Browsing by Author "Ercoli, Giuseppe"
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- Intracellular replication of Streptococcus pneumoniae inside splenic macrophages serves as a reservoir for septicaemiaPublication . Ercoli, Giuseppe; Fernandes, Vitor E.; Chung, Wen Y.; Wanford, Joseph J.; Thomson, Sarah; Bayliss, Christopher D.; Straatman, Kornelis; Crocker, Paul R.; Dennison, Ashley; Martinez-Pomares, Luisa; Andrew, Peter W.; Moxon, E. Richard; Oggioni, Marco R.Bacterial septicaemia is a major cause of mortality, but its pathogenesis remains poorly understood. In experimental pneumococcal murine intravenous infection, an initial reduction of bacteria in the blood is followed hours later by a fatal septicaemia. These events represent a population bottleneck driven by efficient clearance of pneumococci by splenic macrophages and neutrophils, but as we show in this study, accompanied by occasional intracellular replication of bacteria that are taken up by a subset of CD169+ splenic macrophages. In this model, proliferation of these sequestered bacteria provides a reservoir for dissemination of pneumococci into the bloodstream, as demonstrated by its prevention using an anti-CD169 monoclonal antibody treatment. Intracellular replication of pneumococci within CD169+ splenic macrophages was also observed in an ex vivo porcine spleen, where the microanatomy is comparable with humans. We also showed that macrolides, which effectively penetrate macrophages, prevented septicaemia, whereas beta-lactams, with inefficient intracellular penetration, failed to prevent dissemination to the blood. Our findings define a shift in our understanding of the pneumococcus from an exclusively extracellular pathogen to one with an intracellular phase. These findings open the door to the development of treatments that target this early, previously unrecognized intracellular phase of bacterial sepsis.
- The B-cell inhibitory receptor CD22 is a major factor in host resistance to Streptococcus pneumoniae infectionPublication . Fernandes, Vitor E.; Ercoli, Giuseppe; Bénard, Alan; Brandl, Carolin; Fahnenstiel, Hannah; Müller-Winkler, Jennifer; Weber, Georg F; Denny, Paul; Nitschke, Lars; Andrew, Peter WStreptococcus pneumoniae is a major human pathogen, causing pneumonia and sepsis. Genetic components strongly influence host responses to pneumococcal infections, but the responsible loci are unknown. We have previously identified a locus on mouse chromosome 7 from a susceptible mouse strain, CBA/Ca, to be crucial for pneumococcal infection. Here we identify a responsible gene, Cd22, which carries a point mutation in the CBA/Ca strain, leading to loss of CD22 on B cells. CBA/Ca mice and gene-targeted CD22-deficient mice on a C57BL/6 background are both similarly susceptible to pneumococcal infection, as shown by bacterial replication in the lungs, high bacteremia and early death. After bacterial infections, CD22-deficient mice had strongly reduced B cell populations in the lung, including GM-CSF producing, IgM secreting innate response activator B cells, which are crucial for protection. This study provides striking evidence that CD22 is crucial for protection during invasive pneumococcal disease.
- The B-cell inhibitory receptor CD22 is a major factor in host resistance to Streptococcus pneumoniae infectionPublication . Fernandes, Vitor E.; Ercoli, Giuseppe; Bénard, Alan; Brandl, Carolin; Fahnenstiel, Hannah; Müller-Winkler, Jennifer; Weber, Georg F.; Denny, Paul; Nitschke, Lars; Andrew, Peter W.Streptococcus pneumoniae is a major human pathogen, causing pneumonia and sepsis. Genetic components strongly influence host responses to pneumococcal infections, but the responsible loci are unknown. We have previously identified a locus on mouse chromosome 7 from a susceptible mouse strain, CBA/Ca, to be crucial for pneumococcal infection. Here we identify a responsible gene, Cd22, which carries a point mutation in the CBA/Ca strain, leading to loss of CD22 on B cells. CBA/Ca mice and gene-targeted CD22-deficient mice on a C57BL/6 background are both similarly susceptible to pneumococcal infection, as shown by bacterial replication in the lungs, high bacteremia and early death. After bacterial infections, CD22-deficient mice had strongly reduced B cell populations in the lung, including GM-CSF producing, IgM secreting innate response activator B cells, which are crucial for protection. This study provides striking evidence that CD22 is crucial for protection during invasive pneumococcal disease.