Complexity of viral, fungal and bacterial infections in immunocompromised patients, and subclonal architecture of Ph-positive leukemias.
Research, development (R&D) and diagnostics in the field of microbiology and myeloid leukemias are the major areas of activity in the Division Molecular Microbiology established in 1989. The exploitation of diagnostic assays emanating from our R&D work and the performance of specific developmental tasks were transferred to Labdia Labordiagnostik, a non-profit institution established in 2006 as a subsidiary of the St.Anna Children´s Cancer Research Organization. A major part of our work is focused on infectious problems in oncological patients undergoing allogeneic stem cell transplantation (allo-SCT) or chemotherapy. In addition to bacteria, viral and fungal pathogens are particularly frequent causes of life-threatening infections in severely immunocompromised children. Early and reliable diagnosis is an essential prerequisite for successful therapy. We have therefore developed and, in part, patented quantitative molecular detection assays for many pathogenic viruses and clinically relevant fungal species. We were able to demonstrate that the clinical implementation of various methods developed in our division permits early assessment of impending infectious complications and provides a basis for optimized diagnostics (Landlinger et al. Leukemia 2010; Lion et al. Leukemia 2010; Czurda et al. J Clin Microbiol. 2016, 54(1):148-52; Czurda et al. Methods Mol Biol. 2017;1508:257-266; Nogueira et al. J Microbiol Modern Tech 2017; 2(1): 101). The new diagnostic approaches will therefore contribute to improved treatment strategies against life-threatening infections in severely immunocompromised patients. Moreover, we have studied the patterns of persistence and reactivation of adenoviruses, and developed the basis for novel diagnostic and therapeutic strategies for invasive infections which can lead to very severe diseases, particularly in children undergoing allo-SCT (Kneidinger et al. Antiviral Res 2012; Ibrisimovic et al. Antiviral Res 2012 und J Gene Med 2012; Lion T.Clin Microbiol Rev. 2014, 27(3):441-62; Bellutti et al. J Virol. 2015, 89(3):1608-27; Kosulin et al. Clin Microbiol Infect. 2016, 22(4):381.e1-381.e8; Kosulin et al. J Clin Virol. 2016, 80:60-1; Kosulin et al. J Clin Virol. 2016,85:31-36; Kosulin et al. EBioMedicine. 2018 Feb;28:114-119). More recently, we have started studying the interactions between bacteria and fungi, in order to better understand the complexity of infections in immunocompromised patients, and to pave the way for improved diagnostics and treatment. We have demonstrated that the important bacterial pathogen Klebsiella peumoniae inhibits the growth of various fungi. The inhibition is reversible, and fungal growth is re-established upon eliminating the bacteria (Nogueira et al. Scientific Reports. 2018, in press). This observation is of clinical importance because in such instances antibacterial treatment may rapidly unleash fungal growth requiring timely identification and treatment. This example illustrates the potential impact of bacterial-fungal interactions, which represent an essential component of processes occurring within the human microbiome, and emphasizes the need for the identification of novel pertinent biomarkers. An additional focus of our activities is the development of targeted diagnostics in patients after allo-SCT. A European project coordinated by our center has led to the establishment of a standardized methodology for quantitative analysis of patient- and donor-derived cells (chimerism) (Lion et al. Leukemia 2012). The patented technique was exploited to establish a commercially available diagnostic kit. Moreover, we have established diagnostic approaches facilitating early prediction of graft rejection and other complications which will permit timely therapeutic interventions (Breuer et al. Leukemia 2012; Preuner et al. Methods Mol Biol. 2014;1109:271-91; Preuner et al. Haematologica. 2016 Jun;101(6):741-6). Our development and clinical implementation of molecular techniques for the surveillance of mutant, therapy-resistant subclones in patients with chronic myeloid leukemia (CML) provided important information on clonal development of the disease, timely detection of resistance, and clone-specific responses to treatment (Preuner et al. Leukemia 2008; Preuner et al. EJC 2012; Preuner et al. Int J Mol Sci. 2016, 29;17(5):E642). The new insights facilitated ensuing research aimed at improving our understanding of the pathogenesis of this type of leukemia within a long-term project (Special Research Area Program-SFB) funded by the Austrian Science Fund. The results emanating from this work provided important information on the principles of resistance and improved diagnostic approaches in CML and other types of leukemia (Kastner et al. Eur J Cancer. 2014, 50(4):793-800; Preuner et al. J Mol Diagn. 2014, 16(4):459-66; Byrgazov K et al. Oncotarget. 2016, 22;7(47):78083-78094; Byrgazov K et al. Leukemia. 2017 Jan;31(1):237-240; Byrgazov K et al. Haematologica. 2018 Jan;103(1):e10-e12).
- Hiwarkar P, Kosulin K, Cesaro S, Mikulska M, Styczynski J, Wynn R, Lion T. (2018) Management of adenovirus infection in patients after haematopoietic stem cell transplantation: State-of-the-art and real-life current approach: A position statement on behalf of the Infectious Diseases Working Party of the European Society of Blood and Marrow Transplantation. Rev Med Virol. May;28(3):e1980
- Kosulin K, Berkowitsch B, Matthes S, Pichler H, Lawitschka A, Pötschger U, Fritsch G, Lion T. (2018) Intestinal Adenovirus Shedding Before Allogeneic Stem Cell Transplantation Is a Risk Factor for Invasive Infection Post-transplant. EBioMedicine. Feb;28:114-119 Byrgazov K, Lucini CB, Valent P, Hantschel O, Lion T. (2018) BCR-ABL1 compound mutants display differential and dose-dependent responses to ponatinib. Haematologica. 103(1):e10-e12
- Byrgazov K, Kastner R, Gorna M, Hoermann G, Koenig M, Lucini CB, Ulreich R, Benesch M, Strenger V, Lackner H, Schwinger W, Sovinz P, Haas OA, van den Heuvel-Eibrink M, Niemeyer CM, Hantschel O, Valent P, Superti-Furga G, Urban C, Dworzak MN, Lion T. (2017) NDEL1-PDGFRB fusion gene in a myeloid malignancy with eosinophilia associated with resistance to tyrosine kinase inhibitors. Leukemia. Jan;31(1):237-240
- Preuner S, Peters C, Pötschger U, Daxberger H, Fritsch G, Geyeregger R, Schrauder A, von Stackelberg A, Schrappe M, Bader P, Ebell W, Eckert C, Lang P, Sykora KW, Schrum J, Kremens B, Ehlert K, Albert MH, Meisel R, Lawitschka A, Mann G, Panzer-Grümayer R, Güngör T, Holter W, Strahm B, Gruhn B, Schulz A, Woessmann W, Lion T. (2016) Risk assessment of relapse by lineage-specific monitoring of chimerism in children undergoing allogeneic stem cell transplantation for acute lymphoblastic leukemia. Haematologica. 101(6):741-6
Research Team Molecular Microbiology
Research Team Molecular Microbiology
Diagnostics Team Molecular Microbiology
Sabine Breuer, MD Christofer Diakos, MD Gernot Engstler, MD Assoc. Prof. Leo Kager, MD Hubert Kogler, MD Anita Lawitschka, MD Herbert Pichler, MD Andreas Vécsei, MD Natalia Zubarovskaya, MD