Using the pneumococcus as a model, our lab has revealed many features of the biochemical basis of the inflammatory response to bacteria in the brain. How the pneumococcus traffics across the blood brain barrier is shared by other meningeal pathogens. We determined how neurons die by apoptosis during infection and revealed the role of cell wall/TLR2 in host damage. The important discovery of this application is the opening of a new area of pathogenesis at the maternal/fetal interface that will inform new aspects of cell wall/TLR2 effects in the brain. We have determined that cell wall, a universal pathogen associated molecular pattern, circulates in the bloodstream of pregnant mice and traverses the placenta to the fetal brain. The response of fetal neurons is not the well characterized inflammation and neuronal death of the postnatal setting but the exact opposite: neuroproliferation without inflammation. This response involves two new activities of cell wall: 1) induction of cell proliferation without inflammatory signaling via TLR2, and 2) remodeling of embryonic brain anatomy and changes in postnatal behavior. An understanding of the details of this new biology, to be investigated in this application, represents both novel bacterial pathogenesis and an avenue of high potential for tangible medical impact. We propose in Aim 1 to undertake detailed neuroanatomical assessment of the changes in brain architecture and define the window of neuroproliferation in embryogenesis.
In Aim 2 we will characterize the signaling cascades initiated by cell wall to induce neuroproliferation, including via TLR2 and novel sources of PI3 kinase and induction of the neuronal transcription factor FoxG1. This will link innate immune receptors to nuclear transcription factors for the first time.
Aim 3 will determine how cell wall released during the treatment of maternal sepsis recapitulates the neuroproliferation seen in the model of prenatal IV cell wall exposure of the mother. We will define the consequences to postnatal behavior of prenatal neuroproliferation.

Public Health Relevance

/Relevance: Streptococcus pneumoniae, the leading cause of pneumonia, sepsis, and meningitis worldwide, is a model for determining the mechanisms of lethal inflammation and injury in the brain. The cell wall drives tissue injury in the postnatal setting. New data suggests that cell wall crosses from the maternal circulation to fetus and induces neuroproliferation instead of injury. Understanding this switch will reveal new innate immune biology and inform efforts to develop neuroprotective treatments.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Host Interactions with Bacterial Pathogens Study Section (HIBP)
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Lu, Kristina
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St. Jude Children's Research Hospital
United States
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Loughran, Allister J; Tuomanen, Elaine I (2016) Blood borne: bacterial components in mother's blood influence fetal development. Inflamm Cell Signal 3:
Mann, Beth; Loh, Lip Nam; Gao, Geli et al. (2016) Preparation of Purified Gram-positive Bacterial Cell Wall and Detection in Placenta and Fetal Tissues. Bio Protoc 6:
Humann, Jessica; Mann, Beth; Gao, Geli et al. (2016) Bacterial Peptidoglycan Transverses the Placenta to Induce Fetal Neuroproliferation and Aberrant Postnatal Behavior. Cell Host Microbe 19:388-99