Institute of Hygiene and Medical Microbiology

303002, 303013, 303015, 303020,301902,106024

antifungal resistance, complement, dendritic cells, fungal pathogens, hygiene, immunity, infectious diseases, N-chlorotaurine, nosocomial infections, and one health

Understanding infections: from pathogenesis to diagnosis

• Tasks comprise research, teaching, laboratory diagnosis of infectious diseases, hospital services and technical hygiene.
• Scientific activities cover fungal pathogenicity, antifungal resistance, virulence factors, host pathogen-interactions, basic immunological research, fungal carcinogenesis, antimicrobial agents, prevention of nosocomial infections.
• HMM seeks to prevent illness and death from targeted infectious disease threats.

Infectious diseases are turning into one of the most frequent causes of death in the world. Understanding the biological principles underlying the mechanisms by which infectious agents adapt and undermine the host defence mechanisms is critical for fighting diseases. HMM is conducting basic and translational research into the molecular mechanisms of the pathogenesis of bacterial, viral and fungal infections and investigating strategies for their prophylaxis and therapy. HMM is bridging the gap between basic and translational research on microbial pathogenesis. Its mission is to coordinate and strategically align translational infection research with the aim of developing new diagnostic, preventative and therapeutic methods to treat infectious diseases. HMM has formed thematic translational units of scientists, each dedicated to a specific pathogen or infectious disease. HMM is one of the largest microbiology diagnostic laboratories in Austria, with an average sample throughput of 250,000 specimens per year. The Institute is associated with all major hospitals in Tyrol, giving it a key position in the diagnostic laboratory landscape in Austria. The group of Wilfried Posch is working on “Exploiting immune response”, while the groups of Michaela Lackner and Cornelia Lass-Flörl are investigating fungal infections, together with Cornelia Speth and Ulrike Binder. Markus Nagl’s main focus is on “N-chlorotaurine”.

Understanding fungal infections: from risk factors and diagnosis to antifungal treatment

Cornelia Lass-Flörl, Ulrike Binder, Roya Vahedi-Shahandashti

Fungal infections represent a significant and growing public health challenge, especially as they are increasingly affecting immunocompromised individuals, such as those with cancer and organ transplantation. The infections can range from superficial to life-threatening, making timely and accurate diagnosis essential for effective treatment. The increasing prevalence of invasive fungal infections (IFIs) and the rise of antifungal resistance highlight the importance of a multifaceted approach to understanding and managing fungal diseases.

Advances in antifungal therapies, including newer drugs such as ibrexafungerp, fosmanogepix and rezafungin, offer potential improvements in efficacy, pharmacokinetics and safety profiles over older agents. It is hoped that the new drugs will address the growing challenge of antifungal resistance, providing more options for treatment, especially in patients with resistant infections. Our ongoing development of antifungal agents continues to focus on broadening spectrum activity, reducing toxicity and improving patient outcomes.

Our group has focused on the epidemiology, diagnosis, prevention and therapy of fungal infections as well as on optimizing the testing for antifungal susceptibility. Understanding the pathogen and why it can cause infection is key to combating disease. We need new in vivo models to study topics such as the role of particular genes in virulence or to test the efficacy of novel antifungal drugs,. In recent years, we have optimized and extensively used the infection model Galleria mellonella in studies of fungal pathogenicity, establishment of disease and the efficacy of new antifungal drugs. We placed a particular emphasis on Mucorales, as the factors and molecular mechanisms that confer virulence, immune evasion and antifungal efficacy are still poorly understood in this group of fungi. With the generation of bioluminescent reporter strains and the simultaneous deletion of genes that may be necessary for virulence, we have another tool available to investigate the onset of infection and the efficacy of antifungal drugs. As pathogenic fungi are increasingly developing resistance to current treatments, and as the current drugs exhibit very high toxicity in humans, there is an urgent need for novel, better drugs. We are currently screening modified antifungal agents in alternative test systems and selecting promising candidates for further analysis. We are also using the luciferase system as an in vivo tool to monitor gene transcription and are focusing on rare moulds as well as on Aspergillus terreus.

Fungal carcinogenesis

Cornelia Speth

Microbe-associated tumorigenesis is a fairly new research area that may open new therapeutic approaches, particularly for tumour types with a poor prognosis. In collaboration with the departments of Surgery and Pathology, the Speth group is focusing on three aspects of fungus-associated carcinogenesis: (1) the detection, identification and quantification of fungi in a selected spectrum of tumour types, combining a range of methods (FISH, PCR, IHC, staining methods); (2) a detailed investigation of the Malassezia-complement interaction to understand how fungi and fungus-induced inflammation might contribute to pancreatic cancer; a knowledge of the molecular processes is the prerequisite for an immune-based therapy that targets the excessive complement activation, and (3) a study of the possibility to eradicate the fungus by optimising antimycotic therapeutic regimens, by investigating the influence of cytostatic drugs on fungal viability and by testing strategies for immunotherapy against the fungus (e.g. CAR-T cells). We are testing these eradication possibilities for Malassezia as well as for other fungal species that might contribute to carcinogenesis.

Targeting Antifungal Resistance from a One Health Perspective

Michaela Lackner

Our research integrates a One Health perspective, emphasizing the interconnected health of humans, animals and the environment. Antifungal agents are widely used in agriculture and medicine, creating overlapping pressures that drive resistance. Understanding the dynamics is essential to mitigating the impact of resistance on clinical outcomes, animal health and ecosystems. In the innovative PhD training course MYCOS, established in 2024 by Lackner and funded by the MUI, we are focusing on antifungal resistance

, addressing the consequences of dual antifungal use and ensuring the sustainability of effective treatments. This holistic approach is critical for combating resistance, protecting public health and preserving environmental balance. As part of the effort, Lackner and her team are deciphering the molecular basis of antifungal resistance to advance drug discovery and development, with a particular emphasis on azole drugs. Azoles target the cytochrome P450 enzyme sterol 14α-demethylase (SDM), which is essential in fungal ergosterol biosynthesis. Resistance mechanisms include efflux pump upregulation, SDM overexpression and ligand-binding pocket modifications. They compromise drug efficacy by altering binding interactions.

We are using Saccharomyces cerevisiae as a heterologous expression system to study the mechanisms, using techniques such as fluorescence microscopy, enzyme assays and crystal structure analysis. We are hoping to develop broad-spectrum azoles with stronger binding affinities, enhanced specificity and reduced resistance and toxicity.

Exploiting the Immune Response

Infection and immunity of emerging pathogens in disease-on-chip models

Wilfried Posch

The research group led by Wilfried Posch is focusing on antigen-presenting cells (e.g. dendritic cells (DCs), macrophages) and innate humoral components (e.g. complement) and their interactions with emerging pathogens at barrier sites. The team is investigating the entry mechanisms of various pathogens, including HIV, respiratory viruses, Aspergillus and Candida, and using co-infection models to understand how tissue environments and opsonization patterns influence inflammatory and immune responses. Opsonization severely affects DC functions, such as maturation, anti-viral immunity, T-cell stimulation and activation of restriction factors. The group recently received funding from the FWF to investigate the involvement of cellular complement in the processes, extending the exploration of the role of complement in immune responses upon microbial infection.

Posch oversees a team of MDs from the Institute’s routine diagnostic unit, dedicated to advancing translational and diagnostic research in emerging infectious diseases. The efforts focus on translating basic research into clinical applications, utilizing molecular diagnostics and therapeutic innovations to enhance pathogen detection, treatment and prevention, thereby bolstering global health security and pandemic preparedness. Since the onset of the COVID-19 pandemic, the group has expanded its research to study emerging pathogens such as SARS-CoV-2, focusing on immunity in patients with varying disease severities and responses to vaccines or treatment. The group has analysed both humoral and cellular immunity across patient cohorts, emphasizing neutralization abilities and T-cell specificities against different variants. The studies also compared mucosal immunity and antibody titres in vaccinated and convalescent individuals, revealing differences based on immunization regimens. In addition, we are investigating immune cell crosstalk within mucosal tissues within the CONNECT PhD research training network, funded in December 2022 by the MUI and coordinated by Wilfried Posch. The Posch group has developed and standardized complex human cell culture models, including 3D barrier models and interconnected microphysiological systems, to mimic in vivo conditions and enable the detailed analysis of infection, inflammation, tissue damage and therapeutic targets. Utilizing these immunocompetent 3D models, the group has also explored personalized approaches to studying infection and immunity, allowing rapid responses to emerging infections.

N-chlorotaurine

 Markus Nagl

We have synthesized the sodium salt of N-chlorotaurine (NCT), a long-lived oxidant produced by activated human leukocytes, and are investigating it as a new antiseptic for the topical treatment of infections of multiple body regions, including sensitive ones. We are undertaking basic research on its microbicidal activity against emerging pathogens such as mucormycetes and viruses, and its bactericidal activity against planctonic forms and biofilms in surgery and dentistry. In vivo investigations cover the bronchopulmonary system (mechanisms of efficacy of inhaled NCT in mouse fungal pneumonia supported by the FWF; future confirmatory phase II inhalation of NCT in chronic pulmonary diseases such as cystic fibrosis and COPD and acute viral infections planned) and various other topical applications, such as the skin and mucous membranes, the ear-nose-throat region, the urinary tract, the eye and organ abscesses. The advantages of NCT include its high tolerability, a broad spectrum of activity against all strains of pathogens without inducing resistance, the inactivation of virulence factors of pathogens, the enhancement of microbicidal activity in the presence of body fluids and its anti-inflammatory effects.

Laboratory Diagnostics, Hospital and Technical Hygiene

The HMM division fulfils its tasks in the detection and identification of pathogens that cause infections. The work covers bacteriology, parasitology, mycobacteriology and mycology. The diagnostic laboratories are certified according to ISO 9001:2009. Some areas are checked by external audits in accordance with §67 of the Austrian Medicines Law and the FDA, Manufacturing and Product Quality division. The sector of hospital and technical hygiene (accredited under ISO/IEC 17025 and ISO/IEC 17020) is developing guidelines for the prevention of infectious diseases and controlling them in line with the statutory requirements for technical facilities (e.g. disinfection machines).

Lass-Flörl C, Kanj SS, Govender NP, Thompson GR 3rd, Ostrosky-Zeichner L, Govrins MA (2024)

Invasive candidiasis. Nat Rev Dis Primers 10(1):20.

Bellotti R, Speth C, Adolph TE, Lass-Flörl C, Effenberger M, Öfner D, Maglione M (2021)

Micro- and Mycobiota Dysbiosis in Pancreatic Ductal Adenocarcinoma Development

Cancers (Basel). 2021 Jul 8;13(14):3431. doi: 10.3390/cancers13143431. PMID: 34298645

Toepfer S, Lackner M, Keniya MV, Monk BC. Functional Expression of Recombinant Candida auris Proteins in Saccharomyces cerevisiae Enables Azole Susceptibility Evaluation and Drug Discovery. J Fungi (Basel). 2023 Jan 27;9(2):168. doi: 10.3390/jof9020168. PMID: 36836283

Diem G, Lafon E, Bauer A, Lass-Flörl C, Reindl M, Wilflingseder D, Posch W. Salivary IgAs and Their Role in Mucosal Neutralization of SARS-CoV-2 Variants of Concern. J Clin Microbiol. 2022 Sep 21;60(9):e0106522. doi: 10.1128/jcm.01065-22. Epub 2022 Aug 29. PMID: 36036600

Kowalczyk K, Coraça-Huber DC, Wille-Kolmar W, Berktold M and Nagl M. Activity of N-chlorotaurine against periodontal pathogens. Int J Mol Sci. 2024 Jul 30; 25(15): 8357. doi: 10.3390/ijms25158357. PMID: 39125925

• CD-Labor für Invasive Pilzinfektionen; 2015-2022
• FWF, Doctoral programme of excellence, “HOROS”, ZFW012530, Host response in opportunistic infections, 2014-2023
• EU, Horizon2020, Marie Sklodowska Curie Action European Joint Doctorate “CORVOS”, 860044, Complement regulation & variations in opportunistic infections. 2019-2024

• FWF-Einzelprojekt P32329 Titel: Primäre Azoleresistenz in Mucormyzeten; 2019-2024
• MUI-Prototypenförderung 2022 Titel: SolNail; 2023
• FWF P33510: HIV-C entflieht Restriktion, nicht Sensing in DCs; 2020-2024
• FWF P34070: Treating SARS-CoV-2 infection in human 3D respiratory models; 2020-2024
• FWF P32329-B: Intrinsic azole resistance in mucormycetes; 2019-2023
• Fungal Dysbiosis in Pancreatic Ductal Adenocarcinoma Progression – The crosstalk with tumor microenvironment and its clinical implications. In Memoriam Dr. Gabriel Salzner Privatstiftung; 2021-2023
• FWF-Einzelprojekt P36922: Malassezia-induced immune-environment of pancreatic ductal adenocarcinoma; 2023-2026
• FWF-Einzelprojekt PAT7129523; 2025-2028: NCT for therapy and prophylaxis of airborne mycoses

Peter Garred, HOROS Guest Professor, Rikshospitalet, University of Copenhagen, Denmark

Maurizio Brigotti, University of Bologna, Italy

Brian Monk, Department of Oral Sciences, Division of Health Sciences, University of Otago, Dunedin, New Zealand

Erwin Lamping, Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand

Oliver T. Keppler, Ludwig-Maximilians-Universität München, Munich, Germany

Teunis BH Geijtenbeek, Amsterdam UMC, Amsterdam Institute for Infection & Immunity, Amsterdam, The Netherlands

Oliver Cornely, Klinik I für Innere Medizin, Uniklinik Köln, Köln, Germany

Carsten Schwarz, CF Center Westbrandenburg, Campus Potsdam, Potsdam, Germany