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The Orthohantaviridae – more commonly simply known as hantaviruses – are a family of segmented negative-sense RNA viruses that contain many highly pathogenic zoonotic viruses. While hantaviruses naturally circulate in rodents, shrews and bats where they cause asymptomatic and life-long chronic infections, some viruses can cause highly pathogenic disease in humans. Severe cases of hantavirus-associated disease is characterized by ‘cytokine-storm’-like inflammatory disease, vascular leakage and haemorrhaging, acute renal or respiratory failure and death. Case-fatality rates can reach up to 40%, with no licenced antiviral treatments or vaccines available yet.The viral RNA-dependent RNA polymerase is a highly conserved enzyme that is responsible for the transcription and replication of the viral RNA genome. Despite the fact that it is the focal point of all viral processes that occur inside the host cell after virus entry and needs to interact with a multitude of both viral and host factors in an tightly regulated manner, we have only a very limited understanding of the molecular mechanisms of polymerase activity. This project aims to characterise the molecular mechanisms of hantavirus polymerase activity at the single nucleotide and amino acid level, as well as utilize these findings towards understanding the host species barrier that prevents efficient human-to-human transmission and replication of highly pathogenic airborne hantaviruses.

Hantaviruses are a family of zoonotic viruses naturally found in rodents. In humans some hantaviruses can cause highly pathogenic disease. Hantavirus-induced disease is characterised by inflammation, vascular leakage and acute renal and respiratory failure, with mortality rates of up to 40%. Neither effective antiviral treatment options nor vaccines against any hantavirus have been licensed yet. Due to the high prevalence of their reservoir species and their potential lethality, it is of critical importance to gain a better understanding of the molecular mechanisms underlying hantavirus pathogenicity. The error-prone RNA polymerase (RdRp) of all RNA viruses is known to generate aberrant replication products, missing essential regions of viral genomes. These so-called defective viral genomes (DVGs) have been described for many RNA virus families and have been shown to strongly activate the host innate immune system by inducing interferon signalling. In fact, for some viruses, including influenza A virus, the accumulation of DVGs strongly correlates with increased disease severity. This project aims to characterise the defective viral transcriptome of hantaviruses and how (defective) viral RNA induces the innate immune response. The answers to these questions and the tools developed in this project will help us determine the fundamental molecular mechanisms that underlie innate immune sensing, interferon induction and pathogenesis in hantavirus infections.