UC Irvine

Inflammation is a tightly regulated process necessary to protect the body against infection but, in excess, can be dangerous and lead to damage. Toxoplasma gondii is an obligate intracellular foodborne pathogen with the unique ability to cross the blood-brain barrier and form lifelong parasite cysts in neurons. This infection drives a protective immune response in the brain that can control parasitic growth but not clear the infection. CCR2 chemokine receptor-expressing monocytes play a necessary role in controlling T. gondii infection both in the periphery and the brain. Once in the brain, monocytes are specifically recruited to areas containing clusters of T. gondii. However, the drivers of monocyte recruitment to sites of infection, specifically to areas containing T. gondii, are not well understood. This research aimed to understand the signals that drive protective immunity against T. gondii infection. In the brain, we did determine a critical role for chemokine production in neuroinflammation. In the brain, we determined that the cells producing the potent CCR2-binding chemokine, CCL2, changed over the course of infection: microglia were the main CCL2 producers during acute infection, whereas astrocytes became the dominant CCL2 producers during chronic infection. Interestingly, the ablation of CCL2 production from astrocytes reduced immune cell recruitment to the brain during chronic infection and decreased control of the parasitic infection. We also found that activation of the transcription factor, NF-B, and CCL2 production are increased near parasites in the brain. However, the parasite effector protein GRA15 does not drive immune cell recruitment to parasites. Furthermore, T. gondii replication and host cell lysis play significant roles in driving immune cells to parasites in the brain. Additionally, we found that Piezo1 is upregulated during infection and Piezo1 expression in myeloid cells aids in parasite dissemination to the liver during early acute infection. However, Piezo1 expression in myeloid cells does not affect dissemination to the brain during late acute infection nor control of parasitic burden throughout chronic infection. Collectively, this work highlights the role of host cell responses to T. gondii in driving immune cell recruitment to control parasitic infection.