Brain abscess formation is consequent of pyogenic bacterial infection, and can elicit inflammation, edema, neuronal toxicity, and often long-term health problems such as seizures. Diagnosing and treating brain abscesses is complicated, and untreated lesions can rupture into the ventricular space which engenders an 80% mortality rate. The incidence of brain abscesses is likely to persist, in spite of therapy, due to the ubiquitous nature of bacteria and the ever increasing number of multi-drug resistant bacterial strains such as Staphylococcus aureus (S. aureus). The proposed training plan is relevant to the mission of NINDS in that its broad objective is to reduce the burden of neurological disease brought on by bacterial-induced brain abscesses. The innate immune responses elicited during brain abscess development due to S. aureus are relatively well-defined;however, little information is available regarding the importance of adaptive immunity during infection. Preliminary studies have demonstrated CD4+, CD8+, 34 T cell, and NKT cell infiltrates in brain abscesses, suggesting both innate and adaptive immune responses are required to resolve bacterial infections in the CNS. Based on the frequency of T cell populations infiltrating brain abscesses bearing the 12 T cell receptor (TCR), subsequent studies were performed in TCR 12 KO mice, deficient in CD4+, CD8+, and NKT cells. Bacterial burdens were significantly elevated in TCR 12 KO mice at later stages of infection compared to WT animals, which were able to effectively clear S. aureus. The loss of TCR 12+ cells also affected the profiles of infiltrating innate immune cells into the CNS, primarily during the late phase of infection (i.e. days 7-14 following bacterial exposure). The predominant cell types infiltrating the brain, CD4+ and NKT cells, were found to produce IL-17 and IFN-3, which are involved in the activation of innate immune cells and bacterial clearance. The hypothesis of this proposal is that CD4+ Th1/Th17 cells and NKT cells impact the influx and activation status of innate immune populations to regulate bacterial clearance and tissue injury during brain abscess development. To assess the functional effects of Th1 and Th17 cells in brain abscess pathogenesis, the research plan will examine parameters of infection (i.e. bacterial burdens, pro-inflammatory mediator expression, innate immune infiltrates, and tissue injury) after specific CD4+ T helper (Th) cell populations are adoptively transferred into TCR 12 KO mice. In addition, the importance of NKT cells during infection will be evaluated using commercially available CD1d-deficient mice that lack NKT cells. The objective of these studies is to define the functional contributions of Th1/Th17 and NKT cells in brain abscess pathogenesis and establish for the first time a direct link between innate and adaptive immunity during abscess formation. It is envisioned that these studies may identify novel therapeutic targets to limit the excessive neuronal damage that accompanies brain abscesses with the added benefit of not compromising effective bacterial clearance.
Brain abscesses represent a devastating infection, especially due the recent emergence of multi-drug resistant strains of bacteria, and can cause long-term deficits including seizures and cognitive loss. In this proposal, I will assess the functional importance of various T cell subsets for their ability to influence anti-bacterial immunity during brain abscess development. A better understanding of how T cell responses regulate inflammation may reveal novel therapeutic targets to limit the excessive neuronal damage that accompanies brain abscesses with the added benefit of not compromising effective bacterial clearance.
|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|