Skin cells foster rabies viral growth, acting as a gateway to the nervous system even through superficial exposure.
Why even a subtle abrasion from bat and dog scratches poses a significant risk to the nervous system? Molecular evidence from latest research is re-evaluating the role of skin cells in the fatal progression of rabies.
While medical experts previously viewed keratinocytes (outer skin cells) as passive conductors, a groundbreaking study in the Journal of Investigative Dermatology (JID) reveals that skin cells are active participants in the rabies infection process, that transforms our understanding of rabies virus pathogenesis.(1✔ ✔Trusted Source
Rabies virus infection and immune activation in human epidermal keratinocytes: Implications for rabies transmission
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Researchers have found that these skin cells act as replication hubs, allowing the rabies virus (RABV) to multiply directly at the site of entry. This discovery provides a clear explanation for how superficial exposure such as minor dog scratches or bat bites, can lead to fatal neuroinvasion.
By harnessing the skin’s biological mechanism, the virus creates a direct pathway to the nervous system, bypassing the need for deep muscle penetration.
Keratinocytes Act as Active Participants in Rabies Neuroinvasion
Rabies is a fatal zoonotic infection caused by rabies virus (RABV), responsible for at least 59,000 human deaths per year. The virus is transmitted through the saliva of infected animals. While most cases are caused by dog bites, superficial exposures such as bat bites or scratches can also lead to infection, although the underlying mechanisms remain poorly understood.
“In our previous work, we discovered that keratinocytes—cells that form the epidermis, the outermost layer of the skin—were infected at the site of entry of the rabies virus, both in natural and experimental infections.”
“This was unexpected, as rabies pathogenesis has traditionally focused on muscle cells and motor neurons,” explains lead investigator Corine H. Geurts van Kessel, MD, PhD, Department of Viroscience, Erasmus Medical Centre, Rotterdam, The Netherlands.
“Given the strategic position of keratinocytes at the skin barrier and their close proximity to sensory nerve endings, we wanted to understand whether these cells are simply bystanders or active participants in early rabies infection and neuroinvasion.”
Higher Infectivity of Bat and Vaccine Strains vs. Dog-Associated Rabies in Skin Cells
The investigators used primary human keratinocyte cultures to investigate susceptibility to rabies virus infection and characterize the resulting antiviral immune responses. Three viral strains were tested: a vaccine strain and two wild-type (“street”) strains derived from fatal human cases associated with bat and dog exposures.
The dog-associated strain caused only minimal infection and limited keratinocyte immune activation, whereas the other two strains infected keratinocytes more readily and triggered a pronounced antiviral response.
To simulate the close contact between keratinocytes and intra-epidermal nerve endings, a co-culture model of keratinocytes and neurons was developed. In this model, virus produced in infected keratinocytes was successfully transmitted to adjacent neurons, giving the virus a direct route into the nervous system. Once the virus has established infection in the central nervous system, it is almost inevitably fatal.
“Our study demonstrates that the skin might play a more important role in rabies infection than previously recognized. We were particularly surprised by the strong antiviral response mounted by keratinocytes to the bat-related rabies virus strain,” notes co-investigator Keshia Kroh, PhD candidate, Department of Viroscience, Erasmus Medical Centre, Rotterdam, The Netherlands.
“Wild-type rabies viruses are known for their immunosuppressive capacities, and we expected an immune evasive effect in keratinocytes. Instead, we 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.”
Recognition of Superficial Exposure and WHO Guidelines for Rabies Risk Management
This in vitro co-culture model is the first to study rabies virus entry to the nervous system across a cell barrier. Future in-depth studies should be performed to provide mechanistic insight into the differential strain tropism, the interactions of infected keratinocytes with immune cells, and the mechanisms of neuroinvasion from superficial skin contact.
According to the World Health Organization (WHO), any transdermal exposure (including small scratches or abrasions) should be assessed as a potential rabies risk and managed appropriately based on exposure category and clinical context.
“Our study provides a biological rationale for these recommendations,” says co-investigator Carmen W.E. Embregts, PhD, Department of Viroscience, Erasmus Medical Centre, Rotterdam, The Netherlands. “At the same time, it is important to emphasize that the risk of rabies virus infection via superficial exposures depends on multiple factors, including the nature of the exposure and the epidemiological setting. Rather than causing alarm, our findings support informed decision-making.”
“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.”
“The data in this study support the increasingly recognized concept that cells in the skin are in snug communication with the nervous system. That a scratch or bite is needed for the transmission of rabies is further evidence of the importance of an intact skin barrier in health,” observes JID Associate Editor Ethan Lerner, MD, PhD, Associate Professor of Dermatology, Harvard Medical School, and Massachusetts General Hospital, Boston, MA, USA.
Reference:
- Rabies virus infection and immune activation in human epidermal keratinocytes: Implications for rabies transmission – (https://www.jidonline.org/article/S0022-202X(26)00088-6/fulltext)
Source-Eurekalert