Biology subjects

Funk, K. E.

Publications and source records attributed to Funk, K. E..

3 recordsLinked to original sources

bioRxiv2026

CD8⁺ T cells induce interstrand crosslinking-associated DNA damage in neurons

Viral pathogens cause neurologic sequelae during acute and post-acute phases of infection. CD8+ T cells are hypothesized to contribute to these effects, but the mechanisms through which they act are poorly understood. We posited that viral infections and/or antiviral immune responses induce DNA damage, which may underlie neuronal dysfunction. Using a model of neurotropic flavivirus infection, we found that genes associated with interstrand crosslinking (ICL) DNA damage were upregulated post-infection, temporally congruent with T cell infiltration. Using an in vitro co-culture system, our results demonstrate that CD8+ T cells induced ICL-like damage in primary neurons, independent of antigen-specific interactions or direct contact. Human transcriptomic data also showed overexpression of genes associated with ICL damage in the brains of people with Parkinsons disease, Alzheimers disease, and multiple sclerosis, which are neurologic diseases characterized by neuroinflammation. Together, these data indicate that CD8+ T cells cause genotoxic DNA damage in neurons, which may underlie the neurologic dysfunction seen in neurodegenerative conditions. SummaryResults indicate that CD8+ T cells induce interstrand crosslinking-like DNA damage in neurons independent of antigen-specificity in a mouse model of viral infection, in vitro primary cell culture system, and human neurologic diseases. These findings provide insight on the mechanistic connection between neuroinflammation and neurologic dysfunction.

immunology↗

bioRxiv2026

RNA-seq variants reveal distinct patterns in the aging epitranscriptome: an in-depth analysis of age-matched Alzheimer's Disease patients and a cognitively normal cohort

BackgroundPost-transcriptional modifications are those made to the RNA transcript, which can modulate RNA stability and function. Despite robust investigation of the genome, transcriptome, and proteome, little is known about post-transcriptional modifications during normal aging or Alzheimers disease (AD) pathogenesis. Several studies have shown epitranscriptomic changes in AD brains for certain modification types, establishing epitranscriptomic links to the disease; however, the complete set of post-transcriptional modifications have not been assessed in the context of AD. Furthermore, it is not understood which genes or pathways are under epitranscriptomic regulation, how conserved and sporadic modifications are distributed, or which conserved sites are differentially modified in diseased brains. Therefore, there is a need for a more complete analysis to describe the full landscape of the epitranscriptome in AD, helping to bridge the knowledge gap between post-transcriptional modifications and the molecular etiology of AD. MethodsWe designed and implemented a novel bioinformatics pipeline for complex epitranscriptome-wide analysis of potential RNA modification sites in sample-matched, whole-genome sequencing-filtered variant calls from RNA sequencing data. Using parametric and non-parametric tests, we tested differences in patterns for all detectable variant calls between postmortem brains of AD and cognitively normal, aged individuals. ResultsWe identified 544 genes with hyper-modified transcripts in AD samples compared with cognitively normal controls, a notable observation being high enrichment of genes in the "Kaposis sarcoma-associated herpesvirus" pathway. We also identified patterns of recurring and sporadic modification sites that differed complementarily between disease and non-disease conditions. We found 17 genes (33 total sites) that were differentially modified between conditions including several sites found exclusively in the AD epitranscriptome. ConclusionsThese findings provide a more complete profile of the potential molecular underpinnings which differentiate AD brains from their non-diseased, aged counterparts and reveal patterns and modification sites which can be further investigated for how they contribute to the network of molecular interactions underlying AD. These elements are likely to be valuable candidates for investigations that aim to further the search for biomarkers and therapeutic targets.

neuroscience↗

bioRxiv2024

Antigen non-specific CD8+ T cells accelerate cognitive decline in aged mice following respiratory coronavirus infection

Primarily a respiratory infection, numerous patients infected with SARS-CoV-2 present with neurologic symptoms, some continuing long after viral clearance as a persistent symptomatic phase termed "long COVID". Advanced age increases the risk of severe disease, as well as incidence of long COVID. We hypothesized that perturbations in the aged immune response predispose elderly individuals to severe coronavirus infection and post-infectious sequelae. Using a murine model of respiratory coronavirus, mouse hepatitis virus strain A59 (MHV-A59), we found that aging increased clinical illness and lethality to MHV infection, with aged animals harboring increased virus in the brain during acute infection. This was coupled with an unexpected increase in activated CD8+ T cells within the brains of aged animals but reduced antigen specificity of those CD8+ T cells. Aged animals demonstrated spatial learning impairment following MHV infection, which correlated with increased neuronal cell death and reduced neuronal regeneration in aged hippocampus. Using primary cell culture, we demonstrated that activated CD8+ T cells induce neuronal death, independent of antigen-specificity. Specifically, higher levels of CD8+ T cell-derived IFN-{gamma} correlated with neuronal death. These results support the evidence that CD8+ T cells in the brain directly contribute to cognitive dysfunction following coronavirus infection in aged individuals. eTOC summaryUsing a murine model of respiratory coronavirus infection, we show that aging amplifies post-infectious cognitive dysfunction due to activated CD8+ T cells that secrete IFN-{gamma} in the brain. These data provide evidence that CD8+ T cells in the brain negatively impact post-infectious cognitive function.

immunology↗