Microtubule Motors in Axonal Sorting and Transport During Herpesvirus Infections

Princeton University, Princeton NJ

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Abstract

? DESCRIPTION (provided by applicant): Viruses are non-cellular pathogens, which exploit biological processes of their hosts to establish infection leading to the generation of large numbers of progeny. For successful infections, viral genomes must encode gene products to circumvent the host defense mechanisms at an organism and cellular level. Members of the alpha-herpesvirus family, a group of large enveloped dsDNA viruses (e.g.: Pseudorabies Virus, PRV; Herpes Simplex Virus, HSV), specifically infect epithelial and neuronal cells in which they can remain latent for prolonged periods of time. Initial cell entry into the neuron at the distal axon terminal occurs predominantly by fusion and requires high specificity in a sequence of host-pathogen interactions. Following internalization, retrograde transport allows the capsid to move along microtubules (MTs) inside the axon shaft towards the nucleus. Interestingly, engagement of cell surface receptors and the initiation of intracellular signaling cascades allow the virion to prime cytoplasmic conditions for entry and subsequent MT-based transport. At later time points during infection or upon reactivation of a dormant viral genome, a reverse program for egress is started. It includes capsid assembly, axonal sorting, anterograde transport again along axonal MTs, and eventually budding from a distal egress site. Both transport processes inside the axon - retrograde and anterograde - are crucial for infection and spread. Interestingly, both are mediated by molecular motor proteins. Whereas the identity of the motors involved in herpesvirus capsid transport in axons has been established (cytoplasmic dynein and Kif1A, a member of the kinesin-3 family), the actual mechanisms of priming for dynein-mediated transport and of Kif1A recruitment are unknown to date. However, insight into these mechanisms is highly relevant to our understanding of axonal transport processes in general and specifically of herpesviruses as pathogens and potential gene delivery vectors in brain cancer research. The core aims of this proposal are (1) to determine how attachment and entry of herpesviruses into neuronal cells primes the intracellular environment for efficient axonal transport and what cellular factors are involved in the initiation of retrograde motility and (2) t determine how Kif1A and potentially additional motor proteins are specifically recruited to the capsid containing egress vesicle and how blockage of this interaction affects axonal sorting and transport of pathogenic and physiological cargoes. Furthermore, they should shed important new light into the mechanisms underlying herpesvirus pathogenesis, neurological disorders, and motor neuron degeneration.