Biology subjects

Gefen, T.

Publications and source records attributed to Gefen, T..

3 recordsLinked to original sources

bioRxiv2025

Influenza A infection accelerates disease-associated microglia formation during physiological aging

Severe pneumonia is associated with an increased risk of cognitive decline and dementia, particularly in the elderly. Changes in microglia, the most abundant immune cell population in the brain, are also associated with cognitive decline and dementia, including the emergence of a transcriptional cell state referred to as disease-associated microglia (DAM). We sought to test the hypothesis that non-neuroinvasive influenza A virus (IAV) pneumonia results in transcriptional responses in brain microglia that drive premature expansion of DAM. Using bulk and single-cell RNA-sequencing, metabolomics, and spatial transcriptomics, we profiled neuroimmune populations in young, middle-aged, and old male mice during IAV infection and recovery. We observed an increased abundance of DAM, interferon-responsive microglia (IRM), CD4+ T cells, and CD8+ T cells in white matter regions beginning in middle age and persisting in old animals, irrespective of IAV infection. DAM exhibited a metabolic shift toward aerobic glycolysis with disrupted TCA cycling, citrulline depletion, and an elevated itaconate/-ketoglutarate ratio. Spatial transcriptomic profiling of the human middle frontal gyrus (MFG) in normal agers, SuperAgers, and patients with dementia revealed an analogous accumulation of DAM and CD8+ T cells in white matter. IAV pneumonia induced a transient immunosenescent-like response in microglia, marked by glucocorticoid-responsive gene expression and Ccnd3 upregulation. In response to IAV pneumonia, DAM expanded in middle-aged mice, whereas old mice were elevated at baseline and were largely unaffected by IAV infection. The age-related expansion of DAM was unaffected by pharmacological depletion and repopulation of microglia with a CSF1R antagonist or genetic gain or loss of function of the phagocytic receptor MERTK, suggesting the DAM phenotype is driven by the CNS microenvironment, rather than cell-intrinsic mechanisms. Our findings suggest that IAV pneumonia induces an acute immunosenescence response in microglia and accelerates the age-dependent expansion of DAM in white matter.

neuroscience↗

bioRxiv2025

Bacteriophage-driven DNA inversions shape bacterial functionality and long-term co-existence in Bacteroides fragilis

Bacterial genomic DNA inversions, which govern molecular phase-variations, provide the bacteria with functional plasticity and phenotypic diversity. These targeted rearrangements enable bacteria to respond to environmental challenges, such as bacteriophage predation, evading immune detection or gut colonization. This study investigated the short- and long-term effects of the lytic phage Barc2635 on the functional plasticity of Bacteroides fragilis, a gut commensal. Germ-free mice were colonized with B. fragilis and exposed to Barc2635 to identify genomic alterations driving phenotypic changes. Phage exposure triggered dynamic and prolonged bacterial responses, including significant shifts in phase-variable regions (PVRs), particularly in promoter orientations of polysaccharide biosynthesis loci. These shifts coincided with increased entropy in PVR inversion ratios, reflecting heightened genomic variability. In contrast, B. fragilis in control mice exhibited stable genomic configurations after gut adaptation. The phase-variable Type 1 restriction-modification system, which affects broad gene expression patterns, showed variability in both groups. However, phage-exposed bacteria displayed more restrained variability, suggesting phage-derived selection pressures. Our findings reveal that B. fragilis employs DNA inversions to adapt rapidly to phage exposure and colonization, leveraging genomic variability for resilience. This study emphasizes gut bacterial genomic and phenotypic plasticity upon exposure to the mammalian host and to bacteriophages.

microbiology↗

bioRxiv2023

Inflammation and bacteriophages affect DNA inversion states and functionality of the gut microbiota

Reversible genomic DNA-inversions control expression of numerous bacterial molecules in the human gut, but how this relates to disease remains uncertain. By analyzing metagenomic samples from six human Inflammatory Bowel Disease cohorts combined with mice experimentation, we identified multiple invertible regions where a particular orientation was correlated with disease. These include the promoter of the anti-inflammatory polysaccharide-A (PSA) of Bacteroides fragilis, which is mostly oriented OFF during inflammation but is present in the ON orientation when inflammation is resolved. We further detected increased abundances of B. fragilis-associated bacteriophages in patients with the PSA OFF orientation, and a significant reduction in the frequency of the ON orientation, in the presence of the B. fragilis-associated bacteriophage, thereby altering the bacterial induced immune modulation. Altogether, we reveal dynamic and reversible bacterial phase-variations driven both by bacteriophages and the host inflammatory state, signifying bacterial functional plasticity during inflammation and opening future research avenues.

microbiology↗