Molecular pathways elicited by Toll-like receptor 2 (TLR2) signaling during Staphylococcus aureus craniotomy infection
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College, Institute, or Department
MD/PhD Scholars Program
Dr. Tammy Kielian
Dr. Cortney Heim and Dr. Christopher Heim
A craniotomy is required to access the brain during neurosurgery for tumor resection or epilepsy treatment and despite extensive precautionary measures, infectious complications occur at a frequency of 1-3% (1-3). Approximately half of craniotomy infections are caused by S. aureus, which forms a biofilm on the bone flap. Our laboratory has developed a mouse model of S. aureus craniotomy-associated biofilm infection that shares important ultrastructural and MRI attributes with human disease (4). Toll-like receptor 2 (TLR2) is expressed by cells of the innate immune system and is critical for recognizing pathogen-associated molecular patterns (PAMPs) in the cell wall of gram-positive bacteria, such as S. aureus. Recent studies have shown that TLR2 is critical for S. aureus containment during craniotomy infection, in that TLR2 knockout (KO) mice displayed increased bacterial burden in the brain, galea, and bone flap during acute and chronic infection (days 3 and 14, respectively)(5). Cytokine and chemokine expression was dramatically reduced in TLR2 KO mice which did not coincide with a decrease in leukocyte infiltrates in the brain or galea. This suggested that S. aureus outgrowth in the context of TLR2 deficiency is not the result of altered leukocyte recruitment, but instead due to defects in their activation status. To determine this, RNA-sequencing (RNA-seq) was performed on microglia purified from the brain of WT and TLR2 KO mice at either day 3 or 7 post-infection by FACS with the goal of identifying microglial transcripts that are divergent between the two mouse strains (either increased or decreased). RNA-seq revealed Fibroblast Growth Factor Receptor (FGFR) 2 and 3 were upregulated in TLR2 KO microglia. This suggests a direct correlation between TLR2, FGFR2 and FGFR3. Since TLR2 KO animals have a bias toward an anti-inflammatory response to infection and the fact that FGFR2 and FGFR3 are upregulated during wound healing or infection, this could be a reason why higher levels are observed in TLR2 KO microglia. FGRF2 and FGRF3 are key regulators of neuronal protection and repair following brain injury/infection. Therefore, microglia may be increasing the expression of these receptors in an effort to control the damage that is occurring in response to the increased bacterial burden in TLR2 KO animals.
Craniotomy, Toll-like Receptor 2, Fibroblast Growth Factor Receptor
Agba, Chinyere; Heim, Cortney E.; Horn, Christopher M.; and Kielian, Tammy, "Molecular pathways elicited by Toll-like receptor 2 (TLR2) signaling during Staphylococcus aureus craniotomy infection" (2020). Posters: 2020 Summer Undergraduate Research Program. 1.