Streptococcus pneumoniae (pneumococcus) is the primary cause of bacterial meningitis. Pneumococcal bacteria penetrates the blood-brain barrier (BBB), but the bacterial factors that enable this process are not known. Here, we determined that expression of pneumococcal pilus-1, which includes the pilus adhesin RrgA, promotes bacterial penetration through the BBB in a mouse model. S.pneumoniae that colonized the respiratory epithelium and grew in the bloodstream were chains of variable lengths; however, the pneumococci that entered the brain were division-competent, spherical, single cocci that expressed adhesive RrgA–containing pili. The cell division protein DivIVA, which is required for an ovoid shape, was localized at the poles and septum of pneumococcal chains of ovoid, nonseparated bacteria, but was absent in spherical, single cocci. In the bloodstream, a small percentage of pneumococci appeared as piliated, RrgA-expressing, DivIVA-negative single cocci, suggesting that only a minority of S.pneumoniae are poised to cross the BBB. Together, our data indicate that small bacterial cell size, which is signified by the absence of DivIVA, and the presence of an adhesive RrgA-containing pilus-1 mediate pneumococcal passage from the bloodstream through the BBB into the brain to cause lethal meningitis.
Federico Iovino, Disa L. Hammarlöf, Genevieve Garriss, Sarah Brovall, Priyanka Nannapaneni, Birgitta Henriques-Normark
(A) Immunofluorescence staining of the polysaccharide capsule of 6B clinical isolates, TIGR4, and TIGR4ΔrrgA-srtD from brain and lung homogenates and blood and (B) D39, D39▼(rlrA-srtD), TIGR4ΔrrgBC, and TIGR4ΔrrgA from brain homogenates and blood. A mixed phenotype was found for BHN427 (A), and in the brain, among piliated strains, only a minor part formed diplococci (see detailed quantification in the Supplemental Information). For each strain and each type of tissue, 3 mice were analyzed (approximately 300 images per mouse were taken).