Manganese acquisition is essential for virulence of Enterococcus faecalis
| Autor: | Kristi L. Frank, Scott J. Hultgren, José A. Lemos, Aaron J L Lynch, Todd Kitten, Shannon P. Baker, Ana L. Flores-Mireles, Cristina Colomer-Winter |
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| Rok vydání: | 2019 |
| Předmět: |
Bacterial Diseases
0301 basic medicine Physiology Host Defense Mechanism Urine Moths FOS: Health sciences Pathology and Laboratory Medicine Mice Medicine and Health Sciences Enterococcus faecalis lcsh:QH301-705.5 Cation Transport Proteins Mammals 0303 health sciences Virulence biology Eukaryota 60303 Biological Adaptation Animal Models Bacterial Pathogens Body Fluids Mutant Strains Chemistry Infectious Diseases Experimental Organism Systems Medical Microbiology Metals Physical Sciences Vertebrates Urinary Tract Infections Leporids Rabbits Pathogens Anatomy Research Article Biotechnology Chemical Elements lcsh:Immunologic diseases. Allergy Catheters Bladder 030106 microbiology Immunology Research and Analysis Methods Microbiology 60104 Cell Metabolism 03 medical and health sciences Bacterial Proteins 60503 Microbial Genetics Immunity Virology Enterococcus Infections Genetics Animals Humans Microbial Pathogens Molecular Biology Gram-Positive Bacterial Infections 030304 developmental biology Manganese Bacteria 030306 microbiology Permease FOS: Clinical medicine Organisms Biology and Life Sciences Renal System Endocarditis Bacterial biology.organism_classification Disease Models Animal lcsh:Biology (General) Biofilms Catheter-Related Infections FOS: Biological sciences Mutation Amniotes 110309 Infectious Diseases Medical Devices and Equipment ATP-Binding Cassette Transporters Parasitology Calprotectin lcsh:RC581-607 Leukocyte L1 Antigen Complex Enterococcus Ex vivo 60501 Bacteriology |
| Zdroj: | PLoS Pathogens PLoS Pathogens, Vol 14, Iss 9, p e1007102 (2018) |
| DOI: | 10.25376/hra.7804589.v1 |
| Popis: | Manganese (Mn) is an essential micronutrient that is not readily available to pathogens during infection due to an active host defense mechanism known as nutritional immunity. To overcome this nutrient restriction, bacteria utilize high-affinity transporters that allow them to compete with host metal-binding proteins. Despite the established role of Mn in bacterial pathogenesis, little is known about the relevance of Mn in the pathophysiology of E. faecalis. Here, we identified and characterized the major Mn acquisition systems of E. faecalis. We discovered that the ABC-type permease EfaCBA and two Nramp-type transporters, named MntH1 and MntH2, work collectively to promote cell growth under Mn-restricted conditions. The simultaneous inactivation of EfaCBA, MntH1 and MntH2 (ΔefaΔmntH1ΔmntH2 strain) led to drastic reductions (>95%) in cellular Mn content, severe growth defects in body fluids (serum and urine) ex vivo, significant loss of virulence in Galleria mellonella, and virtually complete loss of virulence in rabbit endocarditis and murine catheter-associated urinary tract infection (CAUTI) models. Despite the functional redundancy of EfaCBA, MntH1 and MntH2 under in vitro or ex vivo conditions and in the invertebrate model, dual inactivation of efaCBA and mntH2 (ΔefaΔmntH2 strain) was sufficient to prompt maximal sensitivity to calprotectin, a Mn- and Zn-chelating host antimicrobial protein, and for the loss of virulence in mammalian models. Interestingly, EfaCBA appears to play a prominent role during systemic infection, whereas MntH2 was more important during CAUTI. The different roles of EfaCBA and MntH2 in these sites could be attributed, at least in part, to the differential expression of efaA and mntH2 in cells isolated from hearts or from bladders. Collectively, this study demonstrates that Mn acquisition is essential for the pathogenesis of E. faecalis and validates Mn uptake systems as promising targets for the development of new antimicrobials. Author summary Enterococcus faecalis is a leading cause of hospital-acquired infections that are often difficult to treat due to their exceptional multidrug resistance. Manganese (Mn) is an essential micronutrient for bacterial pathogens during infection. To prevent infection, the host limits Mn bioavailability to invading bacteria in an active process known as nutritional immunity. To overcome this limitation, bacteria produce high-affinity Mn uptake systems to scavenge Mn from host tissues. Here, we identified the main Mn transporters of E. faecalis and show that, by working collectively, they are essential for growth of this opportunistic pathogen in Mn-restricted environments. Notably, the inability to acquire Mn during infection rendered E. faecalis virtually avirulent in different animal models, thereby revealing the essentiality of Mn acquisition to enterococcal pathogenesis. The results reported here highlight that bacterial Mn transport systems are promising targets for the development of novel antimicrobial therapies, which are expected to be particularly powerful to combat enterococcal infections. |
| Databáze: | OpenAIRE |
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