The most important human pathogen among the arenaviruses is Lassa virus that causes several hundred thousand infections per year with high mortality in Africa. Lassa virus is a zoonotic pathogen and infection in man is the result of reservoir-to-human transmission. In our basic research we investigate the molecular and cellular mechanisms that allow this important emerging virus to break the specied barrier and to invade human cells. Using a combination of proteomics, biochemistry, cell biology, and microscopy, we identify cellular proteins and signaling pathways hijacked by the virus during the host cell invasion. Cellular factors that are essential for productive infection are then evaluated as “druggable” targets for therapeutic intervention to combat Lassa virus infection in humans.
Monitoring virus cell entry by confocal microscopy: co-localization of the virus with regulatory proteins of the host cell’s endocytotic machinery such as Tsg101 and Rab7 (from Pasqual et al., PLOS Pathogens 2011).
Collaborators: Prof. Kevin P. Campbell (Howard Hughes Medical Institute, University of Iowa, Iowa City, USA), Dr. Gisa Gerold (TWINCORE University of Hannover).
Funding: Swiss National Science Foundation Grant Nr. 310030-149746/1 (Kunz) "Host cell invasion by Lassa virus"
Once emerging viruses have broken the species barrier and invaded the human organism, they are subject to strong selective pressure. This leads to positive selection of viral variants that express attachment proteins able to efficiently use human receptors and selection of viral proteins involved in cell interactions at later steps of the viral life cycle. Importantly, the subject of selective pressure is not the individual viral variant but the entire viral population, involving complex interactions between variants. In a collaborative project of the SINERGIA program of Swiss National Foundation with the laboratories of Prof. Volker Thiel (University of Bern, Switzerland) and Prof. Stephen Leib (University Hospital Bern, Switzerland), we use next generation sequencing combined with state-of-the art molecular virology to follow human adaptation of emerging arenaviruses in real time. These studies will detect alterations in viral proteins underlying viral adaptation including receptor use, host-, and target cell tropism and illuminate a fundamental aspect of viral emergence.
Selection of novel arenavirus variants: serial passage in human organotopic cultures of human airway epithelia (HAE) and microvasculature (HUVEC). Isolates are analyzed by next generation sequencing to detect molecular changes underlying adaptation.
Collaborators: Prof. Volker Thiel (University of Bern, Switzerland), Prof. Stephen Leib (University Hospital Bern, Switzerland), Dr. Rahel Gäumann (Spiez Laboratory).
Funding: Swiss National Science Foundation Grant SINERGIA Nr. CRSII3_160780/1 (Thiel, Leib, Kunz) "Viral plasticity underlying tropism and pathogenesis/Immune evasion of emerging viruses"