Early Transcriptional Changes within Liver, Adrenal Gland, and Lymphoid Tissues Significantly Contribute to Ebola Virus Pathogenesis in Cynomolgus Macaques

Abstract

Ebola virus (EBOV) continues to pose a significant threat to human health as evidenced by the 2013-2016 epidemic in West Africa and the ongoing outbreak in the Democratic Republic of Congo. EBOV causes hemorrhagic fever, organ damage, and shock culminating in death with case-fatality rates as high as 90%. This high lethality combined with the paucity of licensed medical countermeasures make EBOV a critical human pathogen. Although EBOV infection results in significant damage to the liver and the adrenal glands, little is known about the molecular signatures of injury in these organs. Moreover, while changes in peripheral blood cells are becoming increasingly understood, the host responses within organs and lymphoid tissues remain poorly characterized. To address this knowledge gap, we tracked longitudinal transcriptional changes in tissues collected from EBOV-Makona-infected cynomolgus macaques. Following infection, both liver and adrenal glands exhibited significant and early downregulation of genes involved in metabolism, coagulation, hormone synthesis, angiogenesis; upregulated genes were associated with inflammation. Analysis of lymphoid tissues showed early upregulation of genes that play a role in innate immunity and inflammation and downregulation of genes associated with cell cycle and adaptive immunity. Moreover, transient activation of innate immune responses and downregulation of humoral immune responses were confirmed in lymphoid tissues by flow cytometry. Together, these data suggest that liver, adrenal gland, and lymphatic organs are important sites of EBOV infection and that dysregulating the function of these vital organs contributes to the development of Ebola virus disease. IMPORTANCE Ebola virus (EBOV) remains a high priority pathogen since it continues to cause outbreaks with high case fatality rates. Although it is well-established that EBOV results in severe organ damage, our understanding of tissue injury in the liver, adrenal glands and lymphoid tissues remains limited. We begin to address this knowledge gap by conducting longitudinal gene expression studies in these tissues, which were collected from EBOV-infected cynomolgus macaques. We report robust and early gene expression changes within these tissues, indicating they are primary sites of EBOV infection. Furthermore, genes involved in metabolism, coagulation, and adaptive immunity were downregulated while inflammatory related genes were upregulated. These results indicate significant tissue damage consistent with the development of hemorrhagic fever and lymphopenia. Our study provides novel insight into EBOV-host interactions and elucidates how host responses within the liver, adrenal glands and lymphoid tissues contribute to EBOV pathogenesis.