(I) Disease Models and Pathogenesis Goal: Define animal models for arenaviruses, bunyaviruses, filoviruses and henipaviruses Arenaviruses: The virulence of a new Lassa strain from Mali was assessed in cynomolgus macaques in comparison with well-studied isolates from Sierra Leona and Liberia. The Malian isolate was found to be less pathogenic most likely due to the induction of a stronger early innate immune response. (Safronetz, J Infect Dis, under review) Bunyaviruses: The Andes virus hamster model is characterized by a strong suppression of innate immune responses during the early stage of infection and massive activation of pro-inflammatory and Th1/Th2 responses during the symptomatic phase suggesting that infection-derived immune modulation is important to pathogenesis. (Safronetz 2011;Safronetz 2012) We established an acute disease model for Crimean-Congo hemorrhagic fever (CCHF) using mice lacking the type I interferon receptor. This model recapitulates hallmarks of human CCHF disease including coagulation abnormalities. (Zivcec, J Infect Dis: in press). Filoviruses: The emergence of Reston ebolavirus in domestic swine in the Philippines has caused a renewed interest in its pathogenicity. We have established a mouse disease model based on STAT1-/-mice, which may allow future pathogenesis studies. We have further defined the rhesus macaque model for Zaire ebolavirus infection with focus on coagulation disorders. (de Wit 2011;Ebihara 2011) Henipaviruses: The lethal Syrian hamster model for Henipavirus infections is characterized by acute severe respiratory distress and severe neurological symptoms. Respiratory symptoms were more prevalent in animals challenged with a high dose, whereas animals challenged with a low dose mainly showed neurological signs of infection. The model was used for the first Nipah virus transmission studies indicating contact transmission as the most prominent route. (de Wit 2011;Rockx 2011) (II) Vaccines Goal: To develop and characterize fast-acting vaccines against emerging infections Our main vaccine platform is based on an attenuated recombinant vesicular stomatitis virus (rVSV) vector. This years efforts on rVSV vaccines against filoviruses are summarized in a separate report. Further vaccine efforts are discussed below. Arenavirus: We have studied the cross-protective efficacy of an rVSV-LassaGPC vaccine against challenge with different Lassa virus strains. The vaccine completely protects guinea pigs and nonhuman primates following pre-exposure immunization against challenge with different Lassa virus strains. This indicates that the development of a single cross-protective Lassa vaccine is feasible. Interestingly, the rVSV-LassaGPC does not show post-exposure efficacy against homologous challenge in the nonhuman primate model. (Safronetz, in preparation) Bunyaviruses: We have generated a new rVSV vector expressing Andes virus glycoproteins that provided complete protection in the Syrian hamster model. High titered neutralizing antibodies following a single vaccination seem to be important for protection. The vaccine was partially protective when given post-exposure. Here, a strong innate immune response seems to be the mechanism of protection. (Brown 2011) We are currently investigating a newly designed adenovirus-based CCHF vaccine expressing the nucleoprotein or glycoproteins. Neither vaccine vector alone provided complete protection, but nearly complete protection could be achieved with a blended approach. (Zivcec, in preparation). Filoviruses: Ebola is a serious problem for the endangered great ape population in Central Africa. To address vaccine needs for remote wildlife populations we evaluated in a proof-of-concept study the use of a disseminating cytomegalovirus vaccine vector expressing a single Ebola nucleoprotein T cell epitope. The strategy provided complete protection against lethal challenge in the Ebola mouse model. Future studies will focus on a disseminating vaccine vector for nonhuman primates (Tsuda 2011). Henipaviruses: We demonstrated that vaccination of African green monkeys with a recombinant subunit vaccine based on the henipavirus attachment G glycoprotein affords complete protection against subsequent Nipah virus infection with no evidence of clinical disease, virus replication, or pathology observed in any challenged subjects. Success of the recombinant subunit vaccine in nonhuman primates provides crucial data in supporting its further preclinical development for potential human use. (Bossart 2012) (III) Therapeutics/Antivirals Goal: To develop and characterize therapeutics/antivirals to counteract emerging infectious diseases. Bunyaviruses: We tested the effect of ribavirin on Andes virus replication in the established lethal Syrian hamster model. We concluded that ribavirin treatment is beneficial for postexposure prophylaxis against HPS-causing hantaviruses. (Safronetz 2011) Henipaviruses: We tested the in vivo efficacy of a monoclonal antibody (mAb) directed against the G glycoprotein of henipaviruses. This mAb has potent in vitro neutralizing activity against Nipah and Hendra viruses. Intravenous application of the antibody as late as three days post infection completely protected African green monkeys against lethal Hendra virus challenge. (Bossart 2011) (IV) Virus Biology Goal: To identify potential targets for intervention through better understanding of virus biology Filoviruses: Cellular cysteine proteases are proposed to play an important role in Ebola virus replication. We tested Ebola virus replication in cathepsin B &L knockout mice and could demonstrate that cathepsin cleavage is not necessary for Ebola virus replication. We conclude that other proteases can substitute for cathepsins making it difficult to use proteases as antiviral targets. (Marzi PLoS NTD: in revision) We are currently studying the mechanism of Ebola virus RNA editing. Studies have identified primary and secondary structural requirements and a potential role for VP30 as a necessary factor for RNA editing. (Mehedi, in preparation) Gene expression profiling of in vitro Zaire ebolavirus infections identified the induction of interesting pathways and defined potential targets for intervention. In addition, our studies suggest that the binding of the transmembrane glycoprotein to target cells plays an important role in the immediate cellular response. (Cilloniz 2011;Wahl-Jensen 2011) (V) Ecology and Transmission Goal: Understanding the interaction of virus and reservoir species to prevent transmission into end host Arenaviruses: Our continuous ecological studies have further defined endemic areas for a unique Lassa virus, Soromba R, in Mali. We have started breeding Mastomys natalensis in order to generate a colony for experimental work in the natural reservoir of Lassa virus. (Sogoba, in press) Bunyaviruses: We have established an infection model for Sin nombre virus to study the immune response to infection in the natural reservoir species, the deer mouse. We have found that the deer mouse mounts a strong anti-inflammatory CD4+ T cell response to infection, thereby limiting pathology and allowing virus persistence. We could also demonstrate that Andes virus, carried by the long tailed pygmy rice rat, asymptomatically replicates in deer mice, is immunogenic and gets cleared by the non-reservoir host. We now have a unique system to study the processes of hantavirus adaptation to its natural reservoir in comparison to a non-reservoir host. (Prescott, submitted) Filoviruses: We have further defined the framework for animal and human filovirus surveillance in the Republic of Congo. Facilities for basic research on site have been created and will be expanded. We have refined our long-term sampling sites for bats.

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Emanuel, Jackson; Callison, Julie; Dowd, Kimberly A et al. (2018) A VSV-based Zika virus vaccine protects mice from lethal challenge. Sci Rep 8:11043
Rosenke, Kyle; Mercado-Hernandez, Reinaldo; Cronin, Jacqueline et al. (2018) The Effect of Plasmodium on the Outcome of Ebola Virus Infection in a Mouse Model. J Infect Dis :
Dunham, Eric C; Leske, Anne; Shifflett, Kyle et al. (2018) Lifecycle modelling systems support inosine monophosphate dehydrogenase (IMPDH) as a pro-viral factor and antiviral target for New World arenaviruses. Antiviral Res 157:140-150
Domi, Arban; Feldmann, Friederike; Basu, Rahul et al. (2018) A Single Dose of Modified Vaccinia Ankara expressing Ebola Virus Like Particles Protects Nonhuman Primates from Lethal Ebola Virus Challenge. Sci Rep 8:864
Haddock, Elaine; Feldmann, Heinz; Marzi, Andrea (2018) Ebola Virus Infection in Commonly Used Laboratory Mouse Strains. J Infect Dis :
Feldmann, Heinz (2018) Virus in Semen and the Risk of Sexual Transmission. N Engl J Med 378:1440-1441
Martin, Scott; Chiramel, Abhilash I; Schmidt, Marie Luisa et al. (2018) A genome-wide siRNA screen identifies a druggable host pathway essential for the Ebola virus life cycle. Genome Med 10:58
Haddock, Elaine; Feldmann, Friederike; Hawman, David W et al. (2018) A cynomolgus macaque model for Crimean-Congo haemorrhagic fever. Nat Microbiol 3:556-562
Lavender, Kerry J; Williamson, Brandi N; Saturday, Greg et al. (2018) Pathogenicity of Ebola and Marburg Viruses Is Associated With Differential Activation of the Myeloid Compartment in Humanized Triple Knockout-Bone Marrow, Liver, and Thymus Mice. J Infect Dis :
Hawman, David W; Haddock, Elaine; Meade-White, Kimberly et al. (2018) Favipiravir (T-705) but not ribavirin is effective against two distinct strains of Crimean-Congo hemorrhagic fever virus in mice. Antiviral Res 157:18-26

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