The host anti-bacterial immune response that ensues during brain abscess development not only neutralizes pathogens but also contributes to the destruction of surrounding normal brain parenchyma. Limiting this pathological damage could result in long-term improvements for brain abscess patients. During the previous funding period, we found that the PPAR-? agonist ciglitazone accelerated abscess encapsulation/fibrosis, which coincided with a significant reduction in proinflammatory mediator expression as well as bacterial burdens. Since fibrosis typically ensues subsequent to the dampening of immune responses, it is possible that ciglitazone facilitates brain abscess wall formation by its ability to limit ongoing inflammation. Indeed, recent studies have demonstrated that PPAR-? agonists can transition classically activated (M1) macrophages into an alternatively activated (M2) phenotype as well as enhance the production of Th2 cytokines such as IL-4, IL-5, and IL-13, both of which are pro-fibrotic. However, the signal(s) responsible for regulating fibrosis during brain abscess development and the pathways influenced by ciglitazone to accelerate this process remain unknown. The overall hypothesis of this proposal is that the PPAR-? agonist ciglitazone accelerates brain abscess encapsulation through its ability to transition activated microglia/macrophages into a M2 alternative phenotype that, in turn, triggers a pro- fibrotic (Th2) cytokine profile to accelerate fibrosis. We will also utilize magnetic resonance imaging (MRI) modalities to monitor the effects of ciglitazone on brain abscess size, perfusion, and edema formation as well as density and organization of the abscess wall throughout disease development. These measures will provide a serial non-invasive assessment of brain abscess formation and how ciglitazone modulates these processes. MRI-based methods will include diffusion tensor imaging (DTI) for wall density and edema formation as well as high-resolution T1 and T2 MRI maps for clearly delineating the abscess wall from surrounding tissue. Perfusion maps will be used to monitor regional changes in blood flow along the brain abscess wall using arterial spin labeled (ASL) perfusion MRI. The power of these approaches is that MRI enables a longitudinal assessment of wall formation and perfusion throughout the course of brain abscess development in an individual animal. To address these objectives, the following specific aims will be investigated: 1) to investigate the mechanism(s) responsible for the PPAR-? agonist ciglitazone to accelerate brain abscess wall formation and fibrosis; and 2) to define the events influencing regulated fibrosis along the developing brain abscess wall. By understanding the mechanisms responsible for its ability to accelerate abscess encapsulation, ciglitazone may prove to be an effective adjunct therapy, in concert with conventional antibiotics, for the rapid containment of brain abscesses. Conceivably, this approach could lead to significant improvements in clinical outcomes and quality of life for patients recovering from brain abscesses.

Public Health Relevance

Brain abscesses represent a serious infection, especially due the recent emergence of antibiotic-resistant strains of bacteria, and can cause long-term deficits including seizures and cognitive loss. In this proposal, we will study a synthetic compound that causes brain abscesses to become walled off more rapidly, which may help to protect surrounding brain tissue from damage. This compound may prove beneficial, in combination with conventional antibiotics, for the treatment of brain abscess patients by facilitating rapid abscess containment, effectively limiting bacterial spread throughout the infected hemisphere.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Wong, May
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University of Nebraska Medical Center
Schools of Medicine
United States
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Hanamsagar, Richa; Aldrich, Amy; Kielian, Tammy (2014) Critical role for the AIM2 inflammasome during acute CNS bacterial infection. J Neurochem 129:704-11
Bauer, Christopher; Kielian, Tammy; Wyatt, Todd A et al. (2013) Myeloid differentiation factor 88-dependent signaling is critical for acute organic dust-induced airway inflammation in mice. Am J Respir Cell Mol Biol 48:781-9
Xiong, Juan; Burkovetskaya, Maria; Karpuk, Nikolay et al. (2012) IL-1RI (interleukin-1 receptor type I) signalling is essential for host defence and hemichannel activity during acute central nervous system bacterial infection. ASN Neuro 4:
Hanamsagar, Richa; Hanke, Mark L; Kielian, Tammy (2012) Toll-like receptor (TLR) and inflammasome actions in the central nervous system. Trends Immunol 33:333-42
Holley, Monica M; Kielian, Tammy (2012) Th1 and Th17 cells regulate innate immune responses and bacterial clearance during central nervous system infection. J Immunol 188:1360-70
Hanke, Mark L; Kielian, Tammy (2011) Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Clin Sci (Lond) 121:367-87
Kielian, Tammy (2009) Overview of toll-like receptors in the CNS. Curr Top Microbiol Immunol 336:1-14
Esen, Nilufer; Kielian, Tammy (2009) Toll-like receptors in brain abscess. Curr Top Microbiol Immunol 336:41-61
Liu, Shuliang; Kielian, Tammy (2009) Microglial activation by Citrobacter koseri is mediated by TLR4- and MyD88-dependent pathways. J Immunol 183:5537-47
Mariani, Monica M; Kielian, Tammy (2009) Microglia in infectious diseases of the central nervous system. J Neuroimmune Pharmacol 4:448-61

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