Biology subjects

Sekera, E. R.

Publications and source records attributed to Sekera, E. R..

3 recordsLinked to original sources

bioRxiv2026

Obesity-Driven Lung Lipidome Remodeling Suppresses NK Cell Activation and Antiviral Immunity to Influenza Infection

Obesity is a major risk factor for severe influenza A virus (IAV) infection, however, the innate immune mechanisms underlying this increased vulnerability remain unclear. Here, we identify significant defects in natural killer (NK) cell antiviral responses in mice with diet-induced obesity. In lean mice, NK cells are critical for protection as NK cell depletion during IAV infection led to increased lung viral load, morbidity, and mortality. In contrast, in obese mice NK cell depletion had minimal impact on viral replication or survival. Notably, IAV infection in obese mice recapitulated the phenotype observed in NK cell-depleted lean mice, indicating that obesity is associated with preexisting NK cell dysfunction. Following IAV infection, obese NK cells in the lung were functionally impaired with diminished activation (CD69+), cytokine production (IFN-{gamma}), and cytolytic activity (Granzyme B) accompanied by defects in the mTOR signaling pathway and reduced glycolytic and oxidative metabolism. Bulk and spatial lipidomics revealed obesity and infection-driven remodeling of the lung lipidome. We observed increased triglyceride accumulation, abundance of long-chain free fatty acids, and a shift toward monounsaturated phospholipid species, reshaping the lung microenvironment that coincides with NK cell metabolic dysfunction. Consistent with this lipid-rich environment, obese NK cells sustained high expression of the lipid transporter CD36 post-IAV infection and accumulation of intracellular lipids (LipidTOX+), consistent with mechanisms known to suppress NK cell function. Notably, short-term weight loss (4 weeks) was sufficient to restore NK cell metabolism, antiviral function, and survival following IAV infection. These findings uncover a lipid-associated mechanism regulating NK cell function and show it plays a critical role in defense against infection and that it is dysfunctional in obesity. We suggest that targeting immunometabolism could lead to new antiviral therapies and potentially improve vaccine efficacy, especially in high-risk populations such as obesity. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=101 SRC="FIGDIR/small/710186v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@313263org.highwire.dtl.DTLVardef@1e31111org.highwire.dtl.DTLVardef@758ba6org.highwire.dtl.DTLVardef@12372d0_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2026

Global Proteomic Analysis of Colorectal Cancers Stratified by Microsatellite Instability Subtype Reveals Protein Differences

Lynch syndrome, historically known as hereditary nonpolyposis colorectal cancer, is caused by germline mutations in the DNA mismatch repair (MMR) genes, MLH1, MSH2 (EPCAM), MSH6, and PMS2. While the genetic changes associated with Lynch Syndrome have previously been characterized, there have not been studies of the associated proteomic alterations, in part because of the limited availability of primary samples and the absence of in vitro model systems. In this study, the first large-scale tissue proteomic assessment of Lynch Syndrome samples as well as three other subtypes of colorectal cancer was completed with specimens from the Ohio Colorectal Cancer Prevention Initiative. The cohort contained three groups of microsatellite unstable (MSI-high) CRC patients (Lynch syndrome, double somatic MMR mutation, and MLH1 hypermethylation) and a group of microsatellite stable (MSS) CRC patients. A total of 122 tumor and complimentary normal mucosa samples from 61 patients were evaluated using label-free bottom-up proteomic analysis. Hierarchical clustering analysis of the global proteome showed that the MSS group was significantly different than the three MSI-high groups. Of the 1,084 proteins found to be dysregulated across all four colorectal cancer subtypes, there were age at diagnosis associated shifts in proteins correlated with tumor proliferation and immune regulation for the Lynch syndrome and Double Somatic samples. The proteins TPD52, GMDS, and DSP showed increased protein abundance correlated with older age at diagnosis. In addition, the Lynch syndrome samples showed substantial sex-based differences in immune and inflammatory pathways, for example, downregulation of ZG16, DIS3, and WDR43. This study fills a critical gap as the first proteomic characterization of Lynch syndrome samples to date. Data are available via ProteomeXchange with identifier PXD073693. TeaserThis is the first study of the global proteomic differences between Lynch Syndrome and other forms of colorectal cancer.

cancer biology↗

bioRxiv2024

Single Cell MALDI-MS Imaging of Lipids and Proteins in Senescent Fibroblasts

In this study, we evaluate lipids and select proteins in human lung fibroblasts (hLFs) to interrogate changes occurring due to aging and senescence. To study single cell populations, a comparison of cells adhered onto slides using poly-D-lysine versus centrifugal force deposition was first analyzed to determine whether specific alterations were observed between preparations. The poly-D-lysine approach was than utilized to interrogate the lipidome of the cell populations and further evaluate potential applications of the MALDI-immunohistochemistry (IHC) platform for single-cell level analyses. Two protein markers of senescence, vimentin and p21, were both observed within the fibroblast populations and quantified. Lipidomic analysis of the fibroblasts found twelve lipids significantly altered because of replicative senescence, including fatty acids, such as stearic acid, and ceramide phosphoethanolamine species (CerPE). Similar to previous reports, alterations were detected in putative fatty acid building blocks, ceramides, among other lipid species. Altogether, our results reveal the ability to detect lipids implicated in senescence and show alterations to protein expression between normal and senescent fibroblast populations, including differences between young and aged cells. This report is the first time that the MALDI-IHC system has been utilized at a single-cell level to analyze both protein expression and lipid profiles in cultured cells, with a particular focus on changes associated with aging and senescence.

biochemistry↗