Tolerance and resistance responses of African bats to viral antigens: Immunological tradeoffs in zoonotic reservoir hosts.

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ABSTRACT This project focuses on understanding the role that the unique physiology of bats plays in their ability to act as host reservoirs for diseases that can spill over to humans. The project will be carried out under field conditions in Uganda on three species of bats that have varying links to the spread of Ebola virus (EBOV) to humans. By comparing the ability of these three species of bats to respond to Ebola-like immune challenges, this work will help identify the characteristics that contribute to spillover risk. In the long term, this work will help identify host species for EBOV and other related viruses that present risk to humans. It will also help explain how different species of bats respond to different types of viral infections. The main focus of this project will be to identify behaviors and molecular pathways that enable reservoir hosts to tolerate infections, providing critical insight into one of the mechanisms that leads to spillover. This work is driven by the hypothesis that some bat species have coevolved with particular types of viral infections and, therefore, have adapted mechanisms to minimize pathology during infection. Bats are globally biodiverse and have many unique ecological and physiological adaptations, including flight and the ability to employ both hypo- and hyperthermic body temperature regulation. This project focuses on three bat species chosen because they are in close contact with humans, their habitats cover the range of EBOV exposure risk, and they have divergent coevolutionary histories with viral pathogens; two of the three species have significant ties to EBOV epidemiology. This project addresses these questions under natural conditions in the field by taking the innovative approach of using EBOV virus-like particles as a proxy for experimental infection with biohazardous pathogens. This project has three specific aims that will allow the achievement of its goals. First, the project tests the hypothesis that specific African bat species will display signatures of EBOV disease tolerance in response to challenge with EBOV virus-like particles, and thus are likely to be natural reservoir hosts. These experiments will provide significant insight into disease tolerance in bats and the potential identity of EBOV reservoir(s). Second, this project tests the hypothesis that bats display variable levels of disease tolerance that depend upon innate immune pathways that have undergone unique evolutionary selection in bats. Third, this project explores whether tolerance of and resistance to viral infection are facilitated by the unique metabolic behaviors of bats, namely that they can depress metabolism and enter torpor to conserve energy and can elevate metabolism and thus temperature during flight. The role of changes in body temperature is poorly understood and these experiments will identify whether these physiological responses contribute to immunological tolerance and resistance in important disease reservoirs. Together, the successful completion of these goals will help determine whether infection tolerance confers on African bat species the ability to serve as reservoir hosts for virulent zoonotic viruses and will identify molecular, physiological, and behavioral mechanisms that contribute to tolerance phenotypes.