Alphaherpesvirus Infection Disrupts Mitochondrial Transport in Neurons

Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Cell host & microbe (Impact Factor: 12.33). 05/2012; 11(5):504-14. DOI: 10.1016/j.chom.2012.03.005
Source: PubMed


Mitochondria are dynamic organelles that are essential for cellular metabolism but can be functionally disrupted during pathogen infection. In neurons, mitochondria are transported on microtubules via the molecular motors kinesin-1 and dynein and recruited to energy-requiring regions such as synapses. Previous studies showed that proteins from pseudorabies virus (PRV), an alphaherpesvirus, localize to mitochondria and affect mitochondrial function. We show that PRV and herpes simplex virus type 1 (HSV-1) infection of rodent superior cervical ganglion (SCG) neurons disrupts mitochondrial motility and morphology. During PRV infection, glycoprotein B (gB)-dependent fusion events result in electrical coupling of neurons and increased action potential firing rates. Consequently, intracellular [Ca(2+)] increases and alters mitochondrial dynamics through a mechanism involving the Ca(2+)-sensitive cellular protein Miro and reduced recruitment of kinesin-1 to mitochondria. This disruption in mitochondrial dynamics is required for efficient growth and spread of PRV, indicating that altered mitochondrial transport enhances alphaherpesvirus pathogenesis and infection.

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    • "We hypothesize that incorporation of Us9 and these SNARE proteins within the same membrane microdomains is functionally required for efficient spread of infection. Furthermore, we recently demonstrated that alphaherpesvirus infection disrupts mitochondrial motility in axons (Kramer and Enquist, 2012). Additional work is needed to determine whether the dynamics of synaptic vesicles and other cellular axonal cargoes may be altered. "
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    ABSTRACT: During infection of the nervous system, alphaherpesviruses-including pseudorabies virus (PRV)-use retrograde axonal transport to travel toward the neuronal cell body and anterograde transport to traffic back to the cell periphery upon reactivation from latency. The PRV protein Us9 plays an essential but unknown role in anterograde viral spread. To determine Us9 function, we identified viral and host proteins that interact with Us9 and explored the role of KIF1A, a microtubule-dependent kinesin-3 motor involved in axonal sorting and transport. Viral particles are cotransported with KIF1A in axons of primary rat superior cervical ganglion neurons, and overexpression or disruption of KIF1A function, respectively, increases and reduces anterograde capsid transport. Us9 and KIF1A interact early during infection with the aid of additional viral protein(s) but exhibit diminished binding at later stages, when capsids typically stall in axons. Thus, alphaherpesviruses repurpose the axonal transport and sorting pathway to spread within their hosts.
    Cell host & microbe 12/2012; 12(6):806-14. DOI:10.1016/j.chom.2012.10.013 · 12.33 Impact Factor
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    ABSTRACT: Mitochondria are dynamic organelles with many functions. In this issue of Cell Host & Microbe, Kramer and Enquist (2012) show that mitochondrial motility and morphology are disrupted during alphaherpesvirus infection, which aids viral replication and transport in neurons.
    Cell host & microbe 05/2012; 11(5):420-1. DOI:10.1016/j.chom.2012.05.001 · 12.33 Impact Factor
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    ABSTRACT: Alphaherpesviruses are pathogens that invade the nervous systems of their mammalian hosts. Directional spread of infection in the nervous system is a key component of the viral lifecycle and is critical for the onset of alphaherpesvirus-related diseases. Many alphaherpesvirus infections originate at peripheral sites, such as epithelial tissues, and then enter neurons of the peripheral nervous system (PNS), where lifelong latency is established. Following reactivation from latency and assembly of new viral particles, the infection typically spreads back out towards the periphery. These spread events result in the characteristic lesions (cold sores) commonly associated with herpes simplex virus (HSV) and herpes zoster (shingles) associated with varicella zoster virus (VZV). Occasionally, the infection spreads transsynaptically from the PNS into higher order neurons of the central nervous system (CNS). Spread of infection into the CNS, while rarer in natural hosts, often results in severe consequences, including death. In this review, we discuss the viral and cellular mechanisms that govern directional spread of infection in the nervous system. We focus on the molecular events that mediate long distance directional transport of viral particles in neurons during entry and egress.
    Viruses 02/2013; 5(2):678-707. DOI:10.3390/v5020678 · 3.35 Impact Factor
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