Novel Research Reveals the Active Role that Skin Cells Play in Rabies Infection

While it was previously thought that keratinocytes (skin cells) were only passive conductors that allow the rabies virus to pass through, novel research reveals that these cells play a much more active role. The findings of a new studyopens in new tab/window in the Journal of Investigative Dermatologyopens in new tab/window (JID), published by Elsevier, provide direct evidence that keratinocytes can support viral replication and transmit the rabies virus to neurons. The investigators offer a mechanistic explanation for how superficial skin exposures from scratches or minor bites by dogs and bats can lead to neuroinvasion, contributing to the risk of infection.

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.”

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.”

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.

Notes for editors

The article is “Rabies virus infection and immune activation in human epidermal keratinocytes: Implications for rabies transmission,” by Keshia Kroh, Alisha D. Biharie, Eleanor M. Marshall, Redwan Rahmat, Debby Schipper, Leanne C. Helgers, Teunis B.H. Geijtenbeek, Corine H. GeurtsvanKessel, and Carmen W.E. Embregts (https://doi-org.ucc.idm.oclc.org/10.1016/j.jid.2026.01.036opens in new tab/window). It appears online in the Journal of Investigative Dermatology, published by Elsevier.

The article is openly available at https://www.jidonline.org/article/S0022-202X(26)00088-6/fulltextopens in new tab/window.

The full text of the article is also available to credentialed journalists upon request; contact Eileen Leahy at +1 732 406 1313 or [email protected]opens in new tab/window. Journalists wishing to interview the authors should contact Corine H. Geurts van Kessel, MD, PhD, at +31 107035294 or [email protected]opens in new tab/window.

This research was funded through a VENI grant from the Dutch Research Council (NWO-VENI 09150162010181).

About the Journal of Investigative Dermatology

The Journal of Investigative Dermatologyopens in new tab/window (JID) is the official journal of the Society of Investigative Dermatology and the European Society for Dermatological Research. JID publishes high impact reports describing original research related to all aspects of cutaneous biology and skin diseases. Descriptions of important findings that result from basic, translational, or clinical research are published. Clinical research can include, but is not limited to, interventional trials, genetics studies, epidemiology, and health services research. www.jidonline.orgopens in new tab/window

엘스비어 소개

엘스비어는 첨단 정보와 의사결정 지원 분야의 글로벌 선도 기업으로 100년 넘게 과학과 헬스케어의 발전을 지원하며 인류 진보에 기여해 왔습니다. 우리는 170개국 이상에서 학술 및 기업 연구 커뮤니티, 의사, 간호사, 미래의 의료 전문가와 교육자들을 지원합니다. 근거에 기반한 신뢰할 수 있는 과학·의학 콘텐츠와 최첨단 AI 기술을 결합해 중요한 통찰과 혁신적인 솔루션을 제공해, 의미있는 성과를 이루도록 돕고 있습니다. 또한 다양성과 지속 가능성을 제품과 기업 문화 전반에 내재화하며, 우리가 속한 커뮤니티와 협력합니다. 엘스비어 재단opens in new tab/window은 전 세계에서 연구와 보건 파트너십을 지원합니다.

엘스비어는 전문가 및 기업 고객에게 정보 기반의 분석과 의사결정 도구를 제공하는 글로벌 기업 RELXopens in new tab/window의 일원입니다. 자세한 내용은 www.elsevier.com에서 확인할 수 있으며, 소셜미디어 @elsevierconnect를 통해 최신 소식을 받아보실 수 있습니다.