Marburg and Ebola virus infections elicit a muted inflammatory state in bats

Background The Marburg and Ebola filoviruses cause severe, often fatal, disease in humans and nonhuman primates but have only subclinical effects in bats, including Egyptian rousettes, a natural reservoir of Marburg virus. A fundamental question is why these viruses are highly pathogenic in humans but fail to cause disease in bats. A number of hypotheses have been proposed to explain this unique aspect of bat biology. We hypothesized that the response of bats to filoviruses is systemic, involving multiple interrelated processes, and that the difference in the responses to infection between bats in humans is due to evolutionarily divergent genes. Results To understand how bats resist disease, we challenged two cohorts of Egyptian rousette bats with Marburg virus or Ebola virus and employed RNA-Seq to profile tissue-specific transcriptomic signatures. While we have found the viruses primarily in the liver, we detected transcriptomic changes in multiple tissues. The specific transcriptional responses observed suggest that bats limit viral replication and associated pathology by limiting the inflammatory response. This is largely achieved by tightly controlling expression and activation of acute phase proteins. Furthermore, we found evidence that important features of severe disease in humans, such as disseminated intravascular coagulation, are likely mitigated in bats through processes which involve vasodilation, iron metabolism, and avoidance of thrombosis through transcriptional changes in the coagulation pathway. Finally, we demonstrated transitioning of macrophages from the pro-inflammatory phenotype M1 to the anti-inflammatory, wound-healing phenotype M1. Conclusions Given the involvement of multiple pathways, we propose that Marburg and Ebola viruses induce a systemic response that results in an anti-inflammatory state that enables effective and lasting control of the infection. Our observations and analyses provide an experimental and computational framework for investigation of the resistance of bats to filovirus infection and identify genes involved in a systemic response of bats to Marburg and Ebola viruses that allows these animals to tolerate the infections. This framework and our results have the potential to aid in the development of new strategies to effectively mitigate and treat the effects of filovirus infections in humans. ### Competing Interest Statement The authors have declared no competing interest.