Experimental evolution of Staphylococcus aureus in macrophages: dissection of a conditional adaptive trait promoting intracellular survival.
| Title: | Experimental evolution of Staphylococcus aureus in macrophages: dissection of a conditional adaptive trait promoting intracellular survival. |
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| Authors: | Alves J; The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, Edinburgh, United Kingdom.; Vrieling M; The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, Edinburgh, United Kingdom.; Ring N; The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, Edinburgh, United Kingdom.; Yebra G; The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, Edinburgh, United Kingdom.; Pickering A; The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, Edinburgh, United Kingdom.; Prajsnar TK; Florey Institute, Bateson Centre and Division of Clinical Medicine, School of Medicine and Population Health, Sheffield, United Kingdom.; Renshaw SA; Florey Institute, Bateson Centre and Division of Clinical Medicine, School of Medicine and Population Health, Sheffield, United Kingdom.; Fitzgerald JR; The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, Edinburgh, United Kingdom. |
| Source: | MBio [mBio] 2024 Jun 12; Vol. 15 (6), pp. e0034624. Date of Electronic Publication: 2024 Apr 29. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 101519231 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2150-7511 (Electronic) NLM ISO Abbreviation: mBio Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Washington, D.C. : American Society for Microbiology |
| MeSH Terms: | Staphylococcus aureus*/genetics ; Staphylococcus aureus*/drug effects ; Staphylococcus aureus*/physiology ; Macrophages*/microbiology ; Macrophages*/immunology ; Staphylococcal Infections*/microbiology ; Staphylococcal Infections*/immunology ; Zebrafish*/microbiology; Anti-Bacterial Agents/pharmacology ; Adaptation, Physiological/genetics ; Humans ; Animals ; Phenotype ; Microbial Viability ; Cell Line ; Mice ; Genome, Bacterial ; Evolution, Molecular |
| Abstract: | Staphylococcus aureus is a major pathogen associated with important diseases in humans and animals. Macrophages are a key component of the innate immune response to S. aureus infection and play a major role in disease outcomes. To investigate the adaptive evolution of S. aureus in response to macrophages, we developed an experimental infection assay. S. aureus strains representing major human epidemic clones were passaged many times in a macrophage cell line, accumulating mutations in an array of genomic loci. Phenotypic analysis revealed the emergence of a lineage exhibiting increased survival in macrophages and human blood, and resistance to vancomycin. The evolved lineage exhibited a previously undescribed small colony variant (SCV) phenotype characterized by hyper-pigmentation, which resulted from a missense mutation in rsbW. Notably, the novel SCV was a conditional adaptive trait that was unstable in nutrient-replete conditions in vitro, rapidly converting from hyper-pigmented SCV to a non-pigmented large colony variant via spontaneous sigB deletion events. Importantly, we identified similar deletions in the genome sequences of a limited number of clinical S. aureus isolates from public databases, indicating that related events may occur during clinical infection. Experimental infection of zebrafish did not reveal a difference in virulence between parent and novel SCV but demonstrated an in vivo fitness cost for the compensatory sigB deletion events. Taken together, we report an experimental evolutionary approach for investigating bacterial innate immune cell interactions, revealing a conditional adaptation that promotes S. aureus survival in macrophages and resistance to vancomycin.; Importance: Staphylococcus aureus is an important human bacterial pathogen. The host response to S. aureus involves the production of innate immune cells such as macrophages which are important for fighting infection. Here we report a new model of experimental evolution for studying how S. aureus can evade killing by macrophages. We identified a novel adaptive phenotype that promotes survival in macrophages and blood and resistance to antibiotics. The phenotype is lost rapidly upon growth in nutrient-rich conditions via disruption of the alternative sigma factor sigB, revealing a conditional niche-specific fitness advantage. Genomic analysis of clinical isolates suggests similar adaptations may occur during human infections. Our model may be used broadly to identify adaptations of S. aureus to the innate immune response. |
| Competing Interests: | The authors declare no conflict of interest. |
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| Grant Information: | United Kingdom WT_ Wellcome Trust; BBS/E/D/20002173 UKRI | Biotechnology and Biological Sciences Research Council (BBSRC); MR/N02995X/1 UKRI | Medical Research Council (MRC); 201531/Z/16/Z Wellcome Trust (WT) |
| Contributed Indexing: | Keywords: Staphylococcus aureus; antibiotic resistance; evolution; macrophages |
| Substance Nomenclature: | 0 (Anti-Bacterial Agents) |
| Entry Date(s): | Date Created: 20240429 Date Completed: 20240612 Latest Revision: 20240714 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC11237485 |
| DOI: | 10.1128/mbio.00346-24 |
| PMID: | 38682911 |
| Database: | MEDLINE |
Journal Article