Creepy trick that helps herpes check into the nervous system for life

Central nervous system

Herpes’ commuting into the nervous system is aided by a spooky trick.

  • Researchers discover how herpes kidnaps protein to infect the nervous system
  • Opens a door to long-needed HSV1 and HSV2 vaccines
  • More than half of American adults are carriers of the herpes HSV1
  • Viruses can cause blindness, life-threatening encephalitis and can contribute to dementia

Herpes type 1 is sealed with a kiss in a lifetime. More than half of American adults are carriers of HSV1 (herpes simplex virus type 1), which goes to sleep in the peripheral nervous system and can never be eradicated.

A new Northwestern Medicine study published in Nature has revealed the virus’ sneaky strategy to infect the nervous system, paving the way for long-needed vaccine development for both HSV1 and its close siblings HSV2.

Some carriers will never experience as much as a cold sore from HSV1. But for others, it can cause blindness or life-threatening encephalitis. There is growing evidence that it contributes to dementia.

And HSV2, which is more commonly transmitted through sexual contact, can be transmitted from a mother to a newborn during birth as neonatal herpes, which appears as lesions all over the baby’s body. Most babies recover, but in the worst cases it can cause brain damage or spread through all organs and be fatal.

“We desperately need a vaccine to prevent herpes from invading the nervous system,” said Gregory Smith, PhD, professor of microbiology-immunology.

The new study from Smith’s laboratory has revealed a way to get there. The study discovered how herpes kidnaps a protein from epithelial cells and turns it into a defector to help it travel into the peripheral nervous system. They have called the process “assimilation”. It is a discovery that can have far-reaching consequences for many viruses, including HIV and HIV SARS-CoV-2, Smith said.

Runs on the rails

“The virus needs to inject its genetic code into the nucleus so it can start making more herpes viruses,” Smith said. “It reprograms the cell to become a virus factory. The big question is, how does it get to the nucleus of a neuron?”

Like many viruses, herpes jumps on train tracks in the cell called microtubules and uses protein motors called dynein and kinesin to move along the tracks. Smith’s team discovered that herpes uses a kinesin motor, which it brings with it from other cells, to transport it to the nucleus of the neuron. The kinesin protein becomes a defector to serve the purpose of the virus.

“By learning how the virus achieves this incredible feat of getting into our nervous system, we can now think about how to remove that ability,” Smith said. “If you can prevent it from assimilating kinesin, you would have a virus that could not infect the nervous system. And then you have a candidate for a preventative vaccine.”

Herpes takes a ‘cross-country’ trip

Imagine the cell as a railway station. All tracks lead to the hub called the centrosome. There are two types of train engines: proteins dynein and kinesin. One travels towards the hub – for example downtown – and the other leads away from it to the suburbs.

When a more typical virus, such as the flu, infects mucosal epithelial cells (cells that line your nose and mouth), it intervenes in both engines and moves back and forth on the microtubule ducts until it finally arrives at the nucleus more or less randomly. . Overall, it is a short commute to walk from the suburbs to the core via the centrosome.

But getting on your nerves is like a cross-country trip. Herpes jumps on the dynein engine for this trip, but it also makes sure that kinesin engines do not take it back as it came.

“It’s a long way to go,” Smith said. “It probably takes eight hours for it to travel from the end of the neuron to the hub.”

But the dynein engine can not take it further than to the hub. And herpes should reach the core. It is when it reaches into its ‘pocket’ and pulls out a kinesin motor that it kidnapped from the mucosal epithelial cells and convinced to become part of its team. And in an act of betrayal, the assimilated kinesin leads it straight to the core.

“This is the first discovery of any virus that recycles a cellular protein and uses it to drive subsequent rounds of infection,” said Caitlin Pegg, a student at the Driskill Graduate Program in Life Sciences (DGP) and lead author of the study.

“We are excited to further uncover the molecular mechanisms that these viruses have developed that make them without a doubt the most successful pathogens known to science,” Smith said.

Reference: “Herpes virus assimilates kinesin to produce motorized viral particles” by Caitlin E. Pegg, Sofia V. Zaichick, Ewa Bomba-Warczak, Vladimir Jovasevic, DongHo Kim, Himanshu Kharkwal, Duncan W. Wilson, Derek Walsh, Patricia J. Sollars , Gary E. Pickard, Jeffrey N. Savas and Gregory A. Smith, November 17, 2021, Nature.
DOI: 10.1038 / s41586-021-04106-w

Other Northwestern contributors to the study are Sofia Zaichick, PhD; and the laboratories of Jeffrey Savas, PhD, Assistant Professor in Ken and Ruth Davee Department of Neurology Division of Behavioral Neurology; and Derek Walsh, PhD, professor of microbiology-immunology. The laboratories of Duncan Wilson, PhD (Albert Einstein College of Medicine) and Patricia Sollars, PhD and Gary Pickard, PhD (University of Nebraska-Lincoln) also contributed to the study.

Smith is a member of the Robert H. Lurie Comprehensive Cancer Center in Northwestern University.

The research was primarily funded by the National Institutes of Health AI056346, with additional support from AI125244, AI148780, AI141470 and NS106812, the National Science Foundation and the Cellular and Molecular Basis of Disease Training Grant T32GM08061.

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