Herpes simplex virus 1 (HSV-1) is an important human pathogen which infects the majority of the world`s population and inflicts a substantial burden of disease. Over the past 10 years, systems biology approaches, to which my lab has provided seminal contributions, have substantially broadened our understanding of the complex interaction of this common pathogen with its human host. However, the underlying molecular mechanisms remain poorly understood and their importance for virus latency and reactivation remain elusive. Furthermore, currently available technology lacks the temporospatial resolution to decipher the cellular and viral determinants that govern the virus life cycle. The main goal of DecipherHSV is to close these knowledge and technology gaps and decipher novel mechanisms and their functional interplay by which HSV-1 manipulates its host cells throughout the virus life cycle. Accordingly, the three primary objectives of DecipherHSV are to: (i) decipher the full complement of viral elements that govern productive infection; (ii) decipher how and why HSV-1 manipulates pervasive transcription within the host and viral genome; and (iii) decipher the cellular and viral determinants of HSV-1 latency and reactivation. Alongside, I will develop new computational approaches and integrative analysis tools, and employ artificial intelligence to exploit the wealth of information that is provided by the novel single cell RNA sequencing approaches, which I will pioneer (Heterogeneity-seq and Perturb-scSLAM-seq). Thereby, I will deliver new leads for novel therapeutic approaches targeting HSV-1 latency and reactivation. This will provide a paradigm for the study of other herpesviruses and their complex host-pathogen interactions.
TOPOPOLIS aims at the development of semiconductor microcavity photonic crystal structures which are generally designed for the realization of solid state quantum simulation and specifically for the first ever observation of topological exciton-polariton edge states. With the ongoing refinement of semiconductor growth and etching techniques it has become possible to create microcavity photonic crystals to study new, complex and non-trivial phenomena of light-matter coupling. Here, polaritons in e.g. hexagonal lattice structures (artificial graphene) can serve as a tool to perform quantum simulation and to emulate the systems Hamiltonian. Polaritons are particularly well suited, because of their tunable mass and particle interactions, inherited from the excitons, as well as their open dissipative nature which allows a direct monitoring. In this context it has been proposed that with a suitable photonic crystal design a topological gap can emerge under magnetic field. This topological gap leads to optical quantum-Hall-like edge states that allow for an unidirectionally propagating polariton mode, protected from back-scattering. This exciting goal is of great interest as it will shed light into the physics of topological hybrid interacting bosons as well as from an application point of view. Reaching this goal most importantly requires very high Q-factor microcavities with low overall energetic disorder as well as low etching-induced sidewall damage. In this project, a scaleable photonic-trap method is proposed that allows for a precise control of the confinement potential in the microcavity photonic crystal and does not require an etching into the optically active quantum wells. This approach will be combined with electro-optical tuning to create a versatibe platform for quantum emulation and will allow for the experimental observation of topological polariton edge states that have the potential to enable new technologies in quantum simulation and logics.
The project idea is to implement a new quantum probe based on hexagonal boron nitride (hBN) containing spin defects to study the properties of artificially stacked two-dimensional (2D) materials and devices. The essential building blocks of such van der Waals (vdW) heterostructures are the quantum defects in hBN recently discovered by the PI and his team. These intrinsic lattice defects - negatively charged boron vacancies VB– - can be optically spin-polarized and coherently manipulated, allowing the read-out of quantum information during the coherence time. Our experimental approach is based on coherent manipulation of the spin state using high-frequency pulse protocols, followed by optical readout to explore the adjacent environment, in particular by studying the local lattice strains, pressure, temperature and magnetic fields. The unique feature of hBN is its non-disturbing chemical and crystallographic compatibility with other vdW materials, which gains a new fundamental functionality with the embedded spin centres and allows sensing in heterostructures serving as a boundary itself. Optical readout will be extended by electrical control of spin and charge states, which is an unexplored area and a major step forward in the development of quantum applications of vdW heterostructures. We focus on i) the enhancement of VB– emission and spin resonance contrast by coupling with plasmonic resonators to identify single defects never seen before, ii) the identification of the sources of spin decoherence of these defects, in particular the interaction with other electronic defects and hyperfine-coupled nuclear bath, and their bypassing, and iii) the exploration of semiconducting and magnetic heterostructures and electronic devices based on them. The project aims to establish 2D heterostructures as a flexible platform for new quantum applications based on the optical and electrical control of coherent states and mapping fluctuating external fields on the nanoscale.
Incidences of sexually transmitted diseases (STI) have increased during the past decades with a concomitant rapid spread of antibiotic resistant bacteria. Chlamydia trachomatis is the most frequent cause of bacterial STIs. These infections often remain asymptomatic and are consequently not diagnosed and treated, resulting in the subsequent development of severe chronic pathologies and an enormous economic burden for health systems. The reason for the asymptomatic nature of chlamydial infection is currently unknown. My laboratory made the intriguing observation that exposure of polymorphonuclear neutrophils (PMNs), a major subset of innate immune cells and cause of inflammation and tissue damage, to C. trachomatis causes PMNs to become unresponsive to a broad range of stimuli, including Chlamydia themselves. We identified a chlamydial secreted protease (CPAF) to be the bacterial effector responsible for preventing the activation of the non-stimulated PMNs. Chlamydia not only survive PMN exposure but can also surprisingly exploit the PMN itself as host cell for replication. Unexpectedly, the chlamydial secreted deubiquitinase Cdu1 is required for intracellular adaptation of Chlamydia, indicating that PMNs may posses antibacterial cell-autonomous defence strategies based on the host ubiquitin system. It remains completely unclear how PMNs are converted to host cells for obligate intracellular bacteria. This proposal therefore aims to comprehensively investigate the mechanism of PMN reprogramming from a short-lived major immune effector cells to a host cell for Chlamydia replication and development. PMN paralysis offers an unexpected explanation for the asymptomatic nature of these infections. Furthermore, chlamydial factors involved in PMN reprogramming provide prime targets to rearm the patient’s immune response to effectively resolve Chlamydia infections.
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