Reduced susceptibility of clinical strains of Mycobacterium tuberculosis to reactive nitrogen species promotes survival in activated macrophages

Autor: Blanka Andersson, Daniel Eklund, Hanna Woksepp, Thomas B. Schön, Maria Lerm, Jim Werngren, Olle Stendahl, Johanna Raffetseder, Jonna Idh, Mikael Mansjö, Tommy Sundqvist
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Bacterial Diseases
0301 basic medicine
Antitubercular Agents
lcsh:Medicine
Infektionsmedicin
Pathology and Laboratory Medicine
Biochemistry
Mice
White Blood Cells
chemistry.chemical_compound
Animal Cells
Medicine and Health Sciences
lcsh:Science
Cells
Cultured
Multidisciplinary
biology
Isoniazid
food and beverages
Neurochemistry
Reactive Nitrogen Species
Actinobacteria
Chemistry
Intracellular Pathogens
Infectious Diseases
Physical Sciences
Anaerobic bacteria
Cellular Types
Neurochemicals
Pathogens
Research Article
medicine.drug
Infectious Medicine
Tuberculosis
Immune Cells
Immunology
030106 microbiology
Microbial Sensitivity Tests
Anaerobic Bacteria
Nitric Oxide
Microbiology
Mycobacterium tuberculosis
03 medical and health sciences
Antibiotic resistance
Peroxynitrous Acid
Microbial Control
Drug Resistance
Bacterial
medicine
Animals
Nitrites
Reactive nitrogen species
Pharmacology
Microbial Viability
Blood Cells
Organisms
Genetically Modified
Bacteria
Macrophages
Intracellular parasite
lcsh:R
Organisms
Chemical Compounds
Biology and Life Sciences
Cell Biology
Macrophage Activation
Tropical Diseases
bacterial infections and mycoses
medicine.disease
biology.organism_classification
chemistry
Antibiotic Resistance
Pretomanid
lcsh:Q
Antimicrobial Resistance
Neuroscience
Zdroj: PLoS ONE, Vol 12, Iss 7, p e0181221 (2017)
PLoS ONE
ISSN: 1932-6203
Popis: Background Drugs such as isoniazid (INH) and pretomanid (PRT), used against Mycobacterium tuberculosis are active partly through generation of reactive nitrogen species (RNS). The aim of this study was to explore variability in intracellular susceptibility to nitric oxide (NO) in clinical strains of M. tuberculosis. Method Luciferase-expressing clinical M. tuberculosis strains with or without INH resistance were exposed to RNS donors (DETA/NO and SIN-1) in broth cultures and bacterial survival was analysed by luminometry. NO-dependent intracellular killing in a selection of strains was assessed in interferon gamma/lipopolysaccharide-activated murine macrophages using the NO inhibitor L-NMMA. Results When M. tuberculosis H37Rv was compared to six clinical isolates and CDC1551, three isolates with inhA mediated INH resistance showed significantly reduced NO-susceptibility in broth culture. All strains showed a variable but dose-dependent susceptibility to RNS donors. Two clinical isolates with increased susceptibility to NO exposure in broth compared to H37Rv were significantly inhibited by activated macrophages whereas there was no effect on growth inhibition when activated macrophages were infected by clinical strains with higher survival to NO exposure in broth. Furthermore, the most NO-tolerant clinical isolate showed increased resistance to PRT both in broth culture and the macrophage model compared to H37Rv in the absence of mutational resistance in genes associated to reduced susceptibility against PRT or NO. Conclusion In a limited number of clinical M. tuberculosis isolates we found a significant difference in susceptibility to NO between clinical isolates, both in broth cultures and in macrophages. Our results indicate that mycobacterial susceptibility to cellular host defence mechanisms such as NO need to be taken into consideration when designing new therapeutic strategies. Funding Agencies|Research Council of South East of Sweden; Swedish Heart and Lung Foundation; Swedish Research Council
Databáze: OpenAIRE
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