Related Experiment Video
Updated: Sep 7, 2025
Legionella pneumophila Outer Membrane Vesicles: Isolation and Analysis of Their Pro-inflammatory Potential on Macrophages
Published on: February 22, 2017
Diurnal Differences in Intracellular Replication Within Splenic Macrophages Correlates With the Outcome of
Ryan G Hames1, Zydrune Jasiunaite1, Giuseppe Ercoli2
1Department of Genetics and Genome Biology, University of Leicester, Leicester, United Kingdom.
Abstract:
Circadian rhythms affect the progression and severity of bacterial infections including those caused by Streptococcus pneumoniae, but the mechanisms responsible for this phenomenon remain largely elusive. Following advances in our understanding of the role of replication of S. pneumoniae within splenic macrophages, we sought to investigate whether events within the spleen correlate with differential outcomes of invasive pneumococcal infection. Utilising murine invasive pneumococcal disease (IPD) models, here we report that infection during the murine active phase (zeitgeber time 15; 15h after start of light cycle, 3h after start of dark cycle) resulted in significantly faster onset of septicaemia compared to rest phase (zeitgeber time 3; 3h after start of light cycle) infection. This correlated with significantly higher pneumococcal burden within the spleen of active phase-infected mice at early time points compared to rest phase-infected mice. Whole-section confocal microscopy analysis of these spleens revealed that the number of pneumococci is significantly higher exclusively within marginal zone metallophilic macrophages (MMMs) known to allow intracellular pneumococcal replication as a prerequisite step to the onset of septicaemia. Pneumococcal clusters within MMMs were more abundant and increased in size over time in active phase-infected mice compared to those in rest phase-infected mice which decreased in size and were present in a lower percentage of MMMs. This phenomenon preceded significantly higher levels of bacteraemia alongside serum IL-6 and TNF-α concentrations in active phase-infected mice following re-seeding of pneumococci into the blood. These data greatly advance our fundamental knowledge of pneumococcal infection by linking susceptibility to invasive pneumococcal infection to variation in the propensity of MMMs to allow persistence and replication of phagocytosed bacteria. These findings also outline a somewhat rare scenario whereby the active phase of an organism's circadian cycle plays a seemingly counterproductive role in the control of invasive infection.
Insights
Circadian rhythms influence bacterial infections. This study shows infections during the mouse active phase lead to faster sepsis onset due to increased Streptococcus pneumoniae replication in splenic macrophages.
Area of Science:
- Microbiology
- Immunology
- Chronobiology
Background:
- Circadian rhythms impact bacterial infection severity, but mechanisms are unclear.
- Splenic macrophage replication of Streptococcus pneumoniae is a key factor in invasive pneumococcal disease (IPD).
Purpose of the Study:
- To investigate the correlation between spleen events and differential outcomes in murine invasive pneumococcal infection models.
- To understand how circadian timing influences S. pneumoniae infection progression.
Main Methods:
- Utilized murine invasive pneumococcal disease (IPD) models.
- Infected mice during active and rest phases (ZT15 vs. ZT3).
- Analyzed pneumococcal burden, splenic macrophage (MMM) activity, and serum cytokine levels using confocal microscopy and biochemical assays.
Main Results:
- Active phase infection (ZT15) led to faster sepsis onset and higher pneumococcal burden in the spleen compared to rest phase infection (ZT3).
- Increased S. pneumoniae replication was observed within marginal zone metallophilic macrophages (MMMs) during the active phase.
- Higher bacteraemia and serum IL-6/TNF-α levels correlated with active phase infection.
Conclusions:
- Splenic macrophage (MMM) propensity to harbor and replicate S. pneumoniae varies with circadian rhythm, influencing infection outcomes.
- The active phase of the circadian cycle can paradoxically increase susceptibility to invasive pneumococcal infection.
- Findings link circadian variation to invasive pneumococcal infection susceptibility and disease severity.
More Related Videos
12:30Use of Galleria mellonella as a Model Organism to Study Legionella pneumophila Infection
Published on: November 22, 2013
11:32Following in Real Time the Impact of Pneumococcal Virulence Factors in an Acute Mouse Pneumonia Model Using Bioluminescent Bacteria
Published on: February 23, 2014
