Biology subjects

Tsourmas, K. I.

Publications and source records attributed to Tsourmas, K. I..

4 recordsLinked to original sources

bioRxiv2026

Characterization of effects of a neurotropic murine coronavirus infection on Alzheimer's disease neuropathology of 5xFAD mice

BackgroundRecent studies revealed key immunological mechanisms within the central nervous system (CNS) that contribute to Alzheimers disease pathology. Additionally, analyses of human AD datasets have also associated viral encephalitis exposure (i.e., viral-induced neuroinflammation) with the development of AD and dementia, highlighting the need to better understand how viral encephalitis and neuroimmune mechanisms within the brain may impact AD pathologies such as A{beta} plaque deposition. Intracranial infection of susceptible mice with the neurotropic JHM strain of murine coronavirus (JHMV) results in acute encephalomyelitis characterized by viral infection of glia and a robust inflammatory response comprised of monocytes/macrophages and T cells that aid in controlling viral replication. MethodsTo determine how coronavirus-induced encephalitis may impact established A{beta} plaque deposition, we intracranially inoculated JHMV into aged 5xFAD model of amyloidosis. We utilize immunohistochemical and biochemical analysis to assess the impact on existing A{beta} pathology. We also utilize spatial transcriptomic imaging to explore how viral encephalitis affects cellular responses to plaque pathology with single-cell resolution. ResultsIn aged 5xFAD mice, JHMV-induced encephalitis at 12 days p.i. resulted in minimal changes to overall A{beta} protein within the brain. However, viral encephalitis induces CD4+ and CD8+ T cell infiltration and more Lgals3/MAC2-expressing macrophages surrounding dense-core A{beta} plaques, which appear more compacted in JHMV-infected 5xFAD brains compared to uninfected 5xFAD controls. We compared gene expression within JHMV-infected 5xFAD mice and uninfected controls to identify distinct cellular responses to A{beta} plaques that differed. Utilizing differential gene expression and pathway analysis, we found that viral encephalitis increased the proportion of myeloid cells in the 5xFAD brain, which also showed down-regulated disease-associated (DAM) pathways involving A{beta} clearance, response to lipids, and macrophage activation within the post-encephalitis 5xFAD brains. ConclusionsTogether, these findings suggest an attenuated myeloid cell response to A{beta} plaque burden in 5xFAD mice following acute viral encephalitis. Future experiments aim to further dissect inflammatory mechanisms between infiltrating myeloid cells, T cells, and the progression of A{beta} and tau pathology. Data derived from these experiments will further elucidate the viral-induced neuroimmune mechanisms that affect AD pathology and offer an opportunity to determine how these neuropathologic changes, such as subsequent neuronal damage, occur.

neuroscience↗

bioRxiv2024

Myeloid-derived β-hexosaminidase is essential for neuronal health and lysosome function: implications for Sandhoff disease

Lysosomal storage disorders (LSDs) are a large disease class involving lysosomal dysfunction, often resulting in neurodegeneration. Sandhoff disease (SD) is an LSD caused by a deficiency in the {beta} subunit of the {beta}-hexosaminidase enzyme (Hexb). Although Hexb expression in the brain is specific to microglia, SD primarily affects neurons. To understand how a microglial gene is involved in maintaining neuronal homeostasis, we demonstrated that {beta}-hexosaminidase is secreted by microglia and integrated into the neuronal lysosomal compartment. To assess therapeutic relevance, we treated SD mice with bone marrow transplant and colony stimulating factor 1 receptor inhibition, which broadly replaced Hexb-/- microglia with Hexb-sufficient cells. This intervention reversed apoptotic gene signatures, improved behavior, restored enzymatic activity and Hexb expression, ameliorated substrate accumulation, and normalized neuronal lysosomal phenotypes. These results underscore the critical role of myeloid-derived {beta}- hexosaminidase in neuronal lysosomal function and establish microglial replacement as a potential LSD therapy.

neuroscience↗

bioRxiv2024

Generation of an inducible destabilized-domain Cre mouse line to target disease associated microglia

The function of microglia during progression of Alzheimers disease (AD) can be investigated using mouse models that enable genetic manipulation of microglial subpopulations in a temporal manner. We developed a mouse strain that expresses destabilized-domain Cre recombinase (DD-Cre) from the Cst7 locus (Cst7DD-Cre) and tested this in 5xFAD amyloidogenic, Ai14 tdTomato cre-reporter line mice. Dietary administration of trimethoprim to induce DD-Cre activity produces long-term labeling in disease associated microglia (DAM) without evidence of leakiness, with tdTomato-expression restricted to cells surrounding plaques. Using this model, we found that DAMs are a subset of plaque-associated microglia (PAMs) and their transition to DAM increases with age and disease stage. Spatial transcriptomic analysis revealed that tdTomato+ cells show higher expression of disease and inflammatory genes compared to other microglial populations, including non-labeled PAMs. This model should allow inducible cre-loxP targeting of DAMs, without leakiness. HighlightsO_LIWe developed a new mouse strain which specifically enables recombination of loxP sites in disease associated microglia (DAMs) and can be used to manipulate DAM-gene expression. C_LIO_LIDAMs represent a subset of plaque associated microglia (PAMs), and DAM expression increases with disease progression. C_LIO_LISpatial transcriptomic analyses reveal that DAMs have higher expression of disease and inflammatory genes compared to other PAMs. C_LI

neuroscience↗

bioRxiv2021

Microglia do not restrict SARS-CoV-2 replication following infection of the central nervous system of K18-hACE2 transgenic mice

Unlike SARS-CoV-1 and MERS-CoV, infection with SARS-CoV-2, the viral pathogen responsible for COVID-19, is often associated with neurologic symptoms that range from mild to severe, yet increasing evidence argues the virus does not exhibit extensive neuroinvasive properties. We demonstrate SARS-CoV-2 can infect and replicate in human iPSC-derived neurons and that infection shows limited anti-viral and inflammatory responses but increased activation of EIF2 signaling following infection as determined by RNA sequencing. Intranasal infection of K18 human ACE2 transgenic mice (K18-hACE2) with SARS-CoV-2 resulted in lung pathology associated with viral replication and immune cell infiltration. In addition, [~]50% of infected mice exhibited CNS infection characterized by wide-spread viral replication in neurons accompanied by increased expression of chemokine (Cxcl9, Cxcl10, Ccl2, Ccl5 and Ccl19) and cytokine (Ifn-{lambda} and Tnf-) transcripts associated with microgliosis and a neuroinflammatory response consisting primarily of monocytes/macrophages. Microglia depletion via administration of colony-stimulating factor 1 receptor inhibitor, PLX5622, in SARS-CoV-2 infected mice did not affect survival or viral replication but did result in dampened expression of proinflammatory cytokine/chemokine transcripts and a reduction in monocyte/macrophage infiltration. These results argue that microglia are dispensable in terms of controlling SARS-CoV-2 replication in in the K18-hACE2 model but do contribute to an inflammatory response through expression of pro-inflammatory genes. Collectively, these findings contribute to previous work demonstrating the ability of SARS-CoV-2 to infect neurons as well as emphasizing the potential use of the K18-hACE2 model to study immunological and neuropathological aspects related to SARS-CoV-2-induced neurologic disease. ImportanceUnderstanding the immunological mechanisms contributing to both host defense and disease following viral infection of the CNS is of critical importance given the increasing number of viruses that are capable of infecting and replicating within the nervous system. With this in mind, the present study was undertaken to evaluate the role of microglia in aiding in host defense following experimental infection of the central nervous system (CNS) of K18-hACE2 with SARS-CoV-2, the causative agent of COVID-19. Neurologic symptoms that range in severity are common in COVID-19 patients and understanding immune responses that contribute to restricting neurologic disease can provide important insight into better understanding consequences associated with SARS-CoV-2 infection of the CNS.

microbiology↗