New paper from the lab describing a study led by Dr. Alison Kell shows that Hantavirus triggers innate immune actions in part through RLR signaling to differentially control virus in models of reservoir versus non-reservoir hosts.

Submitted by galeadmin on Wed, 05/06/2020 - 10:17

This research has implications for disease following zoonotic virus transmission, and importantly points to additional, non-RLR innate immune programs impacting innate immunity against Hantaviruses across hosts.  Link to paper:


 2020 Apr 24;16(4):e1008483. doi: 10.1371/journal.ppat.1008483. [Epub ahead of print]

RIG-I-like receptor activation drives type I IFN and antiviral signaling to limit Hantaan orthohantavirus replication.

Kell AM1Hemann EA2Turnbull JB2Gale M Jr2,3.


Pathogenic hantaviruses, genus Orthohantaviridae, are maintained in rodent reservoirs with zoonotic transmission to humans occurring through inhalation of rodent excreta. Hantavirus disease in humans is characterized by localized vascular leakage and elevated levels of circulating proinflammatory cytokines. Despite the constant potential for deadly zoonotic transmission to humans, specific virus-host interactions of hantaviruses that lead to innate immune activation, and how these processes impart disease, remain unclear. In this study, we examined the mechanisms of viral recognition and innate immune activation of Hantaan orthohantavirus (HTNV) infection. We identified the RIG-I-like receptor (RLR) pathway as essential for innate immune activation, interferon (IFN) production, and interferon stimulated gene (ISG) expression in response to HTNV infection in human endothelial cells, and in murine cells representative of a non-reservoir host. Our results demonstrate that innate immune activation and signaling through the RLR pathway depends on viral replication wherein the host response can significantly restrict replication in target cells in a manner dependent on the type 1 interferon receptor (IFNAR). Importantly, following HTNV infection of a non-reservoir host murine model, IFNAR-deficient mice had higher viral loads, increased persistence, and greater viral dissemination to lung, spleen, and kidney compared to wild-type animals. Surprisingly, this response was MAVS independent in vivo. Innate immune profiling in these tissues demonstrates that HTNV infection triggers expression of IFN-regulated cytokines early during infection. We conclude that the RLR pathway is essential for recognition of HTNV infection to direct innate immune activation and control of viral replication in vitro, and that additional virus sensing and innate immune response pathways of IFN and cytokine regulation contribute to control of HTNV in vivo. These results reveal a critical role for innate immune regulation in driving divergent outcomes of HTNV infection, and serve to inform studies to identify therapeutic targets to alleviate human hantavirus disease.