CAR-Associated Vesicular Transport of an Adenovirus in Motor Neuron Axons

Abstract

Axonal transport is responsible for the movement of signals and cargo between nerve termini and cell bodies. Pathogens also exploit this pathway to enter and exit the central nervous system. In this study, we characterised the binding, endocytosis and axonal transport of an adenovirus (CAV-2) that preferentially infects neurons. Using biochemical, cell biology, genetic, ultrastructural and live-cell imaging approaches, we show that interaction with the neuronal membrane correlates with coxsackievirus and adenovirus receptor (CAR) surface expression, followed by endocytosis involving clathrin. In axons, long-range CAV-2 motility was bidirectional with a bias for retrograde transport in nonacidic Rab7-positive organelles. Unexpectedly, we found that CAR was associated with CAV-2 vesicles that also transported cargo as functionally distinct as tetanus toxin, neurotrophins, and their receptors. These results suggest that a single axonal transport carrier is capable of transporting functionally distinct cargoes that target different membrane compartments in the soma. We propose that CAV-2 transport is dictated by an innate trafficking of CAR, suggesting an unsuspected function for this adhesion protein during neuronal homeostasis.

Combined Antiapoptotic and Antioxidant Approach to Acute Neuroprotection for Stroke in Hypertensive Rats

“…Although we cannot distinguish between endogenous or virusmediated upregulation in Ngb expression within the striatum, we can postulate that after tMCAO transduction profiles may differ or that there is an active transport process occurring similar to what has previously been described with CAV-2 vectors. 36 Previous studies determining the neuroprotective effect of Ngb in vivo showed Ngb-overexpressing transgenic mice had lower levels of lipid peroxidation measured by MDA assay in the ipsilateral hemisphere after tMCAO. 11 In addition, reduced numbers of TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling)-positive cells and increased numbers of neurones with a normal morphology (from cresyl violet histology) were seen after delivery of Ngb linked to a fusion protein before tMCAO in C57BL/6J mice.…”

Viruses in human central nervous system — invasion, transmission, and latency: a literature review

“…Эти фундаментальные различия взаимодейс-твия вирус -хозяин лежат в основе патогенеза многих вирусных инфекций. В нейронах после инвазии боль-шинство вирионов остаются внутри эндоцитозной везикулы, и в таком виде по механизму ретроградного транспорта перемещаются вдоль микротрубочек к телу клетки с использованием динеинов -моторных белков [42][43][44]. Микротрубочки ориентированы (+) -на периферии клетки или аксона и (−) -в направ-лении к телу клетки [45].…”

The Intracellular Domain of the Coxsackievirus and Adenovirus Receptor Differentially Influences Adenovirus Entry

“…These data led to the conclusion that HAdV-C5 internalization is mediated by integrins via the engagement of the conserved RGD motif in the AdV penton (4,11,12). Interestingly, CAR is coendocytosed upon engagement of the canine adenovirus type 2 (CAdV-2, commonly referred to as CAV-2) and HAdV-C5 ex vivo in neurons and neuronal cell lines, raising the possibility that CAR actively participates in the endocytosis of some viruses (13,14). CAV-2 vectors are powerful tools for gene transfer to the brain because they preferentially transduce neurons and undergo efficient axonal retrograde transport (15-18).…”