Stefan Kunz Lab

Stefan Kunz, PhD, Assistant Professor
++41(0)21-3147743
stefan.kunz@chuv.ch

Research topics

Viral hemorrhagic fevers caused by arenaviruses belong to the most devastating human diseases and cause considerable suffering in many countries of the Developing World. Apart from the humanitarian burden in endemic regions, air travel regularly imports arenavirus hemorrhagic fever cases into metropolitan areas around the globe, placing local populations at risk. The Old World arena virus Lassa virus is the most prevalent human pathogen among the arenaviruses with several hundred thousand infections per year in Africa. There is no licensed vaccine available and therapeutic options are restricted, resulting in 15-30% mortality in hospitalized patients. The South American hemorrhagic fever viruses Junin, Machupo, Guanarito, and Sabia have emerged as etiological agents of severe hemorrhagic fevers in Latin America. Since arenaviruses are zoonotic diseases carried in nature by rodents, new viruses emerge with, on average, one new species being discovered every three years, representing a serious concern for public health. Our research in collaboration with the group of Dr. Sylvia Rothenberger at IMUL combines the study of fundamental mechanisms of virus-host cell interaction with the development of novel anti-viral strategies against these important pathogens.

Molecular Analysis of the early steps of Lassa virus infection

Project 1: The interaction of Lassa virus with its cellular receptor
One part of our research focuses on the investigation of the initial steps the infection of human cells with pathogenic arenaviruses, binding of the virus to cell surface receptors and subsequent entry into the host cell.
The cellular receptor for Lassa virus is a-dystroglycan, an important cell surface receptor for proteins of the extracellular matrix (ECM). Over the past years we have characterized the molecular interaction between Lassa virus and a-dystroglycan. In collaboration with the laboratory of Dr. Kevin Campbell (Howard Hughes Medical Institute, University of Iowa) we discovered a crucial role of receptor-derived sugars for virus binding. Since the same sugars are also crucial for a-dystroglycan’s function as an ECM receptor, Lassa virus efficiently competes with ECM proteins and affects the normal function of a-DG. Using a combination of biochemical and cell biological techniques we currently study the impact of Lassa virus on a-dystroglycan’s expression and function in the host cell. These studies will illuminate basic aspects of the virus-host cell interaction and reveal novel molecular mechanisms of viral pathogenesis.

Project 2: The cellular mechanisms of Lassa virus entry into human cells
Upon receptor binding, arenaviruses enter the cell by endocytosis and are delivered to endosomes, where pH-dependent fusion of viral envelope and cellular membrane occur. Our initial characterization of the entry pathway of the Old World arenavirus lymphocytic choriomeningitis virus (LCMV) and Lassa virus reveled a mechanism of cell entry that is different from the ones used by other viruses. Using molecular and cell biological approaches, we are currently characterizing the endoctyotic pathway and intracellular trafficking used by Lassa virus to invade human cells. Apart from characterizing fundamental steps of early virus infection, the identification of cellular factors critically involved in Lassa virus entry may also provide promising new targets for the development of anti-viral drugs.

Development of Novel Antiviral Drugs Against Human Pathogenic Arenaviruses

Project 1: Discovery and characterization of novel small molecule inhibitors of arenavirus entry
Human pathogenic arenaviruses are highly lethal because they multiply rapidly and overwhelm the patient’s immune defense, resulting in uncontrolled fatal infection. A promising target for therapeutic intervention is therefore the first step of virus infection, viral entry. Targeting viral entry will slow down viral spread and provide the patient’s immune system a widow of opportunity to develop an anti-viral immune response.
Using high-throughput screening assays for synthetic small molecule libraries we have identified a number of candidate compounds that efficiently block cell entry of human pathogenic arenaviruses. The most promising leads are currently optimized, pharmacologically characterized, and their exact mechanism of action determined. These studies in collaboration with the groups of Dr. Michael B.A. Oldstone and Dr. Dale Boger at the Scripps Research Institute (La Jolla, California) and Dr. Esteban Domingo from the Universidad Autonoma in Madrid (Spain), will provide us with a novel class of anti-arenaviral drugs to improve the limited therapeutic repertoire currently available.

Project 2: Targeting the proteolytic processing of arenavirus glycoproteins as antiviral strategy
A crucial step in the life cycle of arenaviruses is the biosynthesis of the viral envelope glycoprotein (GP) that is essential for virus-host cell attachment and entry. Expression of functional arenavirus GP critically depends on proteolytic processing of the GP precursor to yield the peripheral virion attachment protein GP1 and the fusion-active transmembrane protein GP2. We and others have shown that the cleavage of the GP precursor of human pathogenic arenaviruses is mediated by the cellular site 1 protease (S1P), a serine protease of the convertase family. Processing of arenavirus GP by S1P is crucial for the production of infectious virus from infected cells and cell-to-cell propagation of the virus. Our goals are the characterization of the interaction between arenavirus GPs and S1P protease and the evaluation of S1P as a novel target for anti-viral therapy. Using small molecule screening approaches in collaboration with Dr. Juan Carlos de la Torre (Scripps Research Institute), we aim further at the development of specific inhibitors of S1P-mediated processing of viral GPs.

Selected Publications