Until now, keratinocytes (skin cells) were thought to be just passive conductors that allow the rabies virus to pass through, but new research reveals that these cells play a more active role. Results of new research in Journal of Research Dermatology (method), a paper published by Elsevier provides direct evidence that keratinocytes support viral replication and can transmit rabies virus to neurons. Researchers provide a mechanistic explanation for how exposure of superficial skin through scratches and minor bites by dogs and bats can cause neural invasion and contribute to infection risk.
Rabies is a deadly zoonotic disease caused by rabies virus (RABV), which causes at least 59,000 deaths annually. The virus is transmitted through the saliva of infected animals. Most cases are caused by dog bites, but superficial exposures such as bat bites or scratches can also cause infection, but the underlying mechanisms are still not well understood.
“In our previous research, we found that keratinocytes, the cells that form the epidermis, the outermost layer of the skin, are infected at the site of entry for the rabies virus, both during natural and experimental infections. This was unexpected, as the pathogenesis of rabies has traditionally focused on muscle cells and motor neurons,” explains Corinne H. Goertz van Kessel, MD, PhD, principal investigator, Department of Viral Sciences, Erasmus Medical. In the center of Rotterdam, the Netherlands.
Given the strategic location of keratinocytes in the skin barrier and their proximity to sensory nerve endings, we wanted to understand whether these cells are simply bystanders or actively involved in early rabies infection and neuroinvasion.”
Corinne H. Goertz van Kessel, Department of Viral Sciences, Erasmus Medical Center
Researchers used primary human keratinocyte cultures to investigate susceptibility to rabies virus infection and characterized the resulting antiviral immune response. Three virus strains were tested: a vaccine strain and two wild-type (“street”) strains derived from fatal human cases associated with exposure in bats and dogs. The dog-associated strain caused minimal infection and limited immune activation of keratinocytes, whereas the other two strains more easily infected keratinocytes and elicited significant antiviral responses.
A keratinocyte-neuron coculture model was developed to simulate the close contact between keratinocytes and intraepidermal nerve terminals. In this model, the virus produced in infected keratinocytes was successfully transmitted to neighboring neurons, providing a route for the virus to enter the nervous system directly. Once the virus infects the central nervous system, it is almost inevitably fatal.
“Our study shows that the skin may play a more important role in rabies infection than previously realized. We were particularly surprised by the strong antiviral response elicited by keratinocytes against bat-associated rabies virus strains,” said co-author Kesia Clough, a PhD candidate in the Department of Viral Sciences at the Erasmus Medical Center (Rotterdam, Netherlands). “Wild-type rabies virus is known for its immunosuppressive capabilities, and we expected an immune evasion effect in keratinocytes, but we actually observed the opposite. This raises new questions about how keratinocyte-derived immune responses influence overall disease progression in rabies and other viral infections of the skin.”
this in vitro The co-culture model is the first to study rabies virus entry into the nervous system across cellular barriers. Future detailed studies need to be conducted to provide mechanistic insights into the different strain tropisms, the interaction of infected keratinocytes with immune cells, and the mechanisms of neuroinfiltration from surface skin contact.
According to the World Health Organization (WHO), dermal exposure (including small cuts and abrasions) should be evaluated as a potential rabies risk and managed appropriately based on the exposure category and clinical situation.
“Our study provides a biological basis for these recommendations,” says co-investigator Dr. Carmen W. E. Embreguts of the Department of Viral Sciences at the Erasmus Medical Center. “At the same time, it is important to emphasize that the risk of rabies virus infection through superficial exposure depends on multiple factors, including the nature of the exposure and the epidemiological setting. Rather than cause alarm, our findings support informed decision-making. Recognition that superficial dermal exposure can be a route of neural entry helps ensure that potential risks are recognized and appropriately assessed, while treatment decisions remain guided by established public health standards.”
“The data from this study support the increasingly recognized concept that skin cells are in close communication with the nervous system. The fact that scratches and bites are required for rabies transmission is further evidence of the importance of an intact skin barrier in health,” they observed. method Associate Editor Ethan Lerner, MD, Associate Professor of Dermatology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
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Reference magazines:
Kuro, K. others. (2026). Rabies virus infection and immune activation in human epidermal keratinocytes: Implications for rabies infection. Journal of Research Dermatology. DOI: 10.1016/j.jid.2026.01.036. https://www.jidonline.org/article/S0022-202X(26)00088-6/fulltext.
