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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - EBOPATH (Evaluation of species-specific ebolavirus pathophysiology in xenochimeric mice)

Teaser

Summary

Even though the topic is still under discussion, bats are proposed zoonotic reservoirs of ebolaviruses. The evidence comes from detection of virus RNA in wild bats and from the fact that other filoviruses have been successfully isolated from bats. Experimental evidence also demonstrates that Ebola virus cannot successfully establish infection in bats and inbred laboratory mice. Why do ebolaviruses cause severe disease in some species but not others? This is the central research question of our proposal, and it is paramount to understand pathogenesis of ebolaviruses and perhaps other zoonotic viruses. In addition, it is essential to determine ebolavirus-specific pathophysiology mechanisms across species. There are five different species of Ebola virus (EBOV, Sudan, Tai Forest, Bundingbuyo and Reston virus), however, in terms of pathogenicity and lethality, they are very different between them. The mechanisms responsible of these differences have still not been identified. For public health reasons as well as to determine the need for vaccines and therapeutics it is important to understand pathogenesis of these viruses in comparison with EBOV

IMPORTANCE FOR SOCIETY

Despite their importance as human pathogens the epidemiology of ebolavirus outbreaks is poorly understood. Most studies indicate that most human outbreaks are initiated by a single spillover event followed by human-to-human transmission. This was for example the origin of the current outbreak of Ebola virus disease (EVD) in West Africa. In addition to humans, non-human primates (NHPs), pigs and forest antelopes are known to be susceptible to infection with ebolaviruses and show different degrees of susceptibility. In both NHPs and humans, EBOV cause a systemic disease characterized by fever, viremia, coagulation abnormalities and a multiorgan failure that resembles septic shock. Why are these viruses so pathogenic for humans and NHPs and not for other species? This is the central question of our proposal. To address this question, our proposal included the development of an \'in vivo\' system to test specoes-specific pathogenicity. This system is based on the idea that severely immunodeficient mice cannot reject xenotransplants, and therefore, can be reconstituted with bone marrow progenitor cells from other species. The importance of our project for society thus is based on two milestones: 1) It provides a system to test ebolavirus pathogenicity across species. 2) It provides a system to test the pathogenicity of unknown viruses in a human-like in vivo system.

OVERALL OBJECTIVES

In order to understand Ebola virus pathogenesis we have developed a xenochimeric mice in which its hematopoietic system has been replaced with a donor species (bat and human hematopoietic system) in order to:
(i) Study species-specific susceptibility to EBOV infection (WP1)
a. species specific susceptibility to EBOV infection
b. Kinetics of EBOV infection and target cells
(ii) Determine ebolavirus-specific pathophysiology mechanisms across species (WP2)
a. Evaluation of Reston and Tai Forest pathogenicity virus in humanized mice
b. Dissection of Ebolavirus pathogenesis in huNSG mice

Work performed

During the first year of EBOPATH with HPI as beneficiary we have:

1. Generated a xenochimeric mouse model harboring bat or human hematopoiesis
2. Compared the pathogenicity of different filoviruses in the humanized mouse model and identified differences in host immune responses.
3. Discovered that virus replication in the liver accounts for most of the differences encountered between Reston virus and Ebola virus in the humanized system. This is an important advance as indicates that Reston virus, which is presumably non-pathogenic for humans, can in fact cause severe disease if the innate immune system does not impede replication in the liver. This has important implications, for instance the putative high pathogenicity of Reston virus in immune compromised individuals. These findings are the main body of the first manuscript arising from EBOPATH which will be submitted in the second quarter of 2018. Additional exploitation measures includes presentations at the Negative stranded virus meeting in June 2018 (Verona, Italy) and at the Keystone symposium: Framing the response to Emerging virus infections in Hong Kong in October.

Final results

The use of humanized mice for research on emerging infectious diseases is a developing field, with just a few examples of utilization of these models for Dengue fever and Ebola virus disease (by the host laboratory). We anticipate that the development of xenochimeric mice reconstituted with species-specific hematopoiesis will advance our field as follows:

1- It will provide a system to study species-specific pathogenesis in the same in vivo platform which will impact pathogenesis and ecology studies.
2- It will provide an in vivo context to determine whether NHP models mimic human infection with filoviruses which will impact disease modelling and therapeutic investigations.
3- It will provide insight into whether bats are host reservoirs of ebolaviruses and if so, why are their mechanisms of protection which will impact host reservoir ecology.
4- It will provide a â€˜testâ€™ to evaluate putative pathogenesis of newly discovered viruses which will impact public health.