BacFun

Diagnostics and treatment of bacterial and fungal infections pose a major challenge in pediatric and adult patients with impaired immunity, including particularly patients with cancer and recipients of organ or bone marrow transplantation. Owing to the lack of rapid and reliable diagnostics, treatment of infections often relies on prophylactic or experience-based approaches. Bacteria and fungi occupy the same locations in the human body and aggregate to form so-called biofilms within which they can communicate either in mutually supportive or competitive ways. Communication can occur via production of proteins and secretion of small molecules. The interaction between bacteria and fungi in biofilms can result in increased resistance to antibiotic and antifungal treatment, and can render the microbes capable of evading the immune system. Our recent studies showed that certain bacteria can prevent fungal growth, but upon elimination of the bacteria by antibiotics, the fungi can grow and expand again. Studying how bacteria and fungi interact is therefore of major relevance for appropriate diagnostics and treatment. In the present project, we intend to i) characterize molecular interactions between the pathogens Candida and Klebsiella representative of specific niches in the human host, ii) identify small molecules governing the Candida-Klebsiella interaction as potential biomarkers and iii) characterize the host immune response to polymicrobial infections by Candida and Klebsiella. To pursue the indicated tasks, we will use laboratory techniques already established at our center to investigate how these microbes communicate, and how they evade the immune system. The indicated studies involving the analysis of specific genes, proteins and small molecules are expected to provide the experimental basis for the identification and exploitation of diagnostically useful biomarkers for bacterial-fungal infections. Improved understanding of the complex interactions between microbes affecting their biological properties will ultimately contribute to more efficient management of life- threatening invasive infections in high-risk patients.

Unravelling bacterial-fungal interactions and their impact on infection outcomes This FWF-funded project aims to deepen our understanding of bacterial-fungal interactions (BFIs) in mixed biofilms. Further, the project deciphers implications for infection severity and outcomes, particularly in the context of superinfections. Building on previous work that characterized the antagonistic relationship between Aspergillus fumigatus and Klebsiella pneumoniae (Nogueira et al., 2019), the research team took advantage of multi-omics approaches to identify significant metabolic changes, virulence factors, and potential biomarkers associated with these complex interactions. Their recent findings published in Communications Biology (Bitencourt et al., 2024) reveal that A. fumigatus undergoes substantial metabolic rewiring when facing K. pneumoniae in mixed biofilms. A shutdown of the central carbon metabolism and a shift towards alternative pathways such as the GABA shunt, are leading to the accumulation of specific metabolites that may serve as biomarkers for tracking superinfections. Furthermore, A. fumigatus reduces the activity of its translation machinery to preserve energy and to enhance adaptability in the face of bacterial competition. The full publication is available in Communications Biology, along with an in-depth discussion in the 'Behind the Paper' blog. Expanding their research, the team also examined the clinically relevant interaction between Candida albicans and K. pneumoniae, both of which are significant threats to immunocompromised patients. By conducting biofilm-based co-cultures and RNA sequencing, they identified distinct transcriptional changes that demonstrate metabolic adaptations as a key strategy for fungal survival in environments with dominant bacterial competition. Specifically, C. albicans activated stress response pathways and altered genes related to biofilm formation and dynamics. To further understand the implications of these interactions, the researchers investigated how they influence host-pathogen dynamics using macrophage co-cultures. The interactions between bacteria and fungi elicited unique immune responses that could potentially impact infection outcomes. This raises several critical questions for ongoing studies: Does C. albicans alter its virulence profile in response to infections by bacteria? How do interactions shape the immune response, exacerbate infection severity or support pathogen persistence? The research team is actively exploring these questions, with a manuscript in preparation that highlights the implications of the data. The work will enhance our understanding of infection mechanisms and offer better therapeutic strategies against complex infections involving bacterial-fungal interactions.