UNLABELLED

is a foodborne intracellular parasite that chronically infects the brain. Although infection elicits a protective immune response, the nature of the monocyte response in the immediate vicinity of parasites during initial brain infection is not well understood. By infecting mice with and comparing areas of the brain containing or not containing parasites, we found an increase in CCR2 monocytes, IBA1 myeloid cells, GFAP astrocytes, and CD68 signal near parasites in the brain, indicating immune cell infiltration and phagolysosomal activation in response to the infection. CCR2CD68 monocytes were specifically increased near tachyzoites with minimal localization of these cells near cysts in the brain. This monocyte response was also detected near parasite-interacted cells, identified using parasites that inject Cre recombinase into "interacted" cells of Ai6 CCR2 mice, enabling us to track these events . The chemokine CCL2 and its transcription factor NF-κB were also upregulated surrounding parasites in the brain; however, the effector protein GRA15, which sustains NF-κB activation in infected cells, was not required for CCL2 production, NF-κB activation, or myeloid cell recruitment to parasites in the brain. In contrast, active replication played a more significant role, as CCR2 monocytes were recruited to replication-competent but not replication-deficient delivered via intracranial injection into mice. These findings provide novel insights into the drivers of immune cell mobilization and activation in the brain during initial central nervous system infection and highlight the importance of parasite replication in this process.

IMPORTANCE

is a brain-infecting parasite, and the mobilization of peripheral immune cells to the brain is critical for controlling infection. However, the initial events driving these cells to sites of infection in the brain are poorly understood. We show that peripheral myeloid immune cell recruitment and activation are specific to areas of the brain containing actively replicating parasites, which are capable of lysing host cells. This local immune response is characterized by focal chemokine production, myeloid cell recruitment, and the activation of phagolysosomal pathways. These highly localized host responses were independent of the parasite effector protein that induces NF-κB activation within infected cells, GRA15. However, the localized monocyte recruitment was dependent on live parasites and active parasite replication. This research highlights the importance of host cell sensing of parasite replication in the brain for immune control of infection.