The pneumococcus remains the cause of meningitis with the greatest morbidity and mortality. Over the past 22 years of this application, we have sought to understand the biochemical basis of the inflammatory response to pneumococci in the subarachnoid space and to determine how pneumococci traffic across the blood brain barrier of cerebral microvessels. In the past application cycle, we discovered several overarching principles of central nervous system (CNS) infection: We determined how the pneumococcus localizes to the blood brain barrier (CbpA on the cell wall ligates laminin receptor LR) and then penetrates into the CNS (phosphorylcholine PCho on the cell wall ligates platelet activating factor receptor PAFr) and have shown that these steps are shared by other meningeal pathogens. We showed how neuronal cells die by apoptosis during meningitis and revealed the role of cell wall/TLR2 in host damage. The central hypothesis of this application is that critical bacterial cell wall/host cell ligand-receptor interactions play a dominant role in influencing the course and outcome of pneumococcal infection and that organ specific responses script how the lung recovers relatively unscathed from pneumonia while the brain is devastated by meningitis. An understanding of the driving factors for these differences,to be investigated in this application, represent both new aspects of bacterial pathogenesis and avenues of high potential for tangible medical impact. We propose in Aim 1 to determine the regulation of CbpA, the pneumococcal cell wall-bound adhesin for LR on the blood brain barrier.
In Aim 2, we will map the PCho-PAFr response pathways in epithelia, endothelia, and neurons (adult and fetal) to determine the underlying mechanisms of differences in cell wall uptake and host cell fate. We will also determine the pathway by which PCho-PAFr drives neuronal apoptosis in adult neurons versus neuroregeneration in fetal neurons. Finally, in Aim 3, we have learned that interruption of the cell wall/TLR2 interaction protects against apoptotic organ injury but this is not sufficient to prevent mortality. Understanding of this dichotomy will tie cell fate decisions to TLR2 signaling and introduce pneumococcal manipulation of TGFss into pathogenesis.

Public Health 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. We seek to define how the cell wall of pneumococcus drives bacterial trafficking in the host and causes tissue injury especially in the brain and heart. This information will direct efforts to develop neuroprotective treatments for infants and children.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI027913-25
Application #
8580915
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Taylor, Christopher E,
Project Start
1989-06-01
Project End
2015-10-31
Budget Start
2013-11-01
Budget End
2014-10-31
Support Year
25
Fiscal Year
2014
Total Cost
$378,000
Indirect Cost
$153,000
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Honsa, Erin S; Cooper, Vaughn S; Mhaissen, Mohammed N et al. (2017) RelA Mutant Enterococcus faecium with Multiantibiotic Tolerance Arising in an Immunocompromised Host. MBio 8:
Gratz, Nina; Loh, Lip Nam; Mann, Beth et al. (2017) Pneumococcal neuraminidase activates TGF-? signalling. Microbiology :
Loughran, Allister J; Tuomanen, Elaine I (2016) Blood borne: bacterial components in mother's blood influence fetal development. Inflamm Cell Signal 3:
Brown, Lindsey R; Gunnell, Steven M; Cassella, Adam N et al. (2016) AdcAII of Streptococcus pneumoniae Affects Pneumococcal Invasiveness. PLoS One 11:e0146785
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:
Kamei, Akinobu; Gao, Geli; Neale, Geoffrey et al. (2016) Exogenous remodeling of lung resident macrophages protects against infectious consequences of bone marrow-suppressive chemotherapy. Proc Natl Acad Sci U S A 113:E6153-E6161
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
Thornton, Justin A; Tullos, Nathan A; Sanders, Melissa E et al. (2015) Differential bacterial gene expression during experimental pneumococcal endophthalmitis. Ophthalmic Res 53:149-61
Brown, Armand O; Mann, Beth; Gao, Geli et al. (2014) Streptococcus pneumoniae translocates into the myocardium and forms unique microlesions that disrupt cardiac function. PLoS Pathog 10:e1004383
Carter, Robert; Wolf, Joshua; van Opijnen, Tim et al. (2014) Genomic analyses of pneumococci from children with sickle cell disease expose host-specific bacterial adaptations and deficits in current interventions. Cell Host Microbe 15:587-599

Showing the most recent 10 out of 80 publications