Human Skin Organoids: Modeling Monkeypox Virus Infection and Treatment

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Human Skin Organoids: Modeling Monkeypox Virus Infection and Treatment

Human Skin Organoids: Modeling Monkeypox Virus Infection and Treatment.

Building Skin-Like Organs to Explore Monkeypox Virus Infection and Drug Treatment

Monkeypox is a zoonotic disease caused by Monkeypox Virus (MPXV), and it belongs to the Poxviridae family along with Variola Virus (VARV), Cowpox Virus (CPV), and Vaccinia Virus (VACV). For several decades, Monkeypox was primarily prevalent in a few countries in central Africa. However, in 2022, Monkeypox emerged in regions outside Africa and quickly spread to over 100 countries, resulting in over 90,000 confirmed cases and more than 100 reported deaths.

Compared to smallpox, Monkeypox is generally milder, but it can still have severe consequences, including death, for vulnerable populations such as infants, pregnant women, and immunocompromised individuals. Skin lesions are the most common symptom among Monkeypox-infected individuals, typically appearing on the face and limbs. However, in the 2022 Monkeypox outbreak, infected individuals also commonly exhibited skin lesions in the genital and perianal regions. Although these skin lesions usually cause mild itching or pain and are limited in distribution, reports during this outbreak indicated more severe pain, widespread lesions, and secondary skin bacterial infections. Close contact with skin lesions of Monkeypox-infected individuals is a primary mode of human-to-human transmission.

Therefore, there is an urgent need to better understand the pathophysiology of Monkeypox infection and develop treatments rapidly. This requires robust experimental models that can accurately simulate human skin characteristics. Currently available in vitro infection models for Monkeypox rely on immortalized cell lines and do not faithfully replicate human skin features. Moreover, many animal models developed for Monkeypox infection typically do not exhibit the skin manifestations seen in humans.

Recently, a team led by Dr. Qiuwei Pan at Erasmus University Medical Center in the Netherlands published a research paper titled “Mpox virus infection and drug treatment modelled in human skin organoids” in Nature Microbiology.

The study involved the construction of skin-like organoids derived from human induced pluripotent stem cells (hiPSCs) that are susceptible to Monkeypox virus infection and support the production of infectious Monkeypox virus. The research further revealed that Monkeypox virus infection reshapes the host cell transcriptome and triggers the expression of numerous viral transcripts. The study also found that Tecovirimat, an FDA-approved drug for smallpox treatment (inhibiting the Vaccinia Virus VP37 envelope protein), can inhibit the production of infectious Monkeypox virus and prevent the reshaping of the host transcriptome caused by infection.

In summary, this research established human skin-like organoids as a robust experimental model for studying Monkeypox virus infection, elucidating virus-host interactions, and testing antiviral drugs.

Human Skin Organoids: Modeling Monkeypox Virus Infection and Treatment

Dr. Qiuwei Pan graduated with a bachelor’s degree from Northwest Minzu University in 2004, earned a master’s degree from Zhejiang Sci-Tech University in 2007, and completed his Ph.D. at Erasmus University Medical Center in the Netherlands in 2012. Shortly after, he established his own laboratory at Erasmus University Medical Center. His team is dedicated to translational research on viral infections, with a focus on Hepatitis E virus, Rotavirus, and Norovirus. Additionally, he has initiated research projects on liver cancer primarily induced by Hepatitis viruses, aiming to enhance our understanding of virus-host interactions, develop new antiviral therapies, and gain a better understanding of how Hepatitis viruses lead to liver cancer.

Skin-like organoids derived from human induced pluripotent stem cells (hiPSCs) can faithfully recapitulate key physical and physiological characteristics of human skin. These 3D-cultured organoids display a multi-layered structure with an inverted configuration, meaning that, unlike live skin, the dermis of the organoid interfaces with the external environment while the epidermis faces inward. They also possess various skin appendages, such as hair follicles and sebaceous glands.

The recently developed air-liquid interface (ALI) culture system brings the maturation of skin-like organoids closer to the physiology of human skin. In this system, skin organoids are dissected and grown on Transwells coated with collagen, allowing the dermal layer to be in contact with the culture medium while the epidermis is exposed to the air.

In this study, the research team explored whether skin-like organoids derived from hiPSCs could serve as a robust model system for studying the pathogenesis of Monkeypox virus in the skin and testing antiviral drugs.

The research team found that skin-like organoids derived from hiPSCs supported effective Monkeypox virus infection, leading to the expression of a large number of Monkeypox virus transcripts and affecting the host transcriptome.

The use of Tecovirimat, an FDA-approved drug for smallpox treatment (inhibiting the Vaccinia Virus VP37 envelope protein), was able to inhibit the production of infectious Monkeypox virus particles, demonstrating the potential of this skin-like organoid model system for studying virus-host interactions and testing antiviral drugs.

Human Skin Organoids: Modeling Monkeypox Virus Infection and Treatment