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Streptococcus pneumoniae,  a Gram-positive bacterium, is a major cause of invasive infection-related diseases such as pneumonia and sepsis. In blood, erythrocytes are considered to be an important factor for bacterial growth, as they contain abundant nutrients. However, the relationship between  S. pneumoniae  and erythrocytes remains unclear. We analyzed interactions between  S. pneumoniae  and erythrocytes, and found that iron ion present in human erythrocytes supported the growth of  Staphylococcus aureus , another major Gram-positive sepsis pathogen, while it partially inhibited pneumococcal growth by generating free radicals.  S. pneumoniae  cells incubated with human erythrocytes or blood were subjected to scanning electron and confocal fluorescence microscopic analyses, which showed that the bacterial cells adhered to and invaded human erythrocytes. In addition,  S. pneumoniae  cells were found associated with human erythrocytes in cultures of blood from patients with an invasive pneumococcal infection. Erythrocyte invasion assays indicated that LPXTG motif-containing pneumococcal proteins, erythrocyte lipid rafts, and erythrocyte actin remodeling are all involved in the invasion mechanism. In a neutrophil killing assay, the viability of  S. pneumoniae  co-incubated with erythrocytes was higher than that without erythrocytes. Also, H 2 O 2  killing of  S. pneumoniae  was nearly completely ineffective in the presence of erythrocytes. These results indicate that even when  S. pneumoniae  organisms are partially killed by iron ion-induced free radicals, they can still invade erythrocytes. Furthermore, in the presence of erythrocytes,  S. pneumoniae  can more effectively evade antibiotics, neutrophil phagocytosis, and H 2 O 2  killing.

Streptococcus pneumoniae Invades Erythrocytes and Utilizes Them to Evade Human Innate Immunity