Basic research on human pathogenic arenaviruses

The Lassa virus receptor: its role in virus-host cell interaction and disease

Marie-Laurence Moraz, Dr. Sylvia Rothenberger

The first step of every virus infection is the attachment of the virus to its cellular receptor. The cellular receptor for Lassa virus (LASV) and other human pathogenic arenaviruses is alpha-dystroglycan. This subunit of dystroglycan is an important cell surface receptor for proteins of the extracellular matrix (ECM) and is crucial for normal function and development of the organism. Over the past years, we found that LASV infection critically depends on high affinity binding to dystroglycan. We currently investigate the role of dystrogylcan in the process of host cell entry and productive infection. Moreover, Lassa virus efficiently competes with ECM proteins for receptor binding and likely affects the function of dystroglycan in the host cell. Considering the importance of dystroglycan for normal cell function, virus-induced changes in receptor function likely contribute to the pathology seen in Lassa fever patients.

Collaborators: Dr. Christina Spiropoulou, Special Pathogens Branch, Centers for Disease Control and Prevention, Atlanta, GA, USA; Prof. Kevin P. Campbell, Howard Hughes Medical Institute, University of Iowa, Iowa City, USA

Invasion of human cells by Lassa virus

Giulia Pasqual, Marie-Laurence Moraz, Dr. Sylvia Rothenberger

Upon receptor binding, LASV undergoes endocytosis and is delivered to acidified endosomes where the virus enters the cytoplasm via fusion between the viral and the cellular membrane. While most enveloped viruses use clathrin-mediated endocytosis to enter the host cell, LASV enters the host cell via a novel and unusual endocytotic pathway independent of clathrin and caveolin that delivers the virus to endosomes bypassing the classic routes of incoming vesicular trafficking. We currently aim at an in-depth characterization of this novel pathway and the identification of host cell factors involved, employing a combination of firmly established biochemical, cell biological and microscopic techniques. Using the virus as a molecular probe, our studies will reveal the molecular mechanisms underlying cell entry of an important pathogen and illuminate novel aspects of the normal cell biology of the receptor.

Collaborators: Prof. Gisou van der Goot, Global Health Institute, EPFL

Innate immune defense against human pathogenic arenaviruses

Christelle Pythoud, Dr. Sylvia Rothenberger

Innate immunity represents the first and most important line of defense against virus infections and is crucial for the outcome of viral diseases. A hallmark of lethal arenavirus infections in humans is the inability of the patient’s innate immune system to contain the virus resulting in uncontrolled infection, shock and death. Instead of being recognized and controlled by the powerful innate defense system of the host cell, pathogenic arenaviruses have evolved to escape the normal mechanism of pathogen recognition and establish a productive infection.  A major goal of our research is to investigate how these viruses escape from or subvert the cell’s innate anti-viral defenses. The elucidation of the mechanisms underlying the innate immunity-counteracting activity of arenavirus should contribute to a better understanding of the pathogenesis and immunogenicity of these viral infections. This, in turn, could lead to the development of new antiviral strategies and vaccines to combat human pathogenic arenaviruses.

Collaborators: Dr. Juan-Carlos de la Torre, Scripps Research Institute, La Jolla, CA, USA.

Persistent viral infection of the central nervous system

Christelle Pythoud

Because of their singular immunological status and their post mitotic/non apoptotic state, neurons represent an ideal target for persistent viruses. The prototypic arenavirus lymphocytic choriomenengitis virus (LCMV) is an important model system to investigate viral persistence. It also represents a prevalent human pathogen of particular concern in pediatric medicine and recently, it has been recognized as an underestimated teratogenic pathogen. Congenital LCMV infection can lead to intrauterine death or devastating sequelae of the central nervous system (CNS) including hydrocephalus, microcephaly or macrocephaly, intracranial calcifications and mental retardation. Immature neurons are highly permissive for LCMV infection whereas terminally differentiated neurons provide a much more restrictive environment for the multiplication of LCMV. This inverse correlation between neuronal differentiation and viral replication is a fundamental aspect of many neurotropic viruses thereby being of primary importance in the field of pediatric viral infections.

On the other hand, persistent viral infection of the CNS by various viruses can affect neuronal function and cognitive defects are commonly associated with this kind of infection. This loss of cognition occurs usually in the absence of overt signs of CNS histo- and immuno-pathology. We therefore hypothesize that non-lytic persistent viral infection can contribute to CNS disturbance by virus-induced perturbation of normal neuronal differentiation and function. It is likely that chronic viral replication and/or chronic viral protein expression directly interfere with neuronal signal transduction and gene expression. Furthermore, viral persistence could also induce constant activation of the neuron’s innate immune system which could disturb the differentiation and function of neurons.

The goal of our studies is to identify the molecular mechanisms and cellular factors involved in the defective neuronal differentiation and function resulting from persistent viral infection.

Collaborators: Dr. Juan-Carlos de la Torre, Scripps Research Institute, La Jolla, CA, USA.