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Description
Streptococcus agalactiae (Group B Streptococcus, GBS) is an important human pathogen because of its ability to cross the blood brain barrier (BBB) to cause meningitis in neonates. Previous studies have demonstrated that GBS can invade and transcytose through the cells that constitute the BBB to enter the brain. However, the exact mechanisms of intracellular trafficking have not been characterized. Previous electron micrographs have shown that when GBS invades brain endothelial cells, they reside in membrane-bound vesicles. Therefore, I hypothesized that GBS may be trafficked through the endocytic pathway, which can serve as an important host defense mechanism against intracellular pathogens. In order to examine if GBS is shuttled through this pathway, I infected human brain microvascular endothelial cells (hBMEC) with GFP-expressing GBS and stained for early and late endosomal markers, Rab5 and Rab7 respectively. GFP-GBS was shown to colocalize with early and late endosomes, as well as acidic vesicles. I have also shown that an important GBS response regulator CiaR, which promotes bacterial intracellular survival, acts to limit bacterial trafficking to acidic compartments and that one of the CiaR-regulated genes, SAN_2180, contributed to intracellular survival. Since approximately 50% of GBS was colocalized with acidic compartments, I hypothesized that selective autophagy may be induced in hBMEC to respond to GBS infection. An important indicator of autophagy is the microtubule-associate protein light chain 3 (LC3). LC3 exists in 2 forms: LC3-I, an inactive cytosolic form, and LC3-II, the active lipidated form that associates with the formation of the autophagosome; therefore, an increase in LC3-II conversion is indicative of autophagy activation. During GBS infection, I have observed an increase in LC3-II levels, indicating induction of autophagy. I also demonstrated that autophagy is a critical host defense mechanism against intracellular GBS, and that specific bacterial factors such as the ?- hemolysin/cytolysin may modulate this response. Further studies will focus on examining other host trafficking pathways that are not destined to fuse with lysosomes and further elucidate the various mechanisms associated with autophagy induction.
