학술논문
Identification of novel targets for host-directed therapeutics against intracellular Staphylococcus aureus.
Document Type
Academic Journal
Author
Bravo-Santano N; Health Sciences Research Centre, University of Roehampton, London, UK.; Capilla-Lasheras P; Centre for Ecology and Conservation, University of Exeter, Penryn Campus, Cornwall, UK.; Mateos LM; Department of Molecular Biology, Area of Microbiology, University of León, León, Spain.; Calle Y; Health Sciences Research Centre, University of Roehampton, London, UK.; Behrends V; Health Sciences Research Centre, University of Roehampton, London, UK. Volker.Behrends@roehampton.ac.uk.; Letek M; Health Sciences Research Centre, University of Roehampton, London, UK. Michal.Letek@roehampton.ac.uk.
Source
Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
Subject
Language
English
Abstract
During patient colonization, Staphylococcus aureus is able to invade and proliferate within human cells to evade the immune system and last resort drugs such as vancomycin. Hijacking specific host molecular factors and/or pathways is necessary for pathogens to successfully establish an intracellular infection. In this study, we employed an unbiased shRNA screening coupled with ultra-fast sequencing to screen 16,000 human genes during S. aureus infection and we identified several host genes important for this intracellular pathogen. In addition, we interrogated our screening results to find novel host-targeted therapeutics against intracellular S. aureus. We found that silencing the human gene TRAM2 resulted in a significant reduction of intracellular bacterial load while host cell viability was restored, showing its importance during intracellular infection. Furthermore, TRAM2 is an interactive partner of the endoplasmic reticulum SERCA pumps and treatment with the SERCA-inhibitor Thapsigargin halted intracellular MRSA survival. Our results suggest that Thapsigargin could be repurposed to tackle S. aureus host cell infection in combination with conventional antibiotics.