Amsterdam institute for Immunology and Infectious diseases

Fungal infections are diseases caused by a fungus and usually occur on the nails and skin, but can also penetrate into other parts of the body. Normally, fungi live naturally in our bodies, but under certain conditions they can overgrow. Only a small number of fungi are known to cause disease in humans, a fungal infection. If you have a weakened immune system, you are at greater risk of serious illness from certain fungal infections. Dr. Gringhuis' article ‘Fungal sensing by dectin-1 directs the non-pathogenic polarization of T_H17 cells through balanced type I IFN responses in human DCs’ was recently published in Nature Immunology. In this article Dr. Gringhuis shares the research background, most important insights and her plans for the future.

The occurrence of fungal infections

Our immune system very carefully regulates the response needed to get rid of fungal infections by developing a specialized type of T cells, called T helper 17 cells (T_H17). There are two types of T_H17 cells: the first, known as non-pathogenic T_H17 cell, gets rid of the fungal infection in a patient and does so by producing the cytokines IL-10 and IL-17. The second type of T_H17 cells are so called pathogenic T_H17 cells and produce, beside IL-17, another cytokine called IFNγ; these pathogenic T_H17 cells are notorious for causing or perpetuating many inflammatory and autoimmune diseases.

Dr. Gringhuis: "Therefore, in an ideal world, we would prefer that only non-pathogenic T_H17 cells are developed so that the fungal infection can be cleared without causing damage. Good news is that the main fungal sensor, i.e. the dectin-1 receptor, on our sentinel immune cells, the dendritic cells, can provide the signals for this response and very specifically stimulates development of non-pathogenic T_H17 cells."

Mechanistically, dectin-1 sends out signals to make sure that cytokine interferon-β (IFNβ) is produced. In turn, IFNβ induces production of the membrane protein integrin β8, a protein that in collaboration with an enzyme called MMP14 is in turn responsible for the generation of TGFβ. TGFβ is a cytokine that can ensure that T_H17 cells produce IL-10 and not IFNγ. However, next to leading to production of β8, IFNβ also causes the production of BST2, a membrane protein that is an antagonist of MMP14 activity. The balance between the production of β8 and BST2 determines whether or not only non-pathogenic T_H17 cells are developed. However when this balance is disturbed and also pathogenic T_H17 cells are developed during a fungal infection, the patient can experience painful inflammation at the site of infection, also creating an environment in which fungal growth is not as well contained.

“Before the publication of this article there were numerous insights into the development of the non-pathogenic and pathogenic T_H17, mostly from pre-clinical research projects. However, it was unknown what the impact of dendritic cells was in the regulation and production of TGFβ. And the role of dectin-1 and its signaling pathways in this proces were still unknown.”, Dr. Gringhuis explains.

The difference ten years can make

Over ten years ago, Dr. Gringhuis and colleagues investigated in their laboratory whether fungal infections led to IFNβ production. They found that dendritic cells indeed produced IFNβ when they sensed fungi, but that the production was limited in amount as well as time period. "I believe every response in our body is carefully orchestrated, so this was impactful for me. We started looking at T_H17 cell development in response to fungal infection while blocking IFNβ production, but we saw no differences. At this time, the whole concept of different T_H17 cells had not yet been established. Jump in time: it's 2020 and preclinical research is showing that T_H17 cells come in different flavours: non-pathogenic and pathogenic T_H17 cells and transition states in between. These insights led us to return to our previous research and we found that presence of less or more IFNβ during the development of the T_H17 cells determined whether T_H17 cells co-produced either IL-10 or IFNγ.”

Skin and gut

Dr. Gringhuis: “We hope that our results give more insight into the development of T_H17cells during fungal infections but also inflammatory and auto-immune diseases. Both T_H17 cells and IFNβ are known factors in these disorders and knowing even the slightest bit about how these are connected might enable ‘re-direction’ of responses.”

"Furthermore, we hope that the insights we discovered during this project will provide targets for therapeutic intervention when fungal infections are not controlled and lead to severe inflammation. For example, BST2 could be a target if TGFβ production is blocked by excessive IFNβ production. But of course this would not be the appropriate response if TGFβ production is blocked because IFNβ production itself is blocked, in which case you would need to know what blocks IFNβ production to enable TGFβ production.” Dr. Gringhuis says. As you can already read: there is still much to discover.

Dr. Gringhuis and colleagues are now focusing on processes on the skin and in the gut that are involved in de-railing non-pathogenic T_H17 responses when fungi are present (e.g. substances produced by the fungi themselves, genetic factors of the host that change the signals that are sent out by dectin-1). Dr. Gringhuis: “We have chosen this direction because skin and gut is where most fungi are present. But also inflammatory skin diseases caused by fungi (atopic dermatitis, chromoblastomycosis) as well as inflammatory bowel diseases (Crohn’s disease) are driven by pathogenic T_H17 cells.”

Fungi are sexy

Fungi are often ignored. Research by Paul Verweij, physician microbiologist at
Radboudumc, revealed that of the 114 projects in ZonMW infectious disease
programs, only 1 grant was allocated to fungal research. Dr. Gringhuis: “I
truly believe this needs to change, fungi are becoming more problematic. Not
just because they are developing resistance to known antimycotics but also
because more pathogenic fungi are surfacing. For example Candida auris
is spreading world-wide and has caused enough concern that it has been added to surveillance protocols in patients that have been hospitalized abroad.”

Get to know Dr. Gringhuis

Dr. Gringhuis, a molecular biologist for 30 years, has been working together with Theo Geijtenbeek for nearly 18 years in the Host Defense group at the Department of Experimental Immunology as a principal investigator. When Dr. Gringhuis was introduced to the field of signal transduction, she immediately felt she had found her passion. She compares signal transduction to puzzle pieces that have to fit together and Dr. Gringhuis is the one who figures out how the pieces fit together. Curiosity is something Dr. Gringhuis has by nature: how and why are her two favorite questions. As passionate as Dr. Gringhuis is about her work, she is about wild flower photography throughout Europe: her beautiful work can be found here. Dr. Gringhuis is happily married with fellow researcher Peter and has two children named Azura (20) and Mila (17).

For more information contact Dr. Gringhuis or read the scientific publication.

Image: Two dendritic cells (red with large blue/pink dots) that have "consumed" fungal cells (small dark spots with blue dots).

Text: Esmée Vesseur