STAT1 signaling as a regulator of microglial activation and resistance to CNS infection

Cowan, Maureen, Neuroscience - School of Medicine, University of Virginia
Cowan, Maureen, Neuroscience, University of Virginia

During central nervous system (CNS) infection, the immune system must balance between combating an invading pathogen and preventing excessive inflammation that destroys neural tissue. This balance of control is seen in the case of CNS infection by the ubiquitous neurotropic parasite, Toxoplasma gondii. While relatively benign in immunocompetent individuals, CNS infection with T. gondii must be tightly regulated by the immune system to prevent fatal toxoplasmic encephalitis. In comparison to the extensive characterization of microglia, the resident immune cells of the brain, in neurodevelopmental and neurodegenerative contexts over the past decade, the topic of microglial functional roles during infection models has been surprisingly limited. Several studies have demonstrated brain-resident microglia are functionally distinct from blood-derived myeloid cells that infiltrate the brain and resemble microglia during neuroinflammation. These findings have prompted the need to investigate these distinct myeloid populations independently during infection.

In order to study microglial immune function, we used a genetic targeting approach to generate mice with disrupted IFN-γ-STAT1 signaling specifically in brain-resident microglia. Genetic deletion of Stat1, a transcription factor that is critical for generating cellular responses against intracellular infections, induced a loss of parasite control specific to the brain and uniform lethality in mice challenged with T. gondii. We found that STAT1-deficient mice displayed efficient parasite clearance and immune responses in multiple tissues outside of the brain, and observed that brain-specific pathology occurred despite increased anti-parasitic immune activation in both blood-derived myeloid and T cells within the brain. These results indicated that STAT1-deficiency within the brain-resident microglial compartment was sufficient to induce severe toxoplasmic encephalitis (TE) for which the peripheral immune compartment was unable to compensate – thus underscoring the importance of microglial STAT1-mediated activation in anti-microbial defense.

Contrary to previous in vitro reports, we also found that microglia do not express inducible nitric-oxide synthase (iNOS) during T. gondii infection in vivo. Instead, transcriptomic analyses of microglia reveal that STAT1 regulates both (i) a transcriptional shift from homeostatic to “disease-associated microglia” (DAM) phenotype conserved across several neuroinflammatory models, including T. gondii infection, and (ii) the expression of anti-parasitic cytosolic molecules that are required for eliminating T. gondii in a cell-intrinsic manner. Finally, we show that microglial STAT1-deficiency results in the overrepresentation of the highly replicative, lytic tachyzoite form of T. gondii, relative to its quiescent, semi-dormant bradyzoite form typical of chronic CNS infection. Our data suggest an overall protective role of CNS-resident microglia against T. gondii infection, illuminating (i) general mechanisms of CNS-specific immunity to infection (ii) and a clear role for IFN-STAT1 signaling in regulating a microglial activation phenotype observed across diverse neuroinflammatory disease states.

PHD (Doctor of Philosophy)
Microglia, CNS infection, Neuroimmunology
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