Diurnal differences in intracellular replication within splenic macrophages correlates with the outcome of pneumococcal infection

• Published in: bioRxiv 2022-01
• Main Authors: Hames, Ryan G, Jasiunaite, Zydrune, Ercoli, Giuseppe, Wanford, Joseph J, Carreno, David, Straatman, Kornelis, Martinez-Pomares, Luisa, Yesilkaya, Hasan, Glenn, Sarah, Moxon, E Richard, Andrew, Peter W, Kyriacou, Charalambos P, Marco Rinaldo Oggioni
• Format: Article
• Language: English
• Subjects: Bacteremia; Circadian rhythms; Confocal microscopy; Interleukin 6; Intracellular; Macrophages; Microbiology; Replication; Septicemia; Spleen; Streptococcus infections; Streptococcus pneumoniae; Tumor necrosis factor-α
• ISSN: 2692-8205
• DOI: 10.1101/2022.01.30.478422

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 a specific subset of splenic macrophages, we sought to investigate events within the spleen that 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; 15h after start of light cycle, 3h after start of dark cycle) resulted in significantly faster onset of moderate septicaemia compared to rest phase (zeitgeber time 3; 3h after start of light cycle) infection. These findings 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 in active phase-infected mice compared to those in rest phase-infected mice which decreased in size over time 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. In summary, these data link the difference in susceptibility to invasive pneumococcal infection to variation in the ability of MMMs to successfully control and digest phagocytosed bacteria. Competing Interest Statement The authors have declared no competing interest.