Species-specific responses during Seoul orthohantavirus infection in human and rat lung microvascular endothelial cells
Orthohantaviruses are viruses generally carried by rodents in which they do not cause overt disease. Seoul orthohantavirus (SEOV) predominantly exists as a persistent infection in the omnipresent reservoir host, the Norway rat, Rattus norvegicus. Upon respiratory transmission via aerosolized infectious rodent excreta to humans, SEOV causes an acute disease named hemorrhagic fever with renal syndrome (HFRS). Lack of disease in rats is attributed to downregulation of pro-inflammatory and upregulation of regulatory host responses. As lung microvascular endothelial cells (LMECs) represent a primary target of infection in both human and rats, infections in these cells provide a unique opportunity to study the central role of LMECs in the dichotomy between pathogenicity in both species. In this study, host responses to SEOV infection in primary human and rat LMECs were directly compared on a transcriptional level. As infection of rat LMECs was more efficient than human LMECs, most anti-viral defense responses were also observed earlier in rat LMECs. Most prominently SEOV-induced processes in both species included responses to cytokine stimulus, negative regulation of innate immune responses, responses to type I and II interferons, regulation of pattern recognition receptor signaling and MHC-I signaling. However, over time, in the  rat LMECs, responses shifted from an anti-viral towards a more immunotolerant state displayed by a PD-L1, B2M-, JAK2-focused interaction network aiding in negative regulation of cytotoxic CD8-positive T cell activation. This suggests a novel mechanism demonstrating how species-specific orthohantavirus-induced endothelium and T cell cross-talk might be crucial for development of acute disease in humans and persistence in rodents. Overall design: To investigate the host response of both the reservoir rodent host, Rattus norvegicus and human to Seoul orthohantavirus, we infected primary lung microvascular endothelial cells of both species in triplicate and performed bulk RNA-Sequencing at two time points. We then compared differential gene expressions and performed pathway enrichment analyses between virus- and mock-infected samples