University of Iowa study traces Ebola's route to the skin surface

Ebola is a deadly hemorrhagic disease caused by a virus that is endemic in parts of East-Central and West Africa. Most people are aware that a primary route for person-to-person transmission is through contact with bodily fluids from an infected person. But more recent outbreaks, including the 2013-2016 Ebola epidemic in West Africa, demonstrated that infectious Ebola virus (EBOV) is also found on the skin’s surface of those who have succumbed to infection or at late times during infection. Although evidence suggests that EBOV can be passed on from skin contact with a person in the later stages of the disease, very little is known about how the virus makes its way out of the body and onto the skin’s surface.

In a new study, researchers at University of Iowa Health Care and colleagues at Texas Biomedical Research Institute and Boston University, have traced a cellular route the virus uses to traverse the inner and outer layers of skin and emerge onto the skin’s surface. The study identifies new cell types within the skin that are targeted by EBOV during infection and shows that human skin specimens actively support EBOV infection. Overall, the findings, which were published Jan. 1 in Science Advances, suggest that the skin’s surface may be one route of person-to-person transmission.

“The skin is the largest organ in the human body yet is woefully understudied compared to most other organs. Interactions of EBOV with skin cells have not previously been extensively examined,” says Wendy Maury, PhD, UI professor of microbiology and immunology, and senior author of the study. “Our work provides evidence for one mechanistic avenue that EBOV uses to exit from the human body. A comprehensive understanding of which cells are targeted during virus infection is critical for rational development of antiviral approaches.”

Human skin model helps trace EBOV escape

The research team, led by Maury and Kelly Messingham, PhD, UI research professor of dermatology, developed a new approach to examine which cells within the skin are infected by Ebola virus.They created a human skin explant system using full-thickness skin biopsies from healthy individuals, which contained both deeper (dermal), and surface (epidermal) layers of skin.

To study how Ebola virus moves through skin, the explants were placed dermal side down in culture media and virus particles were added to the media so that they entered the skin from the underside, modeling virus egress from the blood to the surface of the skin. The researchers used virus-tracing and cell-tagging techniques to follow the journey of the virus through the skin layers to the upper surface of the skin, identifying which cells were infected over time.

Previous clinical and animal studies had reported that cells within the skin become infected with EBOV, but the specific cells targeted by the virus had not been identified.

In the new study, the team showed that EBOV infected several different cell types in the skin explant, including macrophages, endothelial cells, fibroblasts, and keratinocytes. While some of these cell types are also found to be infected by EBOV in other organs, keratinocytes, that are unique to the skin, had not been previously appreciated to support EBOV infection.

Interestingly, virus replication was more robust in the epidermal layer than the dermal layers on a per gram basis. Additionally, the infectious virus was detected on the epidermal surface within three days, indicating that the virus rapidly spreads and moves through the explants to the skin’s surface.

The researchers also showed that human skin explants can serve as complex, three- dimensional organ models for studying the efficacy of antivirals against EBOV, providing a new, highly useful, and inexpensive model system for therapeutic testing.

Finally, the team also focused on the interactions of EBOV with two specific skin cell types, fibroblasts and keratinocytes, and identified specific receptors on these cells that allow uptake of Ebola virus.

“This study explores the role of the skin as a potential route of Ebola virus infection and identifies, for the first time, several cell types in the skin that are permissive to infection,” says Messingham. “In total, these findings elucidate a mechanism by which EBOV traffics to the skin’s surface and may explain person-to-person transmission via skin contact.”

In addition to Messingham and Maury, the study team included UI researcher Paige Richards, Anthony Fleck, Radhika Patel, Jonah Elliff, Samuel Connell, Tyler Crowe, Juan Munoz Gonzalez, Francoise Gourronc, Jacob Dillard, and Aloysius Klingelhutz. MarijaDjurkovic and Olena Shtanko at Texas Biomedical Research Institute, and Robert Davey at Boston University were also part of the team.

The research was funded in part by grants from the National Institute of Allergy and Infectious Diseases.