Microglial STAT1-sufficiency is required for resistance to toxoplasmic encephalitis

Area of Science:

• Neuroimmunology
• Infectious Diseases
• Cellular Biology

Background:

• Toxoplasma gondii establishes chronic central nervous system (CNS) infections, requiring constant immune pressure, particularly IFN-γ-STAT1 signaling, to prevent pathology.
• Microglia, the resident CNS immune cells, are implicated in controlling T. gondii, but their specific role and mechanisms, especially concerning STAT1 signaling, remain incompletely understood in vivo.

Purpose of the Study:

• To investigate the role of STAT1 signaling specifically within microglia in controlling chronic Toxoplasma gondii infection in the CNS.
• To elucidate the molecular mechanisms by which microglial STAT1 signaling impacts parasite control and neuroinflammation during T. gondii infection.

Main Methods:

• Utilized a microglia-specific genetic labeling and targeting system to differentiate microglia from infiltrating myeloid cells.
• Employed transcriptomic analyses to identify STAT1-regulated pathways in microglia during infection.
• Generated microglia-specific Stat1 knockout mice to assess the in vivo consequences of abrogated STAT1 signaling on parasite control and pathology.

Main Results:

• Abrogation of STAT1 signaling in microglia led to a loss of parasite control and susceptibility to toxoplasmic encephalitis, even with intact peripheral immune responses.
• STAT1 in microglia regulates a conserved transcriptional shift to a disease-associated microglia (DAM) phenotype and controls the expression of anti-parasitic molecules.
• Microglial STAT1 deficiency resulted in the overrepresentation of the replicative tachyzoite form of T. gondii, indicating impaired parasite elimination.

Conclusions:

• CNS-resident microglia play a critical protective role against T. gondii infection through STAT1-dependent mechanisms.
• IFN-γ-STAT1 signaling in microglia is essential for maintaining parasite control and preventing fatal neuroinflammation by modulating microglial phenotype and intrinsic anti-parasitic functions.
• These findings reveal general mechanisms of CNS immunity and highlight the importance of microglial STAT1 in diverse neuroinflammatory conditions.