Auto-inducing peptides (AIPs) for treatment of skin infections caused by staphylococci

Grantee: Christian Olsen, Professor, University of Copenhagen

Amount: DKK 2,990,405

Grant category: Research grants in open competition

Year: 2021

Geography: Denmark

The research project by Professor Christian Olsen pursues a cutting-edge strategy for the treatment of skin infections.

Staphylococcal bacteria are the most common cause of skin and soft tissue infections, and with the rise of methicillin-resistant Staphylococcus aureus (MRSA), this new strategy could – if successful – help prevent minor infections from becoming severe medical conditions. Furthermore, the strategy could minimize the risk of emerging antibiotic resistance.

Bacteria produce and release molecules known as ‘virulence factors’ which cause damage. The production of these harmful molecules is regulated through a form of cell-to-cell communication called ‘quorum sensing’, where the concentration of virulence factors increases as a function of cell density. The present project aims to weaken the severity of bacterial skin infections by inhibiting ‘quorum sensing’ with synthetic auto-inducing peptide (AIP) analogs, and as a result, decrease the excretion of virulence factors.

‘Quorum sensing’ inhibition will target the severity of the bacterial infection, rather than the viability of the individual bacterium and represents an alternative to antibiotics, as there is no evolutionary pressure on the individual bacterium to develop towards a state that is not affected by these compounds. Therefore, minimal risk of emerging antibiotic resistance is to be expected from this strategy.

PACT: Personalizing Acne Treatment Using Skin Microbiota Transplantation

Grantee: Holger Brüggemann, Associate Professor, Aarhus University

Amount: DKK 2,179,800

Grant category: Research grants in open competition

Year: 2021

Geography: Denmark

This project aims to investigate the potential of using bacteria exchange or “microbiome transplant” as a viable treatment option for acne vulgaris.    

Acne vulgaris remains one of the most prevalent skin conditions worldwide affecting close to 10% of the population and impacting the quality of life of millions of people. Multiple factors contribute to acne, including genetics, excess sebum production, colonization of the skin by Cutibacterium acnes and an inflammatory cascade. Current treatments for acne such as retinoids and antibiotics have varied outcomes and side effects. As antibiotic resistance becomes an increasing concern in clinical practice, there is an unmet need for alternative treatment approaches.   

The team have previously identified a range of bacterial strains, isolated from healthy skin, that can selectively inhibit acne-associated Cutibacterium acnes strains. The current project takes a microbiome transplantation approach to acne treatment, utilizing a pre-existing in-house library of more than 1000 bacterial strains and testing their ability to modulate the skin microbiome and reduce acne symptoms in patients with mild-to-moderate acne.  

This project may pave the way for developing a personalized treatment to a very common skin disease while avoiding the issue of antibiotic resistance. 

Global serum proteome profiling of hidradenitis suppurativa patients

Grantee: Simon Francis Thomsen, Professor, Head of Department, Department of Dermatology, Bispebjerg Hospital

Amount: DKK 2,257,500

Grant category: Research grants in open competition

Year: 2021

Geography: Denmark

The project aims to better understand the molecular basis of Hidradenitis Suppurativa (HS). HS is a debilitating chronic skin disease characterized by the formation of painful nodules and abscesses predominantly in the armpits, groins, and buttocks. With time, the disease may progress resulting in persisting tunnels in the skin and pronounced scarring. While there are many treatment options for HS, successful management often remains difficult and sometimes elusive – which likely reflects the still incompletely understood pathogenesis.  

Simon Francis Thomsen and his team will approach this by doing a large-scale, prospective study where they determine the protein composition of blood from more than 500 HS patients. They will follow the changes during disease progression (identified as Hurley stage I to III) to identify key biomarkers and signaling pathways specific for the disease.  

The study is a unique translational endeavor which brings together clinical dermatologists with basic scientists to explore and characterize the serum proteome of patients with HS through analysis of blood serum samples obtained at the Department of Dermatology, Bispebjerg Hospital.  

Probiotics targeting Staphylococcus aureus toxin production in atopic dermatitis

Grantee: Hanne Ingmer, Professor, University of Copenhagen

Amount: DKK 2,681,665

Grant category: Research grants in open competition

Year: 2020

Geography: Denmark

Patients with atopic dermatitis (AD) are often colonized by the bacterial pathogen, Staphylococcus aureus (S. Aureus). S. aureus produces a large variety of toxins that contribute to the severity of AD and expression of these toxins is controlled by a cell-cell communication process called “quorum sensing”.  

Professor Ingmer and her team has previously demonstrated that some bacteria produce signaling molecules, which in S. aureus abolish toxin production through repression of quorum sensing and preliminary analyses indicate that probiotic bacteria also belong to this group. 

Thus, the goal of this project is to deliver results addressing the efficacy of probiotics. The project proposes that probiotic bacteria can reduce S. aureus toxin production and that some of the reported benefits of probiotics in AD may be associated with such activity. 

Professor Ingmer will address this hypothesis in collaboration with Statens Serum Institut, the LEO Foundation Skin Immunology Research Center, UCPH and Department of Drug Design and Pharmacology, UCPH. 

Understanding the importance of cIAPs as NF-κB molecular switches in psoriasis

Grantee: Vasileios Bekiaris, Associate Professor, Technical University of Denmark

Amount: DKK 2,815,499

Grant category: Research grants in open competition

Year: 2020

Geography: Denmark

Psoriasis is an inflammatory disease characterized by overproduction of tissue-damaging cytokines by immune cells and keratinocytes. Central cytokines in psoriasis are TNF (tumor necrosis factor) and IL-17 (interleukin 17), which are currently approved therapeutic drug targets. To improve current therapies targeted towards TNF and IL-17, it is important to better understand the biology of the two cytokines in relation to psoriasis.  

The goal of this project is to confirm that two enzymes known as cIAPs (cellular inhibitors of apoptosis proteins) play a central role in psoriasis.  

The two cIAPs are believed to modulate the response of the immune system and of keratinocytes to TNF in order to fine-tune IL-17 production. The project will investigate whether lack of the two cIAPs or their pharmacologic inhibition makes the immune response less pathogenic and reduces the pro-inflammatory nature of keratinocytes during psoriasis.  

Systemic effects of atopic dermatitis: Dysregulated immune responses to the intestinal microbiota

Grantee: Jeppe Madura Larsen, Senior Researcher, Technical University of Denmark

Amount: DKK 4,349,062

Grant category: Research grants in open competition

Year: 2020

Geography: Denmark

Atopic Dermatitis (AD) is a common inflammatory skin disease affecting 15% of children and 3-5% of adults. AD is associated with the risk for developing co-morbidities such as other atopic diseases (food allergy, asthma, and rhinitis) and infections. Co-morbidities are believed to occur because of functional changes in the immune system of AD patients, however, it remains unknown how these changes are established. Emerging experimental studies suggest the existence of a skin-gut immune axis, but the role for the gut remains largely unexplored in AD.

The goal of this project is to determine if AD changes the bacterial microbiota composition and function in the gut, alters the intestinal and systemic immune system, and increases the risk for food allergy co-morbidity via oral sensitization. The project hypothesizes that AD drives dysregulated immune responses to the gut microbiota, which in turn changes the immune system giving rise to atopic co-morbidities and risk for infections. In other words, it is envisaged that AD patients become “allergic” to the bacteria present in their intestine – leading to a “persistent allergic reaction” due to continuous presence of bacteria in the intestine.

The project will use a rat model of AD to investigate the hypothesis and perform a human case-control study to support the clinical relevance of the findings. Identification of bacterial drivers of persistent type-2 inflammation could open new avenues for the prevention and treatment of AD and related co-morbidities.

Deciphering the functional role of circular RNAs in psoriasis

Grantee: Lasse Sommer Kristensen, Associate Professor, Department of Biomedicine, Aarhus University

Amount: DKK 2,467,477

Grant category: Research grants in open competition

Year: 2020

Geography: Denmark

This project aims to answer key questions related to a recently discovered new class of biomolecules, called circular RNAs. These RNA molecules appear to have an important role in early immune responses and the project aims to functionally characterize them in psoriasis patients and compare the results with data from healthy controls.

To study the RNA molecules, the project uses a combination of traditional molecular biology approaches and high-throughput technologies such as RNA-sequencing and NanoString technology.

In summary, this project aims to shed light on the distribution and functional relevance of circular RNAs within psoriatic plagues as well as in normal skin and potentially open new avenues for better treatment and management of psoriasis.

Rapid Clinical Assessment of Skin Barrier Function by Corneocytes Nanotexture

Grantee: Edwin En-Te Hwu, Associate Professor, Technical University of Denmark

Amount: DKK 2,824,593

Grant category: Research grants in open competition

Year: 2020

Geography: Denmark

The goal of this project is to develop a clinically applicable imaging method for evaluation of atopic dermatitis (AD) development, progression and impact of therapeutic intervention.

It is known that AD is closely linked to the status of the skin barrier and therefore Edwin En-Te Hwu and his team will utilize a newly developed biomarker for skin barrier function, the Dermal Texture Index. This index is based on the number of circular nano-objects found on corneocytes (skin cells in the outermost part of the epidermis) of the skin by atomic force microscopy (AFM). However, the current analytical setup is both costly and has a limited throughput which makes it less suitable in a clinical setting.

The team has recently developed a new AFM technique and now aims to develop ‘Dermal AFM’, which will allow a ten times higher throughput in a clinically applicable unit. The unit may also help facilitate the understanding of the biology behind the observed corneocyte nanostructures.

The project is a collaboration between Denmark, Netherlands and Taiwan headed by DTU Health Technology.

Read more

Unveiling AMBRA1 as a prognostic biomarker in in vivo pre-clinical models of cutaneous melanoma

Grantee: Daniela De Zio, Danish Cancer Society Research Center, Copenhagen

Amount: DKK 2,900,000

Grant category: Research grants in open competition

Year: 2019

Geography: Denmark

The survival rate of patients with advanced melanoma has improved in recent years due to the clinical application of immune checkpoint inhibitors, as well as kinase inhibitors in BRAF/RAS-mutated melanoma cases.

However, melanoma remains a fatal diagnosis as a consequence of emerging resistance mechanisms and the absence of reliable biomarkers that identify high-risk tumour subsets, therefore impacting the stratification of these subsets for novel adjuvant therapies.

In the search for novel oncosuppressors that are altered in melanoma, we have found a promising candidate in the protein called AMBRA1. AMBRA1 has a fundamental role in the positive regulation of autophagy – a process which can elicit both pro- and anti-tumorigenic roles. Additionally, AMBRA1 finely modulates other crucial oncogenic processes, such as cell proliferation, cell invasion, and cell death.

Our preliminary research in a mouse model of melanoma has proven Ambra1 to be a crucial oncosuppressor, whose expression has been found highly altered in a number of human melanoma cells. Thus, by applying melanoma cell and mouse models in combination with systems biology approaches and state-of-the-art technologies, we aim to decipher the response of Ambra1-deficient melanomas to the current therapies.

Moreover, we will investigate the role of Ambra1 in regulating lipid metabolism in melanoma, which has recently been shown to profoundly affect its progression. Additionally, our aim is to assess the prognostic relevance of AMBRA1 in human cohorts of melanoma patients and understand whether AMBRA1 expression correlates with disease progression and whether it influences treatment.

Outcomes from this project will pave the way for novel clinical insight into the prognosis and treatment of melanoma patients.

This project is co-supported by a Young Investigator award from the Melanoma Research Alliance (MRA) in the USA of 224,500 USD (https://www.curemelanoma.org/research/grants/).

Novel quorum sensing inhibitors for anti-virulence treatment of skin infections caused by pathogenic Gram-positive bacteria

Grantee: Professor Christian Adam Olsen, Department of Drug Design and Pharmacology, University of Copenhagen

Amount: DKK 2,110,500

Grant category: Research grants in open competition

Year: 2019

Geography: Denmark

Staphylococcal bacteria are the most common cause of skin and soft tissue infections (SSTI) and with the rise of methicillin-resistant Staphylococcus aureus (MRSA) minor infections can lead to severe medical conditions.

The increasing antibiotic resistance development demands the search for alternative medicines with differing profiles ranging from prophylactic treatment of small infections to combating life-threatening conditions.

In the present project, we aim to inhibit this quorum sensing through a novel concept and thereby develop pan-staphylococcal inhibitors that are capable of treating the virulence in skin infections without the use of antibiotics.

Targeting the virulence of a bacterial infection rather than the viability of the pathogen represents such an alternative, because it increases the chance of clearance through the human immune system and attenuates disease symptoms while minimizing the risk of emerging resistance.

The expression of virulence factors in Gram-positive bacteria, including staphylococci, is regulated through quorum sensing (QS), which is a mechanism that allows bacteria to change gene expression in response to cell density.

This cell-to-cell communication is mediated by the secretion and detection of molecules termed autoinducing peptides (AIPs).