Mechanisms of innate immune system sensing and evasion during foamy virus infections

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The innate immune system of mammals is one of the first lines of defense against invading pathogens such a bacteria or viruses. The interaction between various pathogen encoded structures, referred to as pattern-associated molecular patterns (PAMPs), and different classes of sensors on the surface or within the host cells, called pattern recognition receptors (PRRs), are the first events that trigger a potential innate immune response, through a complex network of signal cascades. The overall aim of this proposal is to gain insight into the innate sensing mechanism and potential pathogen evasion strategies involved in infection by foamy viruses (FVs). FVs are one of the most ancient retroviruses having co-evolved with their natural hosts and are endemic to non-human primates, cats, cattle and horses. A hallmark of FVs, which are promising candidates as gene transfer vehicles in gene therapeutic strategies, is their apparent apathogenicity in natural hosts and also in zoonotically infected humans. Very little is known on the immunological mechanisms controlling FV replication in vivo, which might be responsible for the benign nature of FV infections. By developing a new FV vector system that enables a regulated, conditional virus replication in tissues, in combination with the use of established and well-characterized replication-deficient or replication competent FV vector systems, we want to examine interactions of the virus with the innate immune system in two relevant immune cell types, namely monocytes/macrophages and plasmacytoid dendritic cells (pDCs). The focus of this proposal is to elucidate the details of potential innate sensing pathways that are or can be stimulated by FV structural components in cell lines and primary cells of monocyte/macrophage and pDC origin, using primate and feline FVs as a model system. Furthermore, potential evasion strategies of innate sensing developed by FVs shall be uncovered. By using a combination of genetic, biochemical, immunologic and imaging techniques we intend to identify the viral structures, cellular sensors and required conditions that are necessary to mount an innate immune response during entry and virus morphogenesis steps of viral replication in these immune cells.