Sanjeevan Jahagirdar1, Lorna Morris2, Nirupama Benis1,3, Oddvar Oppegaard4, Mattias Svenson5, Ole Hyldegaard6,7, Steinar Skrede4,8, Anna Norrby-Teglund5, Vitor A P Martins Dos Santos1,2, Edoardo Saccenti9. 1. Laboratory of Systems and Synthetic Biology, Wageningen University & Research, Stippeneng 4, 6708, WE, Wageningen, the Netherlands. 2. Lifeglimmer GmbH, Markelstraße 38, 12163, Berlin, Germany. 3. Present affiliation: Department of Medical Informatics, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, Netherlands. 4. Department of Medicine, Division for infectious diseases, Haukeland University Hospital, Bergen, Norway. 5. Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden. 6. Department of Anesthesia, Centre of Head and Orthopaedics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. 7. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. 8. Department of Clinical Science, University of Bergen, Bergen, Norway. 9. Laboratory of Systems and Synthetic Biology, Wageningen University & Research, Stippeneng 4, 6708, WE, Wageningen, the Netherlands. edoardo.saccenti@wur.nl.
Abstract
BACKGROUND: Necrotising soft tissue infections (NSTIs) are rapidly progressing bacterial infections usually caused by either several pathogens in unison (polymicrobial infections) or Streptococcus pyogenes (mono-microbial infection). These infections are rare and are associated with high mortality rates. However, the underlying pathogenic mechanisms in this heterogeneous group remain elusive. METHODS: In this study, we built interactomes at both the population and individual levels consisting of host-pathogen interactions inferred from dual RNA-Seq gene transcriptomic profiles of the biopsies from NSTI patients. RESULTS: NSTI type-specific responses in the host were uncovered. The S. pyogenes mono-microbial subnetwork was enriched with host genes annotated with involved in cytokine production and regulation of response to stress. The polymicrobial network consisted of several significant associations between different species (S. pyogenes, Porphyromonas asaccharolytica and Escherichia coli) and host genes. The host genes associated with S. pyogenes in this subnetwork were characterised by cellular response to cytokines. We further found several virulence factors including hyaluronan synthase, Sic1, Isp, SagF, SagG, ScfAB-operon, Fba and genes upstream and downstream of EndoS along with bacterial housekeeping genes interacting with the human stress and immune response in various subnetworks between host and pathogen. CONCLUSIONS: At the population level, we found aetiology-dependent responses showing the potential modes of entry and immune evasion strategies employed by S. pyogenes, congruent with general cellular processes such as differentiation and proliferation. After stratifying the patients based on the subject-specific networks to study the patient-specific response, we observed different patient groups with different collagens, cytoskeleton and actin monomers in association with virulence factors, immunogenic proteins and housekeeping genes which we utilised to postulate differing modes of entry and immune evasion for different bacteria in relationship to the patients' phenotype.
BACKGROUND: Necrotising soft tissue infections (NSTIs) are rapidly progressing bacterial infections usually caused by either several pathogens in unison (polymicrobial infections) or Streptococcus pyogenes (mono-microbial infection). These infections are rare and are associated with high mortality rates. However, the underlying pathogenic mechanisms in this heterogeneous group remain elusive. METHODS: In this study, we built interactomes at both the population and individual levels consisting of host-pathogen interactions inferred from dual RNA-Seq gene transcriptomic profiles of the biopsies from NSTI patients. RESULTS: NSTI type-specific responses in the host were uncovered. The S. pyogenes mono-microbial subnetwork was enriched with host genes annotated with involved in cytokine production and regulation of response to stress. The polymicrobial network consisted of several significant associations between different species (S. pyogenes, Porphyromonas asaccharolytica and Escherichia coli) and host genes. The host genes associated with S. pyogenes in this subnetwork were characterised by cellular response to cytokines. We further found several virulence factors including hyaluronan synthase, Sic1, Isp, SagF, SagG, ScfAB-operon, Fba and genes upstream and downstream of EndoS along with bacterial housekeeping genes interacting with the human stress and immune response in various subnetworks between host and pathogen. CONCLUSIONS: At the population level, we found aetiology-dependent responses showing the potential modes of entry and immune evasion strategies employed by S. pyogenes, congruent with general cellular processes such as differentiation and proliferation. After stratifying the patients based on the subject-specific networks to study the patient-specific response, we observed different patient groups with different collagens, cytoskeleton and actin monomers in association with virulence factors, immunogenic proteins and housekeeping genes which we utilised to postulate differing modes of entry and immune evasion for different bacteria in relationship to the patients' phenotype.
Authors: Suado M Abdillahi; Tobias Maaß; Gopinath Kasetty; Adam A Strömstedt; Maria Baumgarten; Ramesh Tati; Sara L Nordin; Björn Walse; Raimund Wagener; Artur Schmidtchen; Matthias Mörgelin Journal: J Immunol Date: 2018-06-20 Impact factor: 5.422
Authors: Massimo Sartelli; Xavier Guirao; Timothy C Hardcastle; Yoram Kluger; Marja A Boermeester; Kemal Raşa; Luca Ansaloni; Federico Coccolini; Philippe Montravers; Fikri M Abu-Zidan; Michele Bartoletti; Matteo Bassetti; Offir Ben-Ishay; Walter L Biffl; Osvaldo Chiara; Massimo Chiarugi; Raul Coimbra; Francesco Giuseppe De Rosa; Belinda De Simone; Salomone Di Saverio; Maddalena Giannella; George Gkiokas; Vladimir Khokha; Francesco M Labricciosa; Ari Leppäniemi; Andrey Litvin; Ernest E Moore; Ionut Negoi; Leonardo Pagani; Maddalena Peghin; Edoardo Picetti; Tadeja Pintar; Guntars Pupelis; Ines Rubio-Perez; Boris Sakakushev; Helmut Segovia-Lohse; Gabriele Sganga; Vishal Shelat; Michael Sugrue; Antonio Tarasconi; Cristian Tranà; Jan Ulrych; Pierluigi Viale; Fausto Catena Journal: World J Emerg Surg Date: 2018-12-14 Impact factor: 5.469
Authors: Robert Thänert; Andreas Itzek; Jörn Hoßmann; Domenica Hamisch; Martin Bruun Madsen; Ole Hyldegaard; Steinar Skrede; Trond Bruun; Anna Norrby-Teglund; Eva Medina; Dietmar H Pieper Journal: Nat Commun Date: 2019-08-26 Impact factor: 14.919