29.08.2024
Mosquitoes, bugs, and ticks sting and bite humans on the skin. These so-called vectors can infect humans with pathogens. The consequences are diseases such as malaria, dengue fever, and Chagas disease. Not much is known immunologically about the entry gate of the skin.
Researchers from the Bernhard Nocht Institute for Tropical Medicine (BNITM) investigated in a human cell culture model how the pathogen of Chagas disease, Trypanosoma cruzi, enters skin cells and how certain immune cells respond to this.
In the future, they want to use a skin organ model with immune cells for their experiments. Important preliminary work for this research project was recently published by the researchers in the journal PLOS Neglected Tropical Diseases.
Dr. Thomas Jacobs, head of the Protozoan Immunology research group at BNITM, and Dr. Rosa Isela Gálvez chose the infection of human keratinocytes, skin cells of the epidermis, with the parasite Trypanosoma cruzi (= T. cruzi) for the preliminary work. Kissing bugs transmit the single-celled parasite into the skin of humans and other mammals. In host cells like keratinocytes, T. cruzi multiplies. Through the bloodstream, the parasite spreads to other cells and tissues such as the muscle of the host organism. In humans, T. cruzi causes Chagas disease.
Acute symptoms include a local swelling at the entry point in the skin. If the disease becomes chronic, organs such as the heart enlarge, and nerve cells of the gastrointestinal tract are destroyed. Therefore, the disease is usually fatal. Chagas disease is one of the neglected tropical diseases (NTDs) and primarily occurs in Latin America.
The researchers used a novel co-culture model to investigate the interactions between T. cruzi-infected keratinocytes and natural killer cells (NK cells). NK cells are a type of immune cell that can kill infected cells. They selected NK cells because they are essential in combating T. cruzi. The keratinocytes were obtained from biopsies of healthy volunteers. From the same individuals, they isolated natural killer cells from blood samples.
T. cruzi infects keratinocytes in the cell culture model
“In a first important step, we were able to demonstrate that the parasite T. cruzi can infect keratinocytes in a cell culture model. When we later work with skin organ models, it must be ensured that the infection is successful. Otherwise, we would waste valuable resources,” explains immunologist Gálvez.
Natural killer cells recognize T. cruzi-infected keratinocytes
After the successful infection of keratinocytes with T. cruzi, the researchers added the NK cells. The infected keratinocytes strongly activated the NK cells. Gálvez explains: “Our investigations show that keratinocytes not only serve as a reservoir for the parasite but also play an active role in the immune response. The interaction between infected keratinocytes and NK cells strongly activates NK cells. These then release important pro-inflammatory molecules such as interferon-gamma and other cytotoxic molecules to combat the infection.”
Goal: Immune-competent skin organ model
Skin organ models that contain the different types of skin cells already exist. However, these models still lack immune cells. The new findings of the research team led by Gálvez and Jacobs underscore how significant the skin is as an immunological organ. They highlight the importance of developing a model that possesses both skin and immune cells (an immune-competent skin organ model). The researchers could not use the mouse model here, as the composition of immune cells in the skin of mice and humans differs significantly.
“So far, the co-culture model is the only model available for our investigations. With this, we have now illuminated some interactions between host cells, pathogens, and natural killer cells in more detail. A detailed characterization of the immune response in the skin can contribute to developing more effective therapeutic strategies against Trypanosoma cruzi, as well as against other pathogens that penetrate into humans through the skin. For this characterization, it is essential to establish an immune-competent skin organ model,” concludes Jacobs.
Source: Bernhard Nocht Institute for Tropical Medicine
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Emerging Insights into Skin Immunology and Infectious Diseases
Recent research from the Bernhard-Nocht Institute for Tropical Medicine (BNITM) shines a spotlight on the complex interactions between parasites, skin cells, and the immune system. Specifically, the study delves into how Trypanosoma cruzi, the causative agent of Chagas disease, infiltrates human skin cells, sparking a cascade of immune responses.
The significance of skin, often perceived merely as a protective barrier, is being reevaluated as a crucial immunological organ. The findings indicate that keratinocytes, the predominant cells in the outer layer of the skin, do not just serve as passive hosts but actively engage in immune responses. When infected by T. cruzi, keratinocytes were shown to stimulate natural killer (NK) cells, a vital component of the innate immune defense, further highlighting the dynamic role of skin cells in combating infections.
Future research trends will likely focus on developing advanced immune-competent skin organ models. These models aim to encapsulate the interaction between various skin cell types and immune cells, fostering a more comprehensive understanding of skin immunology. Traditional animal models have limitations due to the differing immune cell compositions between humans and mice, which makes these new models essential for accurate disease modeling and therapeutic development.
The implications of these advancements extend beyond Chagas disease. A deeper understanding of host-pathogen interactions at the skin level could lead to innovative therapies for other neglected tropical diseases and infectious agents entering the body via the skin. This research pathway underscores the need for interdisciplinary collaboration, merging immunology, dermatology, and parasitology to forge effective interventions against a myriad of infectious threats.
As studies like those conducted by BNITM unravel the complexities of skin-based immune responses, the potential for developing targeted treatments and preventive measures against vector-borne diseases grows significantly. The future of infectious disease research is poised to rethink and reshape our understanding of the skin’s immune capabilities.