Regulation of Monocyte Entry to the Brain During Neuroinflammation

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Project Summary Neuroinflammation can have both protective and detrimental outcomes in brain health, depending on the context. Immune cells that traffic to the brain may be critical for recognizing and defending against brain- infiltrating pathogens. However, excessive inflammation can lead to neuroinflammatory diseases and brain injury. Therefore, the immune system must be tightly controlled to maintain a balance that allows for host defense against infections in the brain without causing neuropathology. The long-term goal of our research is to define the factors that regulate immune cell infiltration to the central nervous system and neuroinflammation. Monocytes are inflammatory immune cells that circulate in the blood and function in host defense. They are recruited to the central nervous system (CNS) during infection with Toxoplasma gondii, a foodborne parasite that establishes chronic infection in CNS and can cause fatal encephalitis in immune-compromised individuals. Although monocytes are essential for controlling T. gondii infection in the brain, the factors that regulate their trafficking to the CNS remain poorly understood. We recently found that inflammatory monocytes preferentially infiltrate the olfactory tubercle, an interconnected brain region involved in neural processing of sensory information guiding motivated behaviors. The goal of this project is to determine the cellular and molecular basis for monocyte recruitment to the CNS and into specific brain regions. Based on strong preliminary data, we hypothesize that NK cells, adhesion molecules, chemokines, and alarmins released during brain injury contribute to monocyte recruitment to the brain. Aim 1 will determine the role of NK cells in regulating monocyte recruitment to the brain during T. gondii infection in mice. Aim 2 will determine the molecular basis for region-specific monocyte recruitment to the brain. This work is significant because an understanding of the factors regulating monocyte infiltration of the brain may enable the development of strategies to modulate neuroinflammation during CNS disease. My previous training focused on microbiology and the microbiome. The proposed research project will provide me with new training in immunology and neurobiology in the context of infectious disease and enable me to develop skills in immunological methods and high-resolution microscopy. UC Irvine is an R1 institution and Hispanic-serving institution that has demonstrated a commitment to training diverse undergraduate and graduate student populations. Also, UC Irvine was awarded funding for the NIH-BEST program, which exposes graduate students to training opportunity outside of academia and offers courses to improve the communication skills of students. The training and mentoring offered by the Sponsor and Co-Sponsor, highly collaborative and diverse scientific environment, seminars, and conferences available at UC Irvine will provide the guidance and training in research and teaching to help me develop into a successful scientist and prepare me for a future career in academic research as an independent investigator.