UC Riverside

Infection with the protozoan parasite Toxoplasma gondii leads to the formation of lifelong cysts inside neurons in the brain of its host, and it is estimated that approximately one third of the world’s population is infected. Infection in the immunocompromised can cause severe clinical manifestations like neuropathology, toxoplasmic encephalitis, and death. While chronic infection can lead to severe clinical manifestations of disease, infection in immunocompetent hosts remains largely asymptomatic. This suggests there are neuroprotective mechanisms at work that preserve neuronal integrity and maintain a balanced brain environment during chronic infection, but these mechanisms remain largely unknown. The concept of neuroprotection has been demonstrated in other models of central nervous system (CNS) injury and infection such as ischemic stroke and experimental cerebral malaria through the work of neuroprotective molecules such as the NRG-1/ErbB4 signaling pathway and MSR1. In addition, innate and adaptive immune cell responses to chronic Toxoplasma infection play a large role in balancing the fragile CNS environment and preventing clinical manifestations of disease. This collective study identifies host- and parasite-specific transcriptional changes relating to infection-induced neuropathology and neuroprotective repair mechanisms in the CNS via targeted transcriptomic analysis. Through the employment of various techniques such as multi-parameter flow cytometry, single-cell RNA sequencing, and in vivo depletion experiments, it explores a population of functionally heterogenous neutrophils that play a protective role in the brain throughout chronic infection. Additionally, in vitro work using human neutrophil-like cells demonstrates cyst-specific responses tailored to chronic infection. Taken together, this overall study provides important insights into the dependence of neuroprotective mechanisms on host immune status, characterizes a protective chronic neutrophil population, and bridges the gap between neutrophil responses in murine and human models of chronic T. gondii infection.