Lab Members :

The clarification of virus-cell interactions may be the most exciting aspect of modern virology, revealing similarities among virus families, the diversity of tropism, trafficking, and pathogen propagation. Our core theme is the study of Adenoviridae. Human adenoviruses normally cause subclinical symptoms, but in sporadic cases they can be lethal in infants and immunocompromised patients. Our approaches transverse disciplines as diverse as virology, cellular and molecular biology, immunology, physical biochemistry, neurology, biochemistry, and gene transfer. We collaborate with labs throughout Europe, Asia, Australia and North America.

Some EKL news is BrainCAV, (http://www.braincav.eu/) a 4.5 million euro EU-funded proposal to generate gene transfer tools to understand and treat neurodgenerative diseases. BrainCAV began in Oct 2008 with a kick-off meeting in Montpellier and will finish in Oct 2012.

We have two major interests:

Fundamental research themes

We want to understand how Adenoviridae interact with their primary and auxiliary cell surface receptors, how the internalised virus escapes endocytic vesicles, and once in the cytoplasm how it rapidly traffics along microtubules to the nucleus. We approach these questions using physical and classical biochemistry, cell and molecular biology, electron and confocal real-time fluorescent microscopy, as well as proteomics techniques. For example, (i) we recently solved the crystal structure of a part of an Adenoviridae protein (the fibre knob) in complex with its primary cellular attachment molecule (Coxsackievirus adenovirus receptor); (ii) pVI, a multifunctional adenovirus protein involved in the nuclear import of de novo synthesised viral proteins and as a structural protein in the mature virion, may also play a major role in endosomal escape by using the cellular ubiquitylation pathway (see Wodrich et al PLoS Pathogens 2010).; (iii) our studies of adenovirus axonal transport (AXTP) (due to the preferential infection of these terminally differentiated neurons) demonstrate efficient retrograde and, unexpectedly, anterograde transport (see Salinas et al PLoS Pathogens 2009). Our data may lead to a better understanding of viral tropism, the role of post-translational modification, and the proteins involved in AXTP, a process that is often impaired in motoneuron diseases. (Image: Adenovirus-induced agglutination of human red blood cells - see Henaff et al PLoS Pathogens 2009)

Applied research themes

I) We want to use the inherent properties of canine adenovirus (CAV-2), to generate gene transfer vectors that may be used to treat neurodegenerative disorders. CAV-2 preferentially infects neurons and is capable of trafficking via AXTP to afferent regions in the central nervous system. We developed vectors that are poorly immunogenic, have a cloning capacity of >25 kb, and are capable of expressing transgenes in vivo for >1 year. We are focusing on the treatment of an orphan lysosomal storage disorder called "Sly syndrome" and Parkinson’s disease. II) Another basic tenet is to identify and overcome some of the potential clinical problems (e.g., memory and innate immunity) associated with adenovirus-mediated gene transfer. Equally important is to determine if adenovirus-mediated gene transfer will exacerbate or induce adverse effects in the potential clinical settings, like in the case of vaccine therapies.