Biology subjects

Furman, S.

Publications and source records attributed to Furman, S..

5 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↗

bioRxiv2025

Infection of 5xFAD mice with a mouse-adapted SARS-CoV-2 does not alter Alzheimer's disease neuropathology yet induces wide-spread changes in gene expression across diverse cell types

Alzheimers disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia. It is characterized by cognitive decline and accumulation of amyloid beta (A{beta}) plaques and neurofibrillary tangles. Accumulating evidence indicates that viral infection may worsen and/or increase development of established AD pathology. The COVID-19 pandemic has brought attention to the link between SARS-CoV-2 infection and neurologic conditions that vary in severity and duration, as well as the worsening of clinical symptoms in elderly people with dementia. To better understand potential mechanisms by which SARS-CoV-2 infection impacts AD neuropathology, aged 5xFAD and wildtype (WT) mice were intranasally infected with mouse-adapted SARS-CoV-2 (MA10). Intranasal infection of aged-matched (10-14 month) 5xFAD or wild type (WT) C57BL/6 mice with MA10 resulted in viral infection of the lungs that correlated with acute viral pneumonia characterized by lymphocyte inflammation and antiviral immune responses. Viral RNA was not detected within the central nervous system (CNS) of either WT or 5xFAD mice at days 7 or 21 post-infection (p.i.), nor were there signs of overt glial activation or neuroinflammation. There were no differences in either A{beta} plaque volume or number within the brains of MA10-infected 5xFAD mice compared to uninfected 5xFAD mice. However, bulk RNA sequencing and spatial transcriptomics revealed evidence of altered expression of genes associated with neuronal and glial dysfunction, as well as reduced expression of genes encoding adhesion molecules in vascular endothelial cells. Collectively, these findings demonstrate that MA10 infection did not affect A{beta} plaque size or numbers in 5xFAD mice, yet in both WT and 5xFAD mice, there were numerous down-stream effects on gene expression associated with resident CNS cell function.

pathology↗

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↗

bioRxiv2020

Unsupervised cellular phenotypic hierarchy enables spatial intratumor heterogeneity characterization, recurrence-associated microdomains discovery, and harnesses network biology from hyperplexed in-situ fluorescence images of colorectal carcinoma

LEAPH is an unsupervised machine learning algorithm for characterizing in situ phenotypic heterogeneity in tissue samples. LEAPH builds a phenotypic hierarchy of cell types, cell states and their spatial configurations. The recursive modeling steps involve determining cell types with low-ranked mixtures of factor analyzers and optimizing cell states with spatial regularization. We applied LEAPH to hyperplexed (51 biomarkers) immunofluorescence images of colorectal carcinoma primary tumors (N=213). LEAPH, combined with pointwise mutual information (PMI), enables the discovery of phenotypically distinct microdomains, composed of spatially configured computational phenotypes. LEAPH identified a subset of microdomains visualized as the spatial configuration of recurrence-specific signaling networks whose intracellular and intercellular interactions support cancer stem cell maintenance and immunosuppression in the evolving tumor microenvironment. The LEAPH framework, when combined with microdomain discovery and microdomain-specific network biology, has the potential to provide insights into pathophysiological mechanisms, identify novel drug targets and inform therapeutic strategies for individual patients.

cancer biology↗

bioRxiv2019

A spatial analytics computational and systems biology platform predicts risk of colorectal cancer recurrence and identifies emergent spatial domain networks associated with recurrence

An unmet clinical need in solid tumor cancers is the ability to harness the intrinsic spatial information in primary tumors that can be exploited to optimize prognostics, diagnostics and therapeutic strategies for precision medicine. We have developed a transformational spatial analytics (SpAn) computational and systems biology platform that predicts clinical outcomes and captures emergent spatial biology that can potentially inform therapeutic strategies. Here we apply SpAn to primary tumor tissue samples from a cohort of 432 chemo-naive colorectal cancer (CRC) patients iteratively labeled with a highly multiplexed (hyperplexed) panel of fifty-five fluorescently tagged antibodies. SpAn predicted the 5-year risk of CRC recurrence with a mean area under the ROC curve of 88.5% (SE of 0.1%), significantly better than current state-of-the-art methods. SpAn also inferred the emergent network biology of the tumor spatial domains revealing a synergistic role of known features from CRC consensus molecular subtypes that will enhance precision medicine.

cancer biology↗