Neutrophils in the brain are sources of neuroprotective molecules and demonstrate functional heterogeneity during chronic Toxoplasma gondii infection

Infection with the protozoan parasite Toxoplasma gondii leads to the formation of lifelong cysts in neurons of the brain that can have devastating consequences in the immunocompromised. However, despite the establishment of a chronic inflammatory state and infection-induced neurological changes, there are limited signs of clinical neuropathology resulting in an asymptomatic infection in the immunocompetent. This suggests the work of neuroprotective mechanisms to prevent clinical manifestations of disease. However, such sources of neuroprotection during infection remain largely unknown. This study identifies a population of neutrophils chronically present in the brain during Toxoplasma infection that express the neuroprotective molecules NRG-1, ErbB4, and MSR1. Further phenotyping of this population via flow cytometry and singe-cell RNA sequencing reveals two distinct subsets of neutrophils based on age that display functional heterogeneity. This includes cells transcriptionally prepared to function both as anti-parasitic effector cells and in a more alternative protective manner. Chronic depletion of neutrophils results in increased parasite burden and infection-induced vascular pathology. Lack of neutrophils during chronic infection also deleteriously affects neuronal regeneration and repair mechanisms. In conclusion, this work identifies and demonstrates a functionally diverse chronic neutrophil population that plays a dynamic role in controlling infection outcome in the CNS by balancing classical responses with neuroprotective functions. Author SummaryThe predominantly asymptomatic nature of chronic Toxoplasma gondii infection despite the life-long infection of neurons suggests that there are neuroprotective mechanisms at work in the brain to maintain homeostasis and integrity. This study identifies neutrophils, normally considered a first-responding innate immune cell, as a prominent source of neuroprotective molecules during Toxoplasma infection. Aged neutrophils in the brain exhibit an ability to be functionally flexible expressing signatures of classical proinflammatory responses; and neuroprotective, pro-angiogenic indicators. Lack of neutrophils during chronic infection leads to increased parasite burden, increased vascular damage, and decreased neuronal regeneration. We conclude that chronic brain neutrophils are a functionally dynamic population and a source of neuroprotection during infection and suggest that this is a potentially novel target to promote brain tissue repair without compromising anti-microbial activity.