Bioactivities of pneumococcal cell wall in neuropathogenesis

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Principal Investigator: Elaine I Tuomanen
Organization: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
Fiscal Year: 2024
Award: $455,000
Funding agency: National Institute of Allergy and Infectious Diseases

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. The important discovery of this application is the
opening of a new area of pathogenesis at the maternal/fetal interface that will inform newly discovered
cell wall/TLR2 effects as a morphogen 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 via TLR2 without
inflammatory signaling, and 2) remodeling of embryonic brain anatomy and changes in postnatal
behavior. We will further determine the relevance of these findings to the human brain using organoids.
 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. Using
single cell spatial RNASeq and knock out animal models, we propose to identify the signaling cascade
initiated by cell wall to modulate brain structure, including determining the links between TLR2/6, the
signaling node of the neuronal cilium and the neuronal transcription factor FoxG1. This will connect
innate immune receptors to nuclear transcription factors for the first time and define a new activity of
TLRs as morphogens. The involvement of the LANDO autophagy pathway will be characterized as a cell
wall trafficking/removal pathway associated with defects in cognitive function.

Terms: <Abscission><Affect><Amyloid><Amyloid Substance><Anatomic Sites><Anatomic structures><Anatomy><Animal Model><Animal Models and Related Studies><Architecture><Area><Autophagocytosis><Autoregulation><BF1><Bacteria><Basal Transcription Factor><Basal transcription factor genes><Behavior><Binding><Biochemical><Biology><Birth><Blood Circulation><Bloodstream><Brain><Brain Factor 1><Brain Nervous System><Cell Anatomy><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Cycle Kinetics><Cell Death><Cell Growth in Number><Cell Interaction><Cell Kinetics><Cell Multiplication><Cell Proliferation><Cell Signaling><Cell Wall><Cell surface><Cell-to-Cell Interaction><Cells><Cells Placenta-Tissue><Cellular Anatomy><Cellular Proliferation><Cilia><Circulation><D pneumoniae><D. pneumoniae><Data><Defect><Development><Dimensions><Diplococcus pneumoniae><Drosophila><Drosophila genus><Dysfunction><Embryo><Embryonic><Encephalon><Engineering / Architecture><Equilibrium><Evolution><Excision><Exposure to><Extirpation><FKHL1><FOXG1><FOXG1B gene><Fetus><Flies><Forkhead Box G1><Forkhead Box G1B><Forkhead Protein G1B><Forkhead-Like 1><Functional disorder><General Transcription Factor Gene><General Transcription Factors><Gram-Positive Bacterial Infections><Homeostasis><Human><Immune><Immune signaling><Immunes><Immunologic Receptors><Immunological Receptors><Individual><Induced Neurons><Infection><Inflammation><Inflammatory><Inflammatory Response><Injury><Innate Immune Response><Innate Immunity><Intracellular Communication and Signaling><Link><Measures><Medical><Meningitis><Mice><Mice Mammals><Modeling><Modern Man><Modification><Molecular><Molecular Interaction><Morphogenesis><Murine><Mus><Native Immunity><Natural Immunity><Nerve Cells><Nerve Unit><Neural Cell><Neural Development><Neurocyte><Neurons><Neuropathogenesis><Non-Specific Immunity><Nonspecific Immunity><Normal Placentoma><Nuclear><Oncogene QIN><Organ><Organoids><Parturition><Pathogenesis><Pathway interactions><Pattern><Physiological Homeostasis><Physiopathology><Placenta><Placenta Embryonic Tissue><Placentome><Pneumococcus><Pneumonia><Publications><RNA Seq><RNA sequencing><RNAseq><Recycling><Regulation><Removal><Role><S pneumoniae><S. pneumoniae><SHH><SHH gene><Scientific Publication><Sensory><Sepsis><Shapes><Signal Induction><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Sonic Hedgehog><Sonic Hedgehog (Shh) Pathway><Sonic Hedgehog Pathway><Streptococcus pneumoniae><Structure><Subcellular Anatomy><Surgical Removal><TIL4><TLR2><TLR2 gene><TLR2 receptor><Testing><Time><Toll-Like Receptor 2><Toll/Interleukin 1 Receptor-Like 4><Toll/Interleukin 1 Receptor-Like 4 Gene><Toll/Interleukin 1 Receptor-Like Protein 4><Transcription Factor Proto-Oncogene><Transcription factor genes><Work><autophagy><bacteria pathogen><bacterial pathogen><balance><balance function><biological signal transduction><blood infection><bloodstream infection><brain abnormalities><cell type><cognitive function><developmental><differentiation factors><experiment><experimental research><experimental study><experiments><fetal><fly><fork head protein><forkhead protein><forkhead transcription factors><fruit fly><iNeuron><immune receptor><in utero><injuries><injury to tissue><innovate><innovation><innovative><knock-out animal><knockout animal><model of animal><model organism><morphogenetic process><morphogenic factors><morphogens><mouse model><murine model><necrocytosis><neurodevelopment><neurogenesis><neuronal><neuroprotection><neuroprotective><novel><pathogen><pathogenic bacteria><pathophysiology><pathway><post-natal neuronal death><postnatal><postnatal neuronal death><pregnant><programs><pup><receptor recycling><resection><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><tissue injury><trafficking><transcription factor><transcriptome sequencing><transcriptomic sequencing>