Skin cells may help rabies virus spread to the nervous system

New research is reshaping how scientists understand the earliest stages of rabies infection, suggesting that keratinocytes play a more active role than previously believed, according to a Dutch study recently published in the Journal of Investigative Dermatology.

Rabies is a deadly viral infection caused by the rabies virus and is responsible for an estimated 59,000 deaths worldwide each year. It is typically spread through the saliva of infected animals, most commonly via dog bites. However, smaller exposures, such as scratches or minor bites from animals like bats, have also been known to result in infection, though the biological mechanism behind this risk has remained unclear.

Keratinocytes are the skin cells that make up more than 90% of the epidermis, which is the outermost layer of the skin. Nerve cells extend up through the epidermis, where they can detect sensations such as pain, itch and temperature change.

The study shows that keratinocytes can do more than just allow the rabies virus to pass through. Instead, these cells can become infected, support viral replication and even transmit the virus directly to the nearby nerve cells. Once rabies reaches the central nervous system, the disease is almost always fatal, making early prevention critical.

To investigate this process, a team of researchers led by Corine H. Geurts van Kessel, M.D., Ph.D., from the department of viroscience at Erasmus Medical Centre in the Netherlands, used human keratinocyte cell cultures and exposed them to different strains of the rabies virus, including strains associated with fatal human cases from bat and dog bite exposure.

Geurts van Kessel and the team found that some strains, particularly those linked to bat exposures, were more effective at infecting keratinocytes and triggering immune responses.

Rabies is responsible for the deaths of at least 59,000 humans annually, and more than 99% of cases are linked to bites from rabid dogs.

While dog vaccination programs have decreased the transmission of dog bite-transmitted rabies, bat rabies is a growing concern, especially in the United States, where 70% of human rabies cases between 1960 and 2018 originated from contact with infected bats.

“Unlike dog bites, bat bites or scratches typically do not penetrate deeply enough to reach muscle tissue and the innervating motor neurons; instead, they deposit the virus in more superficial layers such as the dermis or epidermis,” Geurts van Kessel writes in the study. “Entry of rabies virus particles into the nervous system is crucial for the development of rabies disease, eventually causing death due to viral encephalitis and a progressive neuronal dysfunction. The dermis and epidermis are rich in sensory nerve endings, providing a potential entry route for rabies virus.”

Guidance from the World Health Organization advises that any break in the skin, including small scratches or abrasions, should be evaluated for rabies risk. The new research reinforces the importance of these precautions by showing how the virus may exploit the skin’s cellular structure to initiate infection.

“Rather than causing alarm, our findings support informed decision-making," co-investigator Carmen W.E. Embregts, Ph.D., also from the Erasmus Medical Centre, said in a news release. “Awareness that superficial skin exposures can represent a route of neuroinvasion helps ensure that potential risks are recognized and evaluated appropriately, while treatment decisions remain guided by established public health criteria.”