Toxoplasma gondii is an intracellular parasite that infects one-third of humans globally. T. gondii establishes a chronic infection in the brain, and immune compromise due to HIV infection, organ transplantation, or chemotherapy can lead to parasite reactivation and fatal encephalitis. This proposal addresses a poorly understood aspect of parasite pathogenesis ? how does T. gondii migrate through the brain? Evidence suggests that T. gondii infection of migratory leukocytes, such as microglia and monocytes, facilitates their dissemination. For the parent R01, the objective of the proposal is to define how T. gondii induces monocyte motility and disseminates through the brain.
Two aims were proposed to test the hypothesis: 1) Determine how T. gondii enhances the migration of infected cells, and 2) Define how T. gondii disseminates through the infected brain. In the second aim, we have been using intravital two-photon imaging of the brains of T. gondii-infected mice to define the myeloid cell type(s) that are infected and potentiate parasite spread through the brain. Transgenic mice that express fluorescent monocytes or microglia are infected with T. gondii, and the dynamics of their migration through the parenchyma is determined during acute infection and in chronically-infected mice undergoing parasite reactivation. Alzheimer?s disease is associated with an accumulation of amyloid b (Ab) plaques in the brain. Microglia are found surrounding Ab plaques in Alzheimer?s disease mouse models, but these microglia are incapable of clearing the amyloid. Interestingly, T. gondii infection of Alzheimer?s disease mouse models causes a reduction in Ab plaques in the brain and improved cognition, but the mechanism of this neuroprotective effect is poorly understood. Data we collected as part of the parent R01 show that T. gondii induces a significant monocyte infiltration of the brain, which is associated with increased microglial activation. Based on these data, we hypothesize that T. gondii infection of Alzheimer?s disease mice re-activates the phagocytic potential of microglia and enhances their clearance of Ab plaques. The objective of the Administrative Supplement is to utilize the same intravital imaging approaches we are using to examine microglial dynamics in the parent R01 to determine how microglia respond to Ab plaques during T. gondii infection of Alzheimer?s disease mice. The proposed experiments fit squarely within the scope of Aim 2 of the parent R01, as the experimental workflow to track microglial responses in the brain is currently being used to address Aim 2 of the parent R01. This proposal will leverage the resources of the Alzheimer?s Disease Research Center (ADRC) at UC Irvine, a center of excellence funded by the NIA. The significance of this research is that understanding how T. gondii infection alters amyloid dynamics may allow for the development of therapeutic interventions to reduce neurotoxicity during Alzheimer?s disease.
Toxoplasma gondii is an opportunistic parasite that infects the brain and can cause life-threatening encephalitis in immune-compromised individuals. Interestingly, T. gondii infection of mouse models of Alzheimer?s disease results in a reduction in Alzheimer?s disease pathology in the brain. The proposed research aims to enhance our understanding of this process, which may allow for targeted interventions that limit neurodegeneration and Alzheimer?s disease.
| Lima, Tatiane S; Gov, Lanny; Lodoen, Melissa B (2018) Evasion of Human Neutrophil-Mediated Host Defense during Toxoplasma gondii Infection. MBio 9: |
| Cook, Joshua H; Ueno, Norikiyo; Lodoen, Melissa B (2018) Toxoplasma gondii disrupts ?1 integrin signaling and focal adhesion formation during monocyte hypermotility. J Biol Chem 293:3374-3385 |
| Gov, Lanny; Schneider, Christine A; Lima, Tatiane S et al. (2017) NLRP3 and Potassium Efflux Drive Rapid IL-1? Release from Primary Human Monocytes during Toxoplasma gondii Infection. J Immunol 199:2855-2864 |
| Chen, E Y; Chu, S; Gov, L et al. (2017) CD200 modulates macrophage cytokine secretion and phagocytosis in response to poly(lactic co-glycolic acid) microparticles and films. J Mater Chem B 5:1574-1584 |
