Rabies virus infection and immune activation in human epidermal keratinocytes: Implications for rabies transmission

Rabies is a fatal zoonotic infection caused by rabies virus (RABV), which is transmitted through the saliva of infected animals. Although 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. We recently detected RABV-positive keratinocytes in skin samples of experimentally infected mice and naturally infected dogs, prompting us to investigate their role in rabies pathogenesis and the antiviral immune response. We confirmed that both the keratinocyte cell line HaCaT and primary keratinocytes are susceptible to RABV infection in vitro, with higher infection rates observed for the attenuated SAD P5/88 Potsdam and silver-haired bat RABV strains than for a dog-related strain. Keratinocytes showed a significant immune activation in response to these 2 strains, as measured by expression of relevant surface markers and cytokine release. To explore whether RABV can be transmitted from infected keratinocytes to neurons, we developed a coculture model using HaCaT and a neuronal cell line separated by a microporous membrane. Virus transfer to the neurons was observed while the barrier integrity remained intact, suggesting that keratinocytes may contribute to RABV transmission and neuroinvasion after superficial exposure.