TY - JOUR A1 - Remmele, Christian W. A1 - Luther, Christian H. A1 - Balkenhol, Johannes A1 - Dandekar, Thomas A1 - Müller, Tobias A1 - Dittrich, Marcus T. T1 - Integrated inference and evaluation of host-fungi interaction networks JF - Frontiers in Microbiology N2 - Fungal microorganisms frequently lead to life-threatening infections. Within this group of pathogens, the commensal Candida albicans and the filamentous fungus Aspergillus fumigatus are by far the most important causes of invasive mycoses in Europe. A key capability for host invasion and immune response evasion are specific molecular interactions between the fungal pathogen and its human host. Experimentally validated knowledge about these crucial interactions is rare in literature and even specialized host pathogen databases mainly focus on bacterial and viral interactions whereas information on fungi is still sparse. To establish large-scale host fungi interaction networks on a systems biology scale, we develop an extended inference approach based on protein orthology and data on gene functions. Using human and yeast intraspecies networks as template, we derive a large network of pathogen host interactions (PHI). Rigorous filtering and refinement steps based on cellular localization and pathogenicity information of predicted interactors yield a primary scaffold of fungi human and fungi mouse interaction networks. Specific enrichment of known pathogenicity-relevant genes indicates the biological relevance of the predicted PHI. A detailed inspection of functionally relevant subnetworks reveals novel host fungal interaction candidates such as the Candida virulence factor PLB1 and the anti-fungal host protein APP. Our results demonstrate the applicability of interolog-based prediction methods for host fungi interactions and underline the importance of filtering and refinement steps to attain biologically more relevant interactions. This integrated network framework can serve as a basis for future analyses of high-throughput host fungi transcriptome and proteome data. KW - candida genome database KW - computational prediction KW - potential role KW - network inference KW - bioinformatics and computational biology KW - protein interaction database KW - Aspergillus fumigatus KW - cell wall KW - functional modules KW - alzheimers disease KW - molecular cloning KW - Candida albicans KW - pathogen-host interaction (PHI) KW - protein-protein interaction KW - pathogenicity KW - interolog Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148278 VL - 6 IS - 764 ER - TY - JOUR A1 - Balkenhol, Johannes A1 - Kaltdorf, Kristin V. A1 - Mammadova-Bach, Elmina A1 - Braun, Attila A1 - Nieswandt, Bernhard A1 - Dittrich, Marcus A1 - Dandekar, Thomas T1 - Comparison of the central human and mouse platelet signaling cascade by systems biological analysis JF - BMC Genomics N2 - Background Understanding the molecular mechanisms of platelet activation and aggregation is of high interest for basic and clinical hemostasis and thrombosis research. The central platelet protein interaction network is involved in major responses to exogenous factors. This is defined by systemsbiological pathway analysis as the central regulating signaling cascade of platelets (CC). Results The CC is systematically compared here between mouse and human and major differences were found. Genetic differences were analysed comparing orthologous human and mouse genes. We next analyzed different expression levels of mRNAs. Considering 4 mouse and 7 human high-quality proteome data sets, we identified then those major mRNA expression differences (81%) which were supported by proteome data. CC is conserved regarding genetic completeness, but we observed major differences in mRNA and protein levels between both species. Looking at central interactors, human PLCB2, MMP9, BDNF, ITPR3 and SLC25A6 (always Entrez notation) show absence in all murine datasets. CC interactors GNG12, PRKCE and ADCY9 occur only in mice. Looking at the common proteins, TLN1, CALM3, PRKCB, APP, SOD2 and TIMP1 are higher abundant in human, whereas RASGRP2, ITGB2, MYL9, EIF4EBP1, ADAM17, ARRB2, CD9 and ZYX are higher abundant in mouse. Pivotal kinase SRC shows different regulation on mRNA and protein level as well as ADP receptor P2RY12. Conclusions Our results highlight species-specific differences in platelet signaling and points of specific fine-tuning in human platelets as well as murine-specific signaling differences. KW - interspecies comparison KW - transcriptome KW - proteome KW - platelet KW - network KW - signaling KW - mouse KW - human KW - interactome KW - cascade Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230377 VL - 21 ER - TY - JOUR A1 - Osmanoglu, Özge A1 - Gupta, Shishir K. A1 - Almasi, Anna A1 - Yagci, Seray A1 - Srivastava, Mugdha A1 - Araujo, Gabriel H. M. A1 - Nagy, Zoltan A1 - Balkenhol, Johannes A1 - Dandekar, Thomas T1 - Signaling network analysis reveals fostamatinib as a potential drug to control platelet hyperactivation during SARS-CoV-2 infection JF - Frontiers in Immunology N2 - Introduction Pro-thrombotic events are one of the prevalent causes of intensive care unit (ICU) admissions among COVID-19 patients, although the signaling events in the stimulated platelets are still unclear. Methods We conducted a comparative analysis of platelet transcriptome data from healthy donors, ICU, and non-ICU COVID-19 patients to elucidate these mechanisms. To surpass previous analyses, we constructed models of involved networks and control cascades by integrating a global human signaling network with transcriptome data. We investigated the control of platelet hyperactivation and the specific proteins involved. Results Our study revealed that control of the platelet network in ICU patients is significantly higher than in non-ICU patients. Non-ICU patients require control over fewer proteins for managing platelet hyperactivity compared to ICU patients. Identification of indispensable proteins highlighted key subnetworks, that are targetable for system control in COVID-19-related platelet hyperactivity. We scrutinized FDA-approved drugs targeting indispensable proteins and identified fostamatinib as a potent candidate for preventing thrombosis in COVID-19 patients. Discussion Our findings shed light on how SARS-CoV-2 efficiently affects host platelets by targeting indispensable and critical proteins involved in the control of platelet activity. We evaluated several drugs for specific control of platelet hyperactivity in ICU patients suffering from platelet hyperactivation. The focus of our approach is repurposing existing drugs for optimal control over the signaling network responsible for platelet hyperactivity in COVID-19 patients. Our study offers specific pharmacological recommendations, with drug prioritization tailored to the distinct network states observed in each patient condition. Interactive networks and detailed results can be accessed at https://fostamatinib.bioinfo-wuerz.eu/. KW - signaling network KW - controllability KW - platelet KW - SARS-CoV-2 KW - fostamatinib KW - drug repurposing KW - COVID-19 Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-354158 VL - 14 ER -