Biology subjects

McNinch, C.

Publications and source records attributed to McNinch, C..

7 recordsLinked to original sources

bioRxiv2026

STING-STAT3-SOX18 Axis Drives EndMT and Epigenetic Reprogramming in SAVI Lung Fibrosis

A high prevalence of early-onset interstitial lung disease, including pulmonary fibrosis, in pediatric patients with Stimulator of interferon genes (STING)-Associated Vasculopathy with onset in infancy (SAVI) suggests a critical role for the cGAS-STING pathway in the pathogenesis of pulmonary fibrosis. We identified an endothelial-to-mesenchymal transition (EndMT) signature in lesional lung biopsies from SAVI patients, marked by a loss of endothelial and acquisition of mesenchymal markers. Consistently, induced pluripotent stem cell-derived endothelial cells (iECs) from SAVI patients harboring gain-of-function STING1 mutations spontaneously undergo EndMT, a process rescued in isogenic-correction. In endothelial cells, STING activation induces IRF3-independent STAT3 phosphorylation, initiating a SLUG-dependent mesenchymal transcriptional program while repressing SOX18 and an epigenetically-regulated endothelial maintenance network. Our studies define a non-canonical cGAS-STING-STAT3 signaling axis that couples a mesenchymal transcriptional program with epigenetic silencing of an endothelial maintenance program, promoting TGF{beta}-independent STING-mediated EndMT and endothelial dysfunction, and suggesting STING as a therapeutic target for inflammatory pulmonary fibrosis.

cell biology↗

bioRxiv2026

Insights into tick-pathogen interactions - a single cell RNA sequencing approach of transcriptional changes during ehrlichial infection

Tick-borne diseases represent a significant threat to human and animal health worldwide. In the United States, the blacklegged tick, Ixodes scapularis (I. scapularis), serves as a competent vector for several bacterial pathogens, including Ehrlichia muris eauclairensis (EME). The I. scapularis embryonic cell line (ISE6) is a valuable tool for propagating tick-borne pathogens and studying tick-pathogen interactions. In this study, we examined the cellular complexity of ISE6 cells and their response to EME infection. Single-cell RNA sequencing revealed 15 distinct cell clusters present. Although ISE6 cells are heterogeneous, they do not display transcriptional similarity to any known tick tissues. Notably, this lack of similarity did not influence their susceptibility to EME infection. Our results demonstrated that EME infection induces time-dependent transcriptional changes in ISE6 cells: early infection is characterized by upregulation of genes associated with stress adaptation, mitochondrial function, and metabolic pathways, whereas late infection leads to broad downregulation of genes involved in the cell cycle, DNA replication, and cytoskeletal organization. These findings enhance our understanding of ehrlichial interactions with ISE6 cells and reinforce the utility of this cell line as a resource for isolating and propagating arthropod endosymbionts and tick-borne pathogens. IMPORTANCEThis study provides a single-cell resolution framework for interpreting tick cell line biology during infection with a medically relevant ehrlichial pathogen. Using scRNA-seq, we show that the I. scapularis embryonic-derived ISE6 cell line comprises multiple transcriptionally distinct cell states, yet these states do not map cleanly onto canonical tick tissue signatures, even when compared against a curated reference tissue atlas. Despite this heterogeneity, EME broadly infects ISE6 cell population, indicating that susceptibility is not restricted to a specific cell type. We further define a time-dependent arthropod vector response in which early infection is marked by activation of stress and metabolic adaptation response, followed by late-stage inhibition of key signaling, transcriptional, and proliferative pathways as bacterial burden increases. Together, these findings strengthen the biological interpretation of ISE6 as an in vitro model for tick-pathogen interactions and provide a resource for future mechanistic studies of ehrlichial persistence, replication, and vector competence.

molecular biology↗

bioRxiv2026

Microbiota-dependent IFN-L controls uterine and placental immunity.

Precise regulation of uterine immunity is required to support fundamental processes including reproduction and pathogen protection. How the local milieu and constitutive stressors, including the cervicovaginal microbiota, shape the delicate balance underlying uterine immunity is poorly understood. Here, we found that the cervicovaginal microbiota promotes both local immunity and the immunoregulatory activity of interferon lambda (IFN-L) in the uterus. Using murine models, we found a keystone role for IFN-L in constraining the immune tone of this site, in particular of innate lymphoid cells and Th17 cells. Further, in the context of pregnancy, IFN-L enhanced antibacterial responses at maternal-fetal barriers to Streptococcus agalactiae infection, thereby controlling fetal and neonatal transmission. Collectively, this work uncovered how IFN-L integrates microbial signals under both steady state and pregnancy conditions and mediates the essential functions of the uterine immune system - antimicrobial protection and immunoregulation.

immunology↗

bioRxiv2025

Cell-specific responses of Anopheles gambiae fat body to blood feeding and infection at a single nuclei resolution

The mosquito fat body plays key roles in metabolism and immunity, yet its cellular diversity and functional specialization remain unclear. We characterized the Anopheles gambiae fat body and associated cells, examining their responses to blood feeding, bacterial infection, and immune priming following Plasmodium berghei infection, at single-cell resolution. We analyzed 97,650 nuclei from the female mosquitos abdominal body wall and identified seven major cell types. Fat body trophocytes were the most abundant ([~]85% of cells), while sessile hemocytes represented 7.4% of cells. Trophocytes consisted of five subpopulations, including basal (T1, T2), metabolic-enriched (T3), immune-responsive (T4), and a vitellogenic population (T5) exclusive to blood-fed females. T4 trophocytes exhibited constitutive expression of immune genes, while multiple cell types, including other trophocytes, hemocytes, and epidermal epithelial cells, responded to a systemic bacterial challenge. Oenocytes (1.1% of cells) induced the expression of enzymes involved in the biosynthesis of lipids in response to immune priming. Blood feeding triggered massive transcriptomic changes, with a strong induction of vitellogenin and multiple genes involved in DNA replication, consistent with trophocyte endoreplication and metabolic reprogramming. Interestingly, vitellogenin mRNA was expressed only in the first layer of trophocytes facing the hemolymph and had an apical subcellular localization. These findings provide a high-resolution atlas of fat body and associated cells, revealing specialized roles in immunity and reproduction and offering insights into how mosquitoes coordinate metabolic and immune functions at the cellular level.

molecular biology↗

bioRxiv2025

Strain-Specific Tropism and Transcriptional Responses of Enterovirus D68 Infection in Human Spinal Cord Organoids

The mechanisms by which Enterovirus D-68 (EV-D68) infection leads to acute flaccid myelitis (AFM), a severe neurological condition characterized by sudden muscle weakness and paralysis, remain poorly understood. To investigate the cellular tropism and infection dynamics of EV-D68, we profiled naive and EV-D68-infected human spinal cord organoids (hSCOs) derived from induced pluripotent stem cells (iPSCs) using single-cell RNA sequencing (scRNA-seq). Examining the cellular composition of healthy hSCOs, we found that hSCOs comprise diverse cell types, including neurons, astrocytes, oligodendrocyte progenitor cells (OPCs), and multipotent glial progenitor cells (mGPCs). Upon infection with two EV-D68 strains, US/IL/14-18952 (a B2 strain) and US/MA/18-23089 (a B3 strain), we observed distinct viral tropism and host transcriptional responses. Notably, US/IL/14-18952 showed a significant preference for neurons, while US/MA/18-23089 exhibited higher rates of infection in cycling astrocytes and OPCs. These findings provide novel insights into the host cell tropism of EV-D68 in the spinal cord, offering insight into the potential mechanisms underlying AFM pathogenesis. Understanding the dynamics of infection at single-cell resolution will inform future therapeutic strategies aimed at mitigating the neurological impact of enteroviral infections.

microbiology↗

bioRxiv2024

Activating FcγRs on monocytes are necessary for optimal Mayaro virus clearance

Mayaro virus (MAYV) is an emerging arbovirus. Previous studies have shown antibody Fc effector functions are critical for optimal monoclonal antibody-mediated protection against alphaviruses; however, the requirement of Fc gamma receptors (Fc{gamma}Rs) for protection during natural infection has not been evaluated. Here, we showed mice lacking activating Fc{gamma}Rs (FcR{gamma}-/-) developed prolonged clinical disease with more virus in joint-associated tissues. Viral clearance was associated with anti-MAYV cell surface binding rather than neutralizing antibodies. Lack of Fc-Fc{gamma}R engagement increased the number of monocytes through chronic timepoints. Single cell RNA sequencing showed elevated levels of pro-inflammatory monocytes in joint-associated tissue with increased MAYV RNA present in FcR{gamma}-/- monocytes and macrophages. Transfer of FcR{gamma}-/- monocytes into wild type animals was sufficient to increase virus in joint-associated tissue. Overall, this study suggests that engagement of antibody Fc with activating Fc{gamma}Rs promotes protective responses during MAYV infection and prevents monocytes from being potential targets of infection.

immunology↗

bioRxiv2022

Cuticle development and underlying transcriptome-metabolome associations during early seedling establishment

The plant cuticle is a complex extracellular lipid barrier that provides protection from numerous environmental stressors and is critical for normal organ development. In this study, we investigated cuticle deposition by integrating metabolomics and transcriptomics data gathered from six different maize seedling organs of four genotypes, the inbred lines B73 and Mo17, and their reciprocal hybrids. These datasets captured the developmental transition of the seedling from heterotrophic skotomorphogenic growth to autotrophic photomorphogenic growth, which is a transition that is highly vulnerable to environmental stresses. Statistical interrogation of these data reveals that the predominant determinant of cuticle composition is seedling organ type, whereas the seedling genotype has a smaller effect on this phenotype. Gene-to-metabolite associations assessed by joint statistical analyses of transcriptome and metabolome datasets identified three gene networks connected with the deposition of different fractions of the cuticle: a) cuticular waxes; b) cutin of aerial organs and suberin of roots; and c) both of these fractions. These networks consist of genes that encode known components of the machinery that supports cuticle deposition, demonstrating the utility of this integrated omics approach. Moreover, these gene networks reveal three additional metabolic programs that appear to support cuticle deposition, including processes of a) chloroplast biogenesis, b) lipid metabolism, and c) molecular regulation (e.g., transcription factors, post-translational regulators and phytohormones). This study demonstrates the wider physiological metabolic context that can determine cuticle deposition and lays the groundwork for new targets for modulating properties of this protective barrier.

systems biology↗