08/28/2024
On the way to a skin organ model with immune cells
Mosquitoes, bugs and ticks bite humans in the skin. These vectors can infect humans with pathogens that cause diseases such as malaria, dengue fever or Chagas disease. From an immunological point of view, not much is known about the skin as an entry point for pathogens into the body.
Researchers at the Bernhard Nocht Institute for Tropical Medicine (BNITM) have used a human cell culture model to study how Trypanosoma cruzi, the parasite causing Chagas disease, enters skin cells and how certain immune cells react.
In the future, they hope to use a skin organ model containing immune cells for their experiments. The researchers have recently published important preliminary work for this future project in the journal PLOS Neglected Tropical Diseases.
Dr Thomas Jacobs, head of the Protozoa Immunology research group at the BNITM, and Dr Rosa Isela Gálvez chose to study the infection of human keratinocytes, the skin cells of the epidermis, with the parasite Trypanosoma cruzi (= T. cruzi). Triatomine bugs transmit the single-celled parasite into the skin of humans and other mammals. T. cruzi multiplies in host cells such as keratinocytes.
Via the bloodstream, the parasite enters other cells and tissues, such as the muscles of the host organism. In humans, T. cruzi causes Chagas disease. Acute symptoms include local swelling at the site of skin entry. If the disease becomes chronic, organs such as the heart become enlarged and nerve cells in the gastrointestinal tract are destroyed. The disease is therefore usually fatal. Chagas disease is one of the neglected tropical diseases (NTDs) and is mainly found in Latin America.
The researchers used a novel co-culture model to study the interactions between T. cruzi-infected keratinocytes and natural killer (NK) cells. NK cells are a type of immune cell that can kill pathogen-infected cells. They chose NK cells because they are essential in the fight against T. cruzi. The scientists obtained keratinocytes from biopsies of healthy volunteers and isolated natural killer cells from blood samples taken from the same people.
T. cruzi infects keratinocytes in cell culture model
"As a first important step, we have shown that the T. cruzi parasite can infect keratinocytes in a cell culture model. When we move on to skin organ models, we need to make sure that the infection is successful. Otherwise, we would be wasting expensive resources," says immunologist Gálvez.
Natural killer cells recognize keratinocytes infected with T. cruzi
After successfully infecting the keratinocytes with T. cruzi, the researchers added NK cells, which were highly activated by the infected keratinocytes. Gálvez explains: "Our studies 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 leads to strong activation of the NK cells, which then release important pro-inflammatory molecules such as interferon-gamma and other cytotoxic molecules to fight the infection."
Toward an immunocompetent skin organ model
Skin organ models containing the different skin cell types already exist. However, these models still lack immune cells. The new findings of the research team led by Gálvez and Jacobs underline the importance of the skin as an immunological organ. They show how critical it is to develop a model that contains both immune cells and skin cells (i.e. an immunocompetent skin organ model). The researchers could not use the mouse model because the composition of immune cells in the skin of mice and humans is very different.
"So far, the co-culture model is the only model available for our investigations. We have now shed more light on some of the interactions between host cells, pathogens and natural killer cells. A detailed characterization of the immune response in the skin will contribute to the development of more effective therapeutic strategies against Tryponosoma cruzi, but also against other pathogens that enter humans via the skin. For this characterization, it is essential to establish an immunocompetent skin organ model," concludes Jacobs.
Source: Bernhard Nocht Institute for Tropical Medicine