of asymptomatic offspring to abnormal development and severe brain lesions in fetuses and infants. There are concerns that offspring affected in utero and born without apparent symptoms may develop mental illnesses. Therefore, animal models are important to test interventions against in utero infection and health sequelae in symptomatic and likely more widespread asymptomatic offspring. To partially reproduce in utero infection in humans, we directly inoculated selected porcine conceptuses with ZIKV. Inoculation resulted in rapid trans-fetal infections, persistent infection in conceptuses, molecular pathology in fetal brains, fetal antibody and type I interferon responses. Offspring infected in utero showed ZIKV in their fetal membranes collected after birth. Some in utero affected piglets were small, depressed, had undersized brains, and showed seizures. Some piglets showed potentially increased activity. Our data suggest that porcine model of persistent in utero ZIKV infection has a strong potential for translational research and can be used to test therapeutic interventions in vivo.
- Published
- 2017
- Full Text
- View/download PDF
35. Vesicular Stomatitis Virus: From Agricultural Pathogen to Vaccine Vector
- Author
-
Guodong Liu, Wenguang Cao, Abdjeleel Salawudeen, Wenjun Zhu, Karla Emeterio, David Safronetz, and Logan Banadyga
- Subjects
vesicular stomatitis virus ,VSV ,vaccine ,countermeasure ,Ebola virus ,VSV-EBOV ,Medicine - Abstract
Vesicular stomatitis virus (VSV), which belongs to the Vesiculovirus genus of the family Rhabdoviridae, is a well studied livestock pathogen and prototypic non-segmented, negative-sense RNA virus. Although VSV is responsible for causing economically significant outbreaks of vesicular stomatitis in cattle, horses, and swine, the virus also represents a valuable research tool for molecular biologists and virologists. Indeed, the establishment of a reverse genetics system for the recovery of infectious VSV from cDNA transformed the utility of this virus and paved the way for its use as a vaccine vector. A highly effective VSV-based vaccine against Ebola virus recently received clinical approval, and many other VSV-based vaccines have been developed, particularly for high-consequence viruses. This review seeks to provide a holistic but concise overview of VSV, covering the virus’s ascension from perennial agricultural scourge to promising medical countermeasure, with a particular focus on vaccines.
- Published
- 2021
- Full Text
- View/download PDF
36. Evaluation of 5 Commercially Available Zika Virus Immunoassays
- Author
-
David Safronetz, Angela Sloan, Derek R. Stein, Emelissa Mendoza, Nicole Barairo, Charlene Ranadheera, Leanne Scharikow, Kimberly Holloway, Alyssia Robinson, Maya Traykova-Andonova, Kai Makowski, Kristina Dimitrova, Elizabeth Giles, Joanne Hiebert, Rhonda Mogk, Sharla Beddome, and Michael Drebot
- Subjects
Zika virus ,viruses ,immunoassays ,evaluation ,vector-borne infections ,zoonoses ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Abstract
Because of the global spread of Zika virus, accurate and high-throughput diagnostic immunoassays are needed. We compared the sensitivity and specificity of 5 commercially available Zika virus serologic assays to the recommended protocol of Zika virus IgM-capture ELISA and plaque-reduction neutralization tests. Most commercial immunoassays showed low sensitivity, which can be increased.
- Published
- 2017
- Full Text
- View/download PDF
37. DNA vaccination protects mice against Zika virus-induced damage to the testes
- Author
-
Bryan D. Griffin, Kar Muthumani, Bryce M. Warner, Anna Majer, Mable Hagan, Jonathan Audet, Derek R. Stein, Charlene Ranadheera, Trina Racine, Marc-Antoine De La Vega, Jocelyne Piret, Stephanie Kucas, Kaylie N. Tran, Kathy L. Frost, Christine De Graff, Geoff Soule, Leanne Scharikow, Jennifer Scott, Gordon McTavish, Valerie Smid, Young K. Park, Joel N. Maslow, Niranjan Y. Sardesai, J. Joseph Kim, Xiao-jian Yao, Alexander Bello, Robbin Lindsay, Guy Boivin, Stephanie A. Booth, Darwyn Kobasa, Carissa Embury-Hyatt, David Safronetz, David B. Weiner, and Gary P. Kobinger
- Subjects
Science - Abstract
Zika virus (ZIKV) can persist in human semen and sperm, which can result in sexual transmission. Here, Griffinet al. show that a DNA vaccine, expressing ZIKV pre-membrane and envelope proteins, protects mice from infection-associated damage to testes and sperm, and prevents viral persistence in testes.
- Published
- 2017
- Full Text
- View/download PDF
38. Fatal Infection with Murray Valley Encephalitis Virus Imported from Australia to Canada, 2011
- Author
-
Daniel J. Niven, Kevin Afra, Mircea Iftinca, Raymond Tellier, Kevin Fonseca, Andreas Kramer, David Safronetz, Kimberly Holloway, Michael Drebot, and Andrew S. Johnson
- Subjects
Murray Valley encephalitis virus ,viruses ,Murray Valley encephalitis ,arbovirus ,encephalomyelitis ,meningitis/encephalitis ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Abstract
Murray Valley encephalitis virus (MVEV), a flavivirus belonging to the Japanese encephalitis serogroup, can cause severe clinical manifestations in humans. We report a fatal case of MVEV infection in a young woman who returned from Australia to Canada. The differential diagnosis for travel-associated encephalitis should include MVEV, particularly during outbreak years.
- Published
- 2017
- Full Text
- View/download PDF
39. Neonatal pigs are susceptible to experimental Zika virus infection
- Author
-
Joseph Darbellay, Kenneth Lai, Shawn Babiuk, Yohannes Berhane, Aruna Ambagala, Colette Wheler, Donald Wilson, Stewart Walker, Andrew Potter, Matthew Gilmour, David Safronetz, Volker Gerdts, and Uladzimir Karniychuk
- Subjects
Infectious and parasitic diseases ,RC109-216 ,Microbiology ,QR1-502 - Abstract
Emerging Microbes & Infections (2017) 6, e6; doi:10.1038/emi.2016.133; published online 15 February 2017
- Published
- 2017
- Full Text
- View/download PDF
40. Establishment of a Genetically Confirmed Breeding Colony of Mastomys natalensis from Wild-Caught Founders from West Africa
- Author
-
David Safronetz, Kyle Rosenke, Robert J. Fischer, Rachel A. LaCasse, Dana P. Scott, Greg Saturday, Patrick W. Hanley, Ousmane Maiga, Nafomon Sogoba, Tom G. Schwan, and Heinz Feldmann
- Subjects
Mastomys natalensis ,natal multimammate mouse ,natal multimammate rat ,soft-furred african mouse ,african rat ,rodent breeding colony ,Microbiology ,QR1-502 - Abstract
Mastomys natalensis are a ubiquitous and often dominant rodent across sub-Saharan Africa. Importantly, they are a natural reservoir for microbial pathogens including Lassa virus (LASV), the etiological agent of Lassa fever in humans. Lassa-infected rodents have been documented across West Africa and coincide with regions where annual outbreaks occur. Zoonotic transmission to humans most often occurs directly from infected rodents. Little is known about LASV infection kinetics and transmissibility in M.natalensis, primarily due to available animals. Here, we describe the establishment of a laboratory breeding colony of genetically confirmed M.natalensis from wild-captured rodents. This colony will provide a convenient source of animals to study LASV and other emerging pathogens that utilize M. natalensis in their enzootic lifecycles.
- Published
- 2021
- Full Text
- View/download PDF
41. Hematology and Clinical Chemistry Reference Ranges for Laboratory-Bred Natal Multimammate Mice (Mastomys natalensis)
- Author
-
David M. Wozniak, Norman Kirchoff, Katharina Hansen-Kant, Nafomon Sogoba, David Safronetz, and Joseph Prescott
- Subjects
Mastomys natalensis ,multimammate mouse ,multimammate rat ,blood ,reference value ,normal value ,Microbiology ,QR1-502 - Abstract
Laboratory-controlled physiological data for the multimammate rat (Mastomys natalensis) are scarce, despite this species being a known reservoir and vector for zoonotic viruses, including the highly pathogenic Lassa virus, as well as other arenaviruses and many species of bacteria. For this reason, M. natalensis is an important rodent for the study of host-virus interactions within laboratory settings. Herein, we provide basic blood parameters for age- and sex-distributed animals in regards to blood counts, cell phenotypes and serum chemistry of a specific-pathogen-monitored M.natalensis breeding colony, to facilitate scientific insight into this important and widespread rodent species.
- Published
- 2021
- Full Text
- View/download PDF
42. Lassa Virus Seroprevalence in Sibirilia Commune, Bougouni District, Southern Mali
- Author
-
Nafomon Sogoba, Kyle Rosenke, Jennifer Adjemian, Sory Ibrahim Diawara, Ousmane Maiga, Moussa Keita, Drissa Konaté, Abdoul Salam Keita, Ibrahim Sissoko, Matt Boisen, Diana Nelson, Darin Oottamasathien, Molly Millett, Robert F. Garry, Luis M. Branco, Sékou F. Traoré, Seydou Doumbia, Heinz Feldmann, and David Safronetz
- Subjects
Lassa fever ,Lassa virus seroprevalence ,arenavirus ,viral hemorrhagic fever ,West Africa ,southern Mali ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Abstract
Lassa virus (LASV) is endemic to several nations in West Africa. In Mali, LASV was unknown until an exported case of Lassa fever was reported in 2009. Since that time, rodent surveys have found evidence of LASV-infected Mastomys natalensis rats in several communities in southern Mali, near the border with Côte d’Ivoire. Despite increased awareness, to date only a single case of Lassa fever has been confirmed in Mali. We conducted a survey to determine the prevalence of LASV exposure among persons in 3 villages in southern Mali where the presence of infected rodents has been documented. LASV IgG seroprevalence ranged from 14.5% to 44% per village. No sex bias was noted; however, seropositivity rates increased with participant age. These findings confirm human LASV exposure in Mali and suggest that LASV infection/Lassa fever is a potential public health concern in southern Mali.
- Published
- 2016
- Full Text
- View/download PDF
43. Nanopore Sequencing as a Rapidly Deployable Ebola Outbreak Tool
- Author
-
Thomas Hoenen, Allison Groseth, Kyle Rosenke, Robert J. Fischer, Andreas Hoenen, Seth D. Judson, Cynthia Martellaro, Darryl Falzarano, Andrea Marzi, R. Burke Squires, Kurt R. Wollenberg, Emmie de Wit, Joseph B. Prescott, David Safronetz, Neeltje van Doremalen, Trenton Bushmaker, Friederike Feldmann, Kristin McNally, Fatorma K. Bolay, Barry Fields, Tara Sealy, Mark Rayfield, Stuart T. Nichol, Kathryn C. Zoon, Moses Massaquoi, Vincent J. Munster, and Heinz Feldmann
- Subjects
Ebola hemorrhagic fever ,Ebola virus ,Ebolavirus ,viruses ,high-throughput nucleotide sequencing ,nanopore sequencing ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Abstract
Rapid sequencing of RNA/DNA from pathogen samples obtained during disease outbreaks provides critical scientific and public health information. However, challenges exist for exporting samples to laboratories or establishing conventional sequencers in remote outbreak regions. We successfully used a novel, pocket-sized nanopore sequencer at a field diagnostic laboratory in Liberia during the current Ebola virus outbreak.
- Published
- 2016
- Full Text
- View/download PDF
44. The Merits of Malaria Diagnostics during an Ebola Virus Disease Outbreak
- Author
-
Emmie de Wit, Darryl Falzarano, Clayton Onyango, Kyle Rosenke, Andrea Marzi, Melvin Ochieng, Bonventure Juma, Robert J. Fischer, Joseph B. Prescott, David Safronetz, Victor Omballa, Collins Owuor, Thomas Hoenen, Allison Groseth, Neeltje van Doremalen, Galina Zemtsova, Joshua Self, Trenton Bushmaker, Kristin McNally, Thomas Rowe, Shannon L. Emery, Friederike Feldmann, Brandi Williamson, Tolbert G. Nyenswah, Allen Grolla, James E. Strong, Gary Kobinger, Ute Stroeher, Mark Rayfield, Fatorma K. Bolay, Kathryn C. Zoon, Jorgen Stassijns, Livia Tampellini, Martin de Smet, Stuart T. Nichol, Barry Fields, Armand Sprecher, Heinz Feldmann, Moses Massaquoi, and Vincent J. Munster
- Subjects
Ebola ,disease outbreak ,malaria ,Plasmodium ,diagnostics ,PCR ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Abstract
Malaria is a major public health concern in the countries affected by the Ebola virus disease epidemic in West Africa. We determined the feasibility of using molecular malaria diagnostics during an Ebola virus disease outbreak and report the incidence of Plasmodium spp. parasitemia in persons with suspected Ebola virus infection.
- Published
- 2016
- Full Text
- View/download PDF
45. Dromedary camels in northern Mali have high seropositivity to MERS-CoV
- Author
-
Darryl Falzarano, Badian Kamissoko, Emmie de Wit, Ousmane Maïga, Jacqueline Cronin, Kassim Samaké, Abdalah Traoré, Shauna Milne-Price, Vincent J. Munster, Nafomon Sogoba, Mamadou Niang, David Safronetz, and Heinz Feldmann
- Subjects
MERS-CoV ,Serology ,Neutralizing antibodies ,Dromedary camels ,Mali ,Middle East respiratory syndrome coronavirus ,Emerging ,Zoonotic infection ,Medicine (General) ,R5-920 - Abstract
A high percentage (up to 90%) of dromedary camels in the Middle East as well as eastern and central Africa have antibodies to Middle East respiratory syndrome coronavirus (MERS-CoV). Here we report comparably high positivity of MERS-CoV antibodies in dromedary camels from northern Mali. This extends the range of MERS-CoV further west in Africa than reported to date and cautions that MERS-CoV should be considered in cases of severe respiratory disease in the region.
- Published
- 2017
- Full Text
- View/download PDF
46. Presence of Flavivirus Antibodies Does Not Lead to a Greater Number of Symptoms in a Small Cohort of Canadian Travelers Infected with Zika Virus
- Author
-
Robert A. Kozak, Lee W. Goneau, Cedric DeLima, Olivia Varsaneux, AliReza Eshaghi, Erik Kristjanson, Romy Olsha, David Safronetz, Stephen Perusini, Christine Frantz, and Jonathan B. Gubbay
- Subjects
zika virus ,dengue virus ,viremia ,antibodies ,clinical disease ,Microbiology ,QR1-502 - Abstract
Zika virus (ZIKV) is a mosquito-borne flavivirus associated with a febrile illness as well as severe complications, including microcephaly and Guillain-Barré Syndrome. Antibody cross-reactivity between flaviviruses has been documented, and in regions where ZIKV is circulating, dengue virus (DENV) is also endemic, leaving the potential that previous exposure to DENV could alter clinical features of ZIKV infection. To investigate this, we performed a retrospective case-control study in which we compared Canadian travellers who had been infected with ZIKV and had serological findings indicating previous DENV or other flavivirus exposure (n = 16) to those without any previous exposure (n = 44). Patient samples were collected between February 2016 and September 2017 and submitted to Public Health Ontario for testing. ZIKV infection was determined using real-time RT-PCR and antibodies against DENV were identified by the plaque-reduction neutralization test. The mean time from symptom onset to sample collection was 5 days for both groups; the magnitude of viremia was not statistically different (Ct values: 35.6 vs. 34.9, p-value = 0.2). Clinical scores were also similar. Our findings indicate that previous DENV or other flavivirus exposure did not result in greater viremia or a higher illness score.
- Published
- 2020
- Full Text
- View/download PDF
47. Nucleocapsid protein-based vaccine provides protection in mice against lethal Crimean-Congo hemorrhagic fever virus challenge.
- Author
-
Marko Zivcec, David Safronetz, Dana P Scott, Shelly Robertson, and Heinz Feldmann
- Subjects
Arctic medicine. Tropical medicine ,RC955-962 ,Public aspects of medicine ,RA1-1270 - Abstract
Crimean-Congo hemorrhagic fever (CCHF) is an acute, often fatal viral disease characterized by rapid onset of febrile symptoms followed by hemorrhagic manifestations. The etiologic agent, CCHF orthonairovirus (CCHFV), can infect several mammals in nature but only seems to cause clinical disease in humans. Over the past two decades there has been an increase in total number of CCHF case reports, including imported CCHF patients, and an expansion of CCHF endemic areas. Despite its increased public health burden there are currently no licensed vaccines or treatments to prevent CCHF. We here report the development and assessment of the protective efficacy of an adenovirus (Ad)-based vaccine expressing the nucleocapsid protein (N) of CCHFV (Ad-N) in a lethal immunocompromised mouse model of CCHF. The results show that Ad-N can protect mice from CCHF mortality and that this platform should be considered for future CCHFV vaccine strategies.
- Published
- 2018
- Full Text
- View/download PDF
48. Lethal Zika Virus Disease Models in Young and Older Interferon α/β Receptor Knock Out Mice
- Author
-
Andrea Marzi, Jackson Emanuel, Julie Callison, Kristin L. McNally, Nicolette Arndt, Spencer Chadinha, Cynthia Martellaro, Rebecca Rosenke, Dana P. Scott, David Safronetz, Stephen S. Whitehead, Sonja M. Best, and Heinz Feldmann
- Subjects
Zika virus ,strains ,pathogenesis ,animal model ,IFNAR−/− mice ,uniform lethality ,Microbiology ,QR1-502 - Abstract
The common small animal disease models for Zika virus (ZIKV) are mice lacking the interferon responses, but infection of interferon receptor α/β knock out (IFNAR−/−) mice is not uniformly lethal particularly in older animals. Here we sought to advance this model in regard to lethality for future countermeasure efficacy testing against more recent ZIKV strains from the Asian lineage, preferably the American sublineage. We first infected IFNAR−/− mice subcutaneously with the contemporary ZIKV-Paraiba strain resulting in predominantly neurological disease with ~50% lethality. Infection with ZIKV-Paraiba by different routes established a uniformly lethal model only in young mice (4-week old) upon intraperitoneal infection. However, intraperitoneal inoculation of ZIKV-French Polynesia resulted in uniform lethality in older IFNAR−/− mice (10–12-weeks old). In conclusion, we have established uniformly lethal mouse disease models for efficacy testing of antivirals and vaccines against recent ZIKV strains representing the Asian lineage.
- Published
- 2018
- Full Text
- View/download PDF
49. Vectorborne Infections, Mali
- Author
-
David Safronetz, Moussa Sacko, Nafomon Sogoba, Kyle Rosenke, Cynthia Martellaro, Sékou F. Traoré, Issa Cissé, Ousmane Maiga, Matt Boisen, Diana Nelson, Darin Oottamasathien, Molly Millett, Robert F. Garry, Luis M. Branco, Seydou Doumbia, Heinz Feldmann, and Mamadou S. Traoré
- Subjects
zoonotic diseases ,Leptospira ,chikungunya virus ,dengue virus ,Crimean-Congo hemorrhagic fever virus ,hantavirus ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Published
- 2016
- Full Text
- View/download PDF
50. Vesicular Stomatitis Virus-Based Vaccines Provide Cross-Protection against Andes and Sin Nombre Viruses
- Author
-
Bryce M Warner, Derek R Stein, Rohit K Jangra, Megan M Slough, Patrycja Sroga, Angela Sloan, Kathy L Frost, Stephanie Booth, Kartik Chandran, and David Safronetz
- Subjects
Hantavirus ,prophylactic immunization ,vaccine ,vaccination ,hantavirus cardiopulmonary syndrome ,Andes virus ,Sin Nombre virus ,Microbiology ,QR1-502 - Abstract
Andes virus (ANDV) and Sin Nombre virus (SNV) are the main causative agents responsible for hantavirus cardiopulmonary syndrome (HCPS) in the Americas. HCPS is a severe respiratory disease with a high fatality rate for which there are no approved therapeutics or vaccines available. Some vaccine approaches for HCPS have been tested in preclinical models, but none have been tested in infectious models in regard to their ability to protect against multiple species of HCPS-causing viruses. Here, we utilize recombinant vesicular stomatitis virus-based (VSV) vaccines for Andes virus (ANDV) and Sin Nombre virus (SNV) and assess their ability to provide cross-protection in infectious challenge models. We show that, while both rVSVΔG/ANDVGPC and rVSVΔG/SNVGPC display attenuated growth as compared to wild type VSV, each vaccine is able to induce a cross-reactive antibody response. Both vaccines protected against both homologous and heterologous challenge with ANDV and SNV and prevented HCPS in a lethal ANDV challenge model. This study provides evidence that the development of a single vaccine against HCPS-causing hantaviruses could provide protection against multiple agents.
- Published
- 2019
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.