Fig. 2

Neuroimmunological processes of chronic T. gondii infection and TBI, including the hypothesized synergy between conditions. a Chronic T. gondii brain. After migration into brain parenchyma, T. gondii profilin is detected by non-infected dendritic cells. This leads to production of IL-12 which activates lymphocytes to secrete IFNγ mediating host resistance. Infected and IFNγ-primed dendritic cells prime T cells and trigger production of IFNγ. IFNγ then activates astrocytes, leading to secretion of pro-inflammatory cytokines such as IL-1β, IL-6, and GM-CSF. GM-CSF can prime microglia, leading to the production of TNF-α, IL-6, and ROS. IFNγ and TNFα further activate macrophages, leading to secretion of pro-inflammatory cytokines and ROS, thereby further inhibiting T. gondii replication in macrophages. However, T. gondii preferentially infects neurons, and once inside, bradyzoites develop to avoid clearance. b TBI. Immediately following injury, damaged pericytes and parenchyma release alarmins such as ATP and ROS. These signaling molecules activate microglia and astrocytes to promote release of inflammatory cytokines and ROS. Leukocyte recruitment to the injury site begins with neutrophil infiltration, followed by macrophages and T cells. In response to cellular debris, T cells and macrophages produce additional pro-inflammatory cytokines. c Chronic T. gondii + TBI Brain. If an individual harboring a chronic T. gondii infection were to sustain a TBI, the neuroinflammatory profile may be exacerbated. A greater population of ‘pro-inflammatory’ and ‘anti-inflammatory’ microglia, as well as activated astrocytes, may be present not only at the onset of injury but also post-TBI. Increased populations of these cells may result in an increase of the relative abundance of inflammatory mediators post-TBI. Increased numbers of activated neutrophils, T cell, and macrophages may additionally be present, with the potential for these cells to further produce inflammatory mediators. Additionally, hyperphosphorylated tau and amyloid-β may accumulate more readily, potentially accelerating the neurodegenerative process. Figure created with BioRender.com