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Heinz Feldmann – One of the best experts on this subject based on the ideXlab platform.
Neutralizing Monoclonal Antibodies Against the Gn and the Gc of the Andes Virus Glycoprotein Spike Complex Protect From Virus Challenge in a Preclinical Hamster ModelmBio, 2020Co-Authors: James Duehr, Meagan Mcmahon, Brandi N. Williamson, Fatima Amanat, Alan Durbin, David W. Hawman, Danny Noack, Skyler Uhl, Gene S. Tan, Heinz FeldmannAbstract:
ABSTRACT HantaViruses are the etiological agent of hemorrhagic fever with renal syndrome (HFRS) and hantaVirus cardiopulmonary syndrome (HCPS). The latter is associated with case fatality rates ranging from 30% to 50%. HCPS cases are rare, with approximately 300 recorded annually in the Americas. Recently, an HCPS outbreak of unprecedented size has been occurring in and around Epuyen, in the southwestern Argentinian state of Chubut. Since November of 2018, at least 29 cases have been laboratory confirmed, and human-to-human transmission is suspected. Despite posing a significant threat to public health, no treatment or vaccine is available for hantaviral disease. Here, we describe an effort to identify, characterize, and develop neutralizing and protective antibodies against the glycoprotein complex (Gn and Gc) of Andes Virus (ANDV), the causative agent of the Epuyen outbreak. Using murine hybridoma technology, we generated 19 distinct monoclonal antibodies (MAbs) against ANDV GnGc. When tested for neutralization against a recombinant vesicular stomatitis Virus expressing the Andes glycoprotein (GP) (VSV-ANDV), 12 MAbs showed potent neutralization and 8 showed activity in an antibody-dependent cellular cytotoxicity reporter assay. Escape mutant analysis revealed that neutralizing MAbs targeted both the Gn and the Gc. Four MAbs that bound different epitopes were selected for preclinical studies and were found to be 100% protective against lethality in a Syrian hamster model of ANDV infection. These data suggest the existence of a wide array of neutralizing antibody epitopes on hantaVirus GnGc with unique properties and mechanisms of action. IMPORTANCE Infections with New World hantaViruses are associated with high case fatality rates, and no specific vaccine or treatment options exist. Furthermore, the biology of the hantaviral GnGc complex, its antigenicity, and its fusion machinery are poorly understood. Protective monoclonal antibodies against GnGc have the potential to be developed into therapeutics against hantaviral disease and are also great tools to elucidate the biology of the glycoprotein complex.
Experimental Andes Virus infection in deer mice: Characteristics of infection and clearance in a heterologous rodent host. PLoS One 2013, 2016Co-Authors: Jessica R Spengler, Brian Hjelle, Heinz Feldmann, Elaine Haddock, Don Gardner, Joseph PrescottAbstract:
New World hantaViruses can cause hantaVirus cardiopulmonary syndrome with high mortality in humans. Distinct Virus species are hosted by specific rodent reservoirs, which also serve as the vectors. Although regional spillover has been documented, it is unknown whether rodent reservoirs are competent for infection by hantaViruses that are geographically separated, and known to have related, but distinct rodent reservoir hosts. We show that Andes Virus (ANDV) of South America, carried by the long tailed pygmy rice rat (Oligoryzomys longicaudatus), infects and replicates in vitro and in vivo in the deer mouse (Peromyscus maniculatus), the reservoir host of Sin Nombre Virus (SNV), found in North America. In experimentally infected deer mice, viral RNA was detected in the blood, lung, heart and spleen, but Virus was cleared by 56 days post inoculation (dpi). All of the inoculated deer mice mounted a humoral immune response by 14 dpi, and produced measurable amounts of neutralizing antibodies by 21 dpi. An up-regulation of Ccl3, Ccl4, Ccl5, and Tgfb, a strong CD4+ T-cell response, and down-regulation of Il17, Il21 and Il23 occurred during infection. Infection was transient with an absence of clinical signs or histopathological changes. This is the first evidence that ANDV asymptomatically infects, and is immunogenic in deer mice, a non-natural host species of ANDV. Comparing the immune response in this model to that of the immune response in the natural hosts upon infection with their co-adapted hantaViruses may help clarify th
Long-term single-dose efficacy of a vesicular stomatitis Virus-based Andes Virus vaccine in Syrian hamsters.Viruses, 2014Co-Authors: Joseph Prescott, Kyle S. Brown, Blair L. Debuysscher, Heinz FeldmannAbstract:
Andes Virus (ANDV) is highly pathogenic in humans and is the primary etiologic agent of hantaVirus cardiopulmonary syndrome (HCPS) in South America. Case-fatality rates are as high as 50% and there are no approved vaccines or specific therapies for infection. Our laboratory has recently developed a replication-competent recombinant vesicular stomatitis Virus (VSV)-based vaccine that expressed the glycoproteins of Andes Virus in place of the native VSV glycoprotein (G). This vaccine is highly efficacious in the Syrian hamster model of HCPS when given 28 days before challenge with ANDV, or when given around the time of challenge (peri-exposure), and even protects when administered post-exposure. Herein, we sought to test the durability of the immune response to a single dose of this vaccine in Syrian hamsters. This vaccine was efficacious in hamsters challenged intranasally with ANDV 6 months after vaccination (p = 0.025), but animals were not significantly protected following 1 year of vaccination (p = 0.090). The decrease in protection correlated with a reduction of measurable neutralizing antibody responses, and suggests that a more robust vaccination schedule might be required to provide long-term immunity.
Jay W. Hooper – One of the best experts on this subject based on the ideXlab platform.
Innate immune responses elicited by Sin Nombre Virus or type I IFN agonists protect hamsters from lethal Andes Virus infections.The Journal of general virology, 2018Co-Authors: Rebecca L. Brocato, Anita K. Mcelroy, Jeffrey M. Smith, Victoria Wahl, Christopher D. Hammerbeck, Matthew Josleyn, Jay W. HooperAbstract:
Sin Nombre Virus (SNV) and Andes Virus (ANDV) cause hantaVirus pulmonary syndrome (HPS) in humans. Both SNV and ANDV infect Syrian hamsters, but only ANDV causes lethal disease. A co-infection study was performed to determine which Virus, SNV or ANDV, would dominate the survival outcome in hamsters. Infection of hamsters with SNV 1 day before ANDV challenge did not result in disease characteristic of the latter Virus, and all animals survived challenge. Control animals infected solely with ANDV all succumbed by day 14. In contrast, when Viruses were injected at the same site concurrently, all hamsters succumbed to HPS disease. HantaViruses are segmented Viruses; therefore we investigated which segment might be responsible for the protective phenotype of SNV by using two SNV/ANDV reassortant Viruses, both with reciprocal M-segments from the other Virus (denoted ASA and SAS). Both reassortants asymptomatically infect hamsters, similar to SNV. However, unlike SNV, 1 day prior preinfection with the reassortant Virus did not prevent ANDV lethality. The ASA reassortant Virus, but not SAS, protected hamsters from lethal ANDV infection when administered 3 days prior to ANDV challenge. Similar to SNV preinfection, the potent innate immune stimulator poly I:C administered to hamsters 1 day before ANDV challenge prevented lethal ANDV disease. Combined, these results suggest that the difference in pathogenicity of SNV and ANDV in hamsters involves differences in early host-pathogen interactions and resultant anti-viral immune responses of both the innate and adaptive immune system.
A lethal disease model for New World hantaViruses using immunosuppressed Syrian hamsters.PLoS neglected tropical diseases, 2017Co-Authors: Valentijn Vergote, Jay W. Hooper, Lies Laenen, Bert Vanmechelen, Marc Van Ranst, Erik Verbeken, Piet MaesAbstract:
HantaVirus, the hemorrhagic causative agent of two clinical diseases, is found worldwide with variation in severity, incidence and mortality. The most lethal hantaViruses are found on the American continent where the most prevalent Viruses like Andes Virus and Sin Nombre Virus are known to cause hantaVirus pulmonary syndrome. New World hantaVirus infection of immunocompetent hamsters results in an asymptomatic infection except for Andes Virus and Maporal Virus; the only hantaViruses causing a lethal disease in immunocompetent Syrian hamsters mimicking hantaVirus pulmonary syndrome in humans.
Hamsters, immunosuppressed with dexamethasone and cyclophosphamide, were infected intramuscularly with different New World hantaVirus strains (Bayou Virus, Black Creek Canal Virus, Cano Delgadito Virus, Choclo Virus, Laguna Negra Virus, and Maporal Virus). In the present study, we show that immunosuppression of hamsters followed by infection with a New World hantaVirus results in an acute disease that precisely mimics both hantaVirus disease in humans and Andes Virus infection of hamsters.
Infected hamsters showed specific clinical signs of disease and moreover, histological analysis of lung tissue showed signs of pulmonary edema and inflammation within alveolar septa. In this study, we were able to infect immunosuppressed hamsters with different New World hantaViruses reaching a lethal outcome with signs of disease mimicking human disease.
Gastrointestinal Tract As Entry Route for HantaVirus InfectionFrontiers in microbiology, 2017Co-Authors: Peter T. Witkowski, Jay W. Hooper, Rebecca L. Brocato, Casey C. Perley, Christian Jürgensen, Jörg-dieter Schulzke, Detlev H. Krüger, Roland BückerAbstract:
Background. HantaViruses are zoonotic agents that cause hemorrhagic fevers and are thought to be transmitted to humans by exposure to aerosolized excreta of infected rodents. Puumala Virus (PUUV) is the predominant endemic hantaVirus in Europe. A large proportion of PUUV-infected patients suffer from gastrointestinal symptoms of unclear origin. In this study we demonstrate that PUUV infection can occur via the alimentary tract. Methods. We investigated susceptibility of the human small intestinal epithelium for PUUV infection and analyzed the resistance of virions to gastric juice. As model for intestinal Virus translocation we performed infection experiments with human intestinal Caco-2 monolayers. In animal experiments we infected Syrian hamsters with PUUV via the intragastric route and tested seroconversion and protective immunity against subsequent Andes Virus challenge. Results. PUUV retained infectivity in gastric juice at pH >3. The Virus invaded Caco-2 monolayers in association with endosomal antigen EEA1, followed by Virus replication and loss of epithelial barrier function with basolateral Virus occurrence. Cellular disturbance and depletion of the tight junction protein ZO-1 appeared after prolonged infection, leading to paracellular leakage (leak flux diarrhea). Moreover, animal experiments led to dose-dependent seroconversion and protection against lethal Andes Virus challenge. Conclusions. We provide evidence that hantaVirus can infect the organism via the alimentary tract and suggest a novel aspect of hantaVirus infection and pathogenesis. Significance. HantaViruses are zoonotic pathogens causing severe hemorrhagic fevers worldwide. They are transmitted to humans by small mammals. To date these Viruses were thought to infect exclusively through the airborne route by inhalation of aerosols from infectious animal droppings or by rodent bites. In our work we could show that the alimentary tract is an alternative path of infection for hantaViruses, meaning a new association of Virus and disease. These findings have impact on current textbook knowledge and bring many implications for hantaVirus epidemiology and outbreak prevention measures.
David Safronetz – One of the best experts on this subject based on the ideXlab platform.
Vesicular Stomatitis Virus-Based Vaccines Provide Cross-Protection against Andes and Sin Nombre VirusesViruses, 2019Co-Authors: Bryce M. Warner, Derek R. Stein, Rohit K. Jangra, Megan M. Slough, Patrycja Sroga, Angela Sloan, Kathy L Frost, Stephanie A. Booth, Kartik Chandran, David SafronetzAbstract:
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.
Hamster-Adapted Sin Nombre Virus Causes Disseminated Infection and Efficiently Replicates in Pulmonary Endothelial Cells without Signs of DiseaseJournal of virology, 2013Co-Authors: David Safronetz, Heinz Feldmann, Joseph Prescott, Elaine Haddock, Dana P. Scott, Hideki EbiharaAbstract:
To date, a laboratory animal model for the study of Sin Nombre Virus (SNV) infection or associated disease has not been described. Unlike infection with Andes Virus, which causes lethal hantaVirus pulmonary syndrome (HPS)-like disease in hamsters, SNV infection is short-lived, with no viremia and little dissemination. Here we investigated the effect of passaging SNV in hamsters. We found that a host-adapted SNV achieves prolonged and disseminated infection in hamsters, including efficient replication in pulmonary endothelial cells, albeit without signs of disease.
The Syrian hamster model of hantaVirus pulmonary syndrome.Antiviral research, 2012Co-Authors: David Safronetz, Hideki Ebihara, Heinz Feldmann, Jay W. HooperAbstract:
HantaVirus pulmonary syndrome (HPS) is a relatively rare, but frequently fatal disease associated with New World hantaViruses, most commonly Sin Nombre and Andes Viruses in North and South America, respectively. It is characterized by fever and the sudden, rapid onset of severe respiratory distress and cardiogenic shock, which can be fatal in up to 50% of cases. Currently there are no approved antiviral therapies or vaccines for the treatment or prevention of HPS. A major obstacle in the development of effective medical countermeasures against highly pathogenic agents like the hantaViruses is recapitulating the human disease as closely as possible in an appropriate and reliable animal model. To date, the only animal model that resembles HPS in humans is the Syrian hamster model. Following infection with Andes Virus, hamsters develop HPS-like disease which faithfully mimics the human condition with respect to incubation period and pathophysiology of disease. Perhaps most importantly, the sudden and rapid onset of severe respiratory distress observed in humans also occurs in hamsters. The last several years has seen an increase in studies utilizing the Andes Virus hamster model which have provided unique insight into HPS pathogenesis as well as potential therapeutic and vaccine strategies to treat and prevent HPS. The purpose of this article is to review the current understanding of HPS disease progression in Syrian hamsters and discuss the suitability of utilizing this model to evaluate potential medical countermeasures against HPS.