Seilhean, D. | bioRxiv Science

bioRxiv2024

Mechanism of neurodegeneration mediated by clonal inflammatory microglia

Langerhans cell Histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders, associated with MAP-Kinase activating mutations and an increased risk of neurodegeneration. Surprisingly, we found pervasive PU.1+ microglia mutant clones across the brain of LCH and ECD patients with and without neurological symptoms, associated with microgliosis, reactive astrocytosis, and neuronal loss. The disease predominated in the grey nuclei of the rhombencephalon, a topography attributable to a local proliferative advantage of mutant microglia. Presence of clinical symptoms was associated with a longer evolution of the disease and a larger size of PU.1+ clones (p= 0.0003). Genetic lineage tracing of PU.1+ clones suggest a resident macrophage lineage or a bone marrow precursor origin depending on patients. Finally, a CSF1R-inhibitor depleted mutant microglia and limited neuronal loss in mice suggesting an alternative to MAPK inhibitors. These studies characterize a progressive neurodegenerative disease, caused by clonal proliferation of inflammatory microglia (CPIM), with a decade(s)-long preclinical stage of incipient disease that represent a therapeutic window for prevention of neuronal death.

immunology↗

bioRxiv2022

Imbalanced immune response and dysregulation of neural functions underline fatal opportunistic encephalitis caused by astrovirus

The incidence of infections of the central nervous system (CNS) in humans is increasing due to emergence and reemergence of pathogens and an increase in the number of immunocompromised patients. Many viruses are opportunists and can invade the CNS if the immune response of the host is impaired. Here we investigate neuropathogenesis of a rare CNS infection in immunocompromised patients caused by astrovirus and show that it shares many features with another opportunistic infection of the CNS caused by human immunodeficiency virus. We show that astrovirus infects CNS neurons with a major impact on the brainstem. In the setting of impaired peripheral adaptive immunity, host responses in the astrovirus infected brain are skewed to the innate immune response with exuberant activation of microglia and macrophages. Astrovirus infection of neurons and responses by phagocytic cells lead to disrupted synaptic integrity, loss of afferent innervation related to infected neurons, and global impairment of both excitatory and inhibitory neurotransmission. The response employed in the CNS against opportunistic viruses, such as astrovirus and HIV, may be a common compensatory defense mechanism which inadvertently leads to loss of neural functions due to the hosts exuberant innate immune response to pathogens when adaptive immunity is impaired.

microbiology↗