Macrophage-driven nutrient delivery to phagosomal Staphylococcus aureus supports bacterial growth
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Updated: Dec 20, 2025
Development and Assessment of Intracellular Infection Models for Staphylococcus aureus
Published on: January 17, 2025
Ronald S Flannagan1, David E Heinrichs1
1Department of Microbiology and Immunology, The University of Western Ontario, London, ON, Canada.
Abstract:
Staphylococcus aureus is a notorious pathogen causing significant morbidity and mortality worldwide. The ability of S. aureus to survive and replicate within phagocytes such as macrophages represents an important facet of immune evasion and contributes to pathogenesis. The mechanisms by which S. aureus acquires nutrients within host cells to support growth remain poorly characterized. Here, we demonstrate that macrophages infected with S. aureus maintain their dynamic ruffling behavior and consume macromolecules from the extracellular milieu. To support the notion that fluid-phase uptake by macrophages can provide S. aureus with nutrients, we utilized the pharmacological inhibitors PIK-III and Dynasore to impair uptake of extracellular macromolecules. Inhibitor treatment also impaired S. aureus replication within macrophages. Finally, using a mutant of S. aureus that is defective in purine biosynthesis we show that intracellular growth is inhibited unless the macrophage culture medium is supplemented with the metabolite inosine monophosphate. This growth rescue can be impaired by inhibition of fluid-phase uptake. In summary, through consumption of the extracellular environment macrophages deliver nutrients to phagolysosomal S. aureus to promote bacterial growth.
Insights
Staphylococcus aureus utilizes macrophage fluid-phase uptake to acquire nutrients for intracellular growth. Inhibiting this process and blocking purine biosynthesis restricts pathogen replication, revealing a key immune evasion mechanism.
Area of Science:
- Microbiology
- Immunology
- Cell Biology
Background:
- Staphylococcus aureus is a major human pathogen.
- Intracellular survival within macrophages is a key immune evasion strategy for S. aureus.
- Nutrient acquisition mechanisms for intracellular S. aureus are poorly understood.
Purpose of the Study:
- To investigate how Staphylococcus aureus obtains nutrients within macrophages.
- To determine the role of macrophage macropinocytosis in supporting intracellular S. aureus growth.
- To identify specific nutrient requirements for intracellular S. aureus replication.
Main Methods:
- Macrophage infection models with Staphylococcus aureus.
- Pharmacological inhibition of fluid-phase uptake (PIK-III, Dynasore).
- Utilizing a purine auxotrophic S. aureus mutant and inosine monophosphate supplementation.
Main Results:
- Macrophages infected with S. aureus exhibit sustained macropinocytosis, consuming extracellular macromolecules.
- Inhibition of macropinocytosis significantly impairs intracellular S. aureus replication.
- A purine auxotrophic S. aureus mutant's growth is rescued by inosine monophosphate, but this rescue is blocked by inhibiting fluid-phase uptake.
Conclusions:
- Macrophages supply intracellular Staphylococcus aureus with essential nutrients via fluid-phase uptake.
- Macropinocytosis is crucial for S. aureus pathogenesis by providing nutrients for intracellular growth.
- Targeting macrophage nutrient delivery presents a potential therapeutic strategy against intracellular S. aureus infections.
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