infection . pathogen . host-pathogen interactions . molecular diagnostics . immunopathology . immuno-oncology . drug safety
Pathology of Infectious and Immunologic Diseases
Identification of pathogens in patient tissues, analysis of host-pathogen interactions and immune responses to infections.
Microbes leave a molecular and morphological footprint in infected patient tissues which reflects immune reactions and adaptive tissue responses. Analysis of this footprint enables (1) identification of novel pathogens and accompanying superinfections in tissues, (2) descriptions of pathogen-specific tissue perturbations, (3) inferences about pathogenic mechanisms via correlation with clinical data. The analysis of host-pathogen interactions in our lab has two starting points: Patients presenting with clinical symptoms of unknown infectious etiology or confirmed cases of infections with unknown spectrum of tissue reactions. We are also interested in changes of the susceptibility of patients to infections in the context of tumors or immunomodulatory treatments. Our integrative approach combines cutting-edge molecular techniques and traditional histopathology to advance our understanding of infectious diseases, enhance diagnostic precision, and improve patient care. An integrated analysis of morphologic and molecular changes in infected tissues provides comprehensive insights of host reactions and lays the foundation for: 1. Enhanced diagnostic precision and targeted treatment by molecular profiling We use techniques such as metagenomic next-generation sequencing (mNGS) for identification of microbial communities within tissues. This enables the detection of pathogens, disease-associated changes of the microbiota, resistance factors and personalized treatment strategies. Further, tissue profiling can identify disease-associated microbial and host markers which may become diagnostic and prognostic indicators. 2. Broad-spectrum pathogen identification Metagenomic NGS enables the identification of rare emerging microorganisms that traditional culture methods cannot detect. This can uncover unexpected pathogens in tissue samples from patients with unexplained inflammatory reactions. 3. Understanding host-pathogen interactions Molecular tissue analysis can reveal how pathogens interact with host tissues and immune responses during acute and chronic infections, disease progression or resolution. This can shed light on how virulence factors of pathogens in situ contribute to immune evasion and help in the development of preventive strategies and vaccines. 4. Understanding the impact of pharmacological interventions on pathogen profiles Immunosuppressive therapies, while essential for conditions such as cancer, autoimmune diseases, and organ transplants, weaken the immune system, making patients more susceptible to infections. Specifically, these treatments can alter the body's ability to control and eliminate common and opportunistic pathogens, leading to changes in the types and behavior of infectious agents. Understanding how pharmacological interventions impact pathogen profiles is crucial for developing strategies to prevent and manage infections in immunocompromised patients. Our research group is deeply committed to advancing the mechanistic understanding of infectious diseases and the complex interactions between pathogens and the immune system. Our research focuses on host-pathogen interactions, patient susceptibility and pathogen adaptation, emphasizing the bidirectional nature of these interactions and their impact on disease and treatment. Our ultimate goal is to make a significant contribution to the fight against infectious diseases at a unique intersection between morphology, molecular pathology and microbiology, through scientific excellence and innovation.
The study of the dialogue between pathogens and tissues is pivotal for translating basic research into clinical practice. It provides critical insights into the mechanisms of disease development and progression, as well as the body's response to infections. We investigate the dynamic interactions between host tissues and pathogens, focusing on how these interactions influence both the host's immune response and the pathogen's adaptive strategies. Our research encompasses the susceptibility of patients to various pathogens and explores how pathogens evolve to survive and thrive within the host environment. This includes the development of virulence factors, mechanisms of persistence, and resistance to treatments. By understanding the complex interdependence between hosts and pathogens, we aim to uncover new insights into infection processes and identify key factors that contribute to disease severity and patient susceptibility. This knowledge is essential for developing targeted therapies and effective treatments, guiding therapy decisions, improving diagnostic methods, and designing preventive strategies. Ultimately, our research bridges the gap between bench and bedside, enhancing our ability to manage infectious diseases and improve patient outcomes.
Figure 1. Shotgun metagenomic next-generation sequencing (mNGS). The vast majority of sequence information in tissue samples (formalin-fixed paraffin-embedded, FFPE) in pathology is of human origin. Shotgun metagenomics is the untargeted sequencing of all (“meta”) microbial genomes (“genomics”) present in a sample. We discard the human reads, ending up with non-human sequence information. This unique approach is used to profile the taxonomic composition and the functional potential of microbial communities and to recover whole-genome sequences. This assay allows for the unbiased identification of bacteria, at least 10’000 DNA viruses, fungi, protozoa and parasites from FFPE samples. The pathologist can interpret the results in the tissue context. We observe the host reaction in tissues, and we can integrate morphology and the microbial patterns / pathogens that we identify with this assay. This offers endless opportunities for hypothesis-free identification of pathogens and for comprehensive profiling of the microbiome at the tissue level.