Biological consequences of alternative receptor usage during arenavirus entry

• Applicant: Privatdozentin Dr. Allison Groseth, Ph.D.
• Subject Area: Virology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 527109165

Arenaviruses are important causes of severe human disease, including hemorrhagic fever (HF), for which few treatments are currently available. Interestingly, for the genetic lineage of viruses found in South America, the ability to cause HF is closely correlated with their ability to use the human form of Transferrin Receptor 1 (hTfR1), e.g. for Junín virus (JUNV). Nonetheless, despite lacking hTfR1-binding, also closely related apathogenic viruses (e.g. Tacaribe virus, TCRV) can still enter human cells through the use of alternative receptors, such as phosphatidylserine (PS) receptors. These and other observations indicate that the role of receptor usage in pathogenesis goes beyond simply facilitating entry, and rather includes critical role in shaping the host response to infection, which we have previously shown differs between JUNV and TCRV. However, the mechanism responsible for this remains unclear. This project aims to create variants of JUNVs and TCRVs that are modified in their ability to interact with hTfR1 or are enriched/de-enriched for PS content (and thus modified in their ability to engage PS-receptors). We will also generate cell lines that either express modified versions of hTfR1 with altered virus binding preferences or that are deficient in one of more PS-receptors. Using these tools, we will then characterize mechanistic aspects of the entry process (including the efficiency of binding, rate of uptake, and fusion pH) under conditions where hTfR1 and/or PS-receptor binding is taking place. We will accomplish this using a combination of classical cellular assays and live cell microscopy. In addition, we will use these viruses with modified receptor binding properties to study the role of receptor binding in shaping the host cell response to infection in macrophages, and especially cytokine production, which is suggested to be an important determinant in ensuring early control of virus infection. Taken together, these planned experiments will reveal important mechanistic information regarding the contribution of receptor usage to arenavirus biology, and particularly pathogenesis. As such, they will both provide insights into the risk of future emergence of currently apathogenic arenaviruses into the human population and help to identify mechanisms associated with disease development that can serve as novel targets for antiviral intervention.

• DFG Programme: Research Grants