Biology subjects

Sanchez, K. R.

Publications and source records attributed to Sanchez, K. R..

5 recordsLinked to original sources

bioRxiv2026

Neonatal Enteric Infection Disrupts the Microbiota-Gut-Brain Axis Through Pattern Recognition Receptors and Altered Neuroimmune Signaling

Early-life enteric infection can have long-lasting effects on the microbiota-gut-brain (MGB) axis. Using a neonatal Enteropathogenic Escherichia coli (EPEC) model, we show that intestinal epithelial cell (IEC) NOD1 signaling coordinates mucosal immunity, barrier repair, and neuroimmune outcomes throughout early development and into adulthood. Neonates infected at postnatal day (P) 7 exhibited ileal inflammation, as demonstrated by increased expression of inflammatory cytokines (Il1{beta}, Il6, Il12, Il22), chemokines/chemokine receptors (Ccl2, Cxcl1, Ccr2), and barrier-repair genes (Muc2, Slc26a3), with increased monocyte/macrophage infiltration and reduced epithelial proliferation in WT mice that was blunted in Nod1{Delta}IEC mice. Neonatal infection of WT mice induced persistent defects into adulthood (P56), including increased intestinal permeability, sustained inflammatory/repair signatures, hippocampal inflammation, altered neurogenesis, and impaired recognition memory, which were largely absent in Nod1{Delta}IEC mice, establishing a crucial role for IEC NOD1 as a determinant of long-term MGB remodeling. Microbially derived ligands of NOD2, muropeptides, isolated from probiotic Lactobacillus species attenuated EPEC-induced mucosal inflammation and chemokine induction without altering bacterial burden, demonstrating NOD2 host-directed immunomodulation. Together, these findings identify an important role for NOD-dependent signaling axis in the gastrointestinal tract that links early-life infection to enduring gut-brain dysfunction and reveals probiotic-derived muropeptides as candidate microbial therapeutics.

physiology↗

bioRxiv2025

The sensitising effect of IgG in fibromyalgia syndrome is mediated by Mrgprb2 in mast cells

Fibromyalgia syndrome (FMS) is characterized by elevated levels of immunoglobulin G (IgG), altered bowel habits, and increased pain sensitivity, suggesting immune dysregulation, but the exact mechanism remains unclear. Here, we found that FMS-IgG binds to mast cells in a MRGPRX2/b2-dependent manner, leading to mast cell recruitment and IL-6 secretion. Transferring serum-IgG from FMS patients to mice induced FMS-like symptoms and increased skin mast cells, indicating that FMS-IgG acts through mast cell activation. The ablation of mice Mrgprb2 mast cells or deleting Mrgprb2 receptors prevented IgG-induced heightened sensitivity to mechanical and cold stimuli. Stimulating human LAD2 cells with FMS IgG elicited MRGPRX2-dependent IL-6 production. Consistent with mice findings, mast cell density and tryptase levels increased in human FMS skin samples compared to healthy controls. Taken together our results suggests that FMS IgG mediates hypersensitivity via activation of mast cells bearing the MRGPRX2 receptor and that these cells are a potential therapeutic target.

immunology↗

bioRxiv2025

The sympathetic nervous system enhances host immune responses to enteric bacterial pathogens.

Mucosal immune responses to enteric bacterial infections are highly coordinated processes that orchestrate host protection while minimizing the potential for immune-triggered pathology. In the intestinal tract, bidirectional communication occurs between the nervous and immune systems to affect local immune responses by modulating the activity of resident and recruited immune cells, and indirectly on the supporting stromal cells. These neuroimmune signaling pathways that alter host defense have focused on specialized sensory innervation and the unique neurotransmitters released from them. Although the sympathetic nervous system has been established to induce a tissue-protective phenotype in subpopulations of neuron-associated macrophages in the small intestine, the role of these neurons during enteric bacterial infection was unknown. Using genetic labeling of activated neurons with ArcTRAP, we demonstrate that colonic infection induces activation of the rostral ventrolateral medulla, a major sympathetic center in the brainstem. The importance of peripheral sympathetic neurons was further demonstrated using chemical sympathectomy that significantly increased bacterial burden during Citrobacter rodentium (C. rodentium) infection. Increased bacterial burden was matched by a deficit in host protection due to reduced IFN{gamma} production by colonic CD4+ T-cells. Sympathectomy, however, did not diminish the capacity to differentiate into IFN{gamma}- or IL-17A- producing T-cells in vitro, suggesting that the lack of sympathetic innervation during infection may alter this process in vivo without causing sustained T-cell intrinsic defects. In assessing which receptors could mediate these effects, pharmacological antagonists selective for - adrenergic receptors (AR), but not {beta}-adrenergic receptors, increased bacterial burden and reduced colonic IFN{gamma} production. Using isolated cell types from the colon of uninfected and infected mice, we identified the AR subtypes expressed on immune and stromal cells, with significant upregulation of these receptors on T-cells during C. rodentium infection. Together these data demonstrate the unique role of the sympathetic nervous system and AR in mucosal immune responses against enteric bacterial pathogens.

immunology↗

bioRxiv2025

Inhibition of acute lung inflammation by a neuroimmune circuit induced by vagal nerve stimulation.

Vagus nerve stimulation (VNS) has been shown to limit immune cell activity across several pathologies ranging from sepsis to auto-immune diseases. While stimulation of vagal efferent neurons has been previously demonstrated to reduce maladaptive host responses during endotoxemia, only selective stimulation of vagal afferent neurons was able to inhibit TLR7-induced macrophage activation and neutrophil recruitment in the lung. These anti-inflammatory actions are facilitated by systemic increases in epinephrine, as VNS significantly increased epinephrine in the serum and bronchoalveolar lavage fluid, and inhibition of epinephrine production eliminated the protection afforded by VNS. Selective afferent VNS induced activation in the nucleus tractus solitarius and the rostral ventrolateral medulla. Inhibition of neuronal activity in this brain region that controls peripheral sympathetic nervous system activity rendered VNS ineffective. Activation of the {beta}2-adrenergic receptor ({beta}2AR) is critical for innate immune cell suppression, as the anti-inflammatory effects of VNS were eliminated in {beta}2AR-knock out mice, and with pharmacological inhibition of the {beta}2AR. Analysis of the immune cells responding to R848 critically identified that plasmacytoid dendritic cells were refractive to inhibition by VNS, and this corresponded to lack of {beta}2AR expression. These findings demonstrate a novel neuro-immune circuit elicited by VNS that can control acute lung inflammation. SummaryWe have identified a novel neuro-immune circuit activated by afferent vagus nerve stimulation to reduce acute lung inflammation. This effect was dependent on vagal-induced adrenal gland-derived epinephrine release that initiates anti-inflammatory {beta}2-adrenergic receptor signaling in innate immune cells within the lung.

immunology↗

bioRxiv2021

MAVS mediates a protective immune response in the brain to Rift Valley fever virus

Rift Valley fever virus (RVFV) is a highly pathogenic mosquito-borne virus capable of causing hepatitis, encephalitis, blindness, hemorrhagic syndrome, and death in humans and livestock. Upon aerosol infection with RVFV, the brain is a major site of viral replication and tissue damage, yet pathogenesis in this organ has been understudied. Here, we investigated the immune response in the brain of RVFV infected mice. In response to infection, microglia initiate robust transcriptional upregulation of antiviral immune genes, as well as increased levels of activation markers and cytokine secretion that is dependent on mitochondrial antiviral-signaling protein (MAVS) and independent of toll-like receptors 3 and 7. In vivo, Mavs-/- mice displayed enhanced susceptibility to RVFV as determined by increased brain viral burden and higher mortality. Single-cell RNA sequence analysis identified microglia-specific defects in type I interferon and interferon responsive gene expression in Mavs-/- mice, as well as dysregulated lymphocyte infiltration. The results of this study provide a crucial step towards understanding the precise molecular mechanisms by which RVFV infection is controlled in the brain and will help inform the development of vaccines and antiviral therapies that are effective in preventing encephalitis. Author SummaryRift Valley fever virus causes severe disease in humans and livestock and in some cases can be fatal. There is concern about the use of Rift Valley fever virus as a bioweapon since it can be transmitted through the air, and there are no vaccines or antiviral treatments. Airborne transmission of the virus causes severe inflammation of the brain, yet little is known about the immune response against the virus in this organ. Here, we investigated the immune response in the brain to Rift Valley fever virus following intranasal infection. We determined that microglia, the resident immune cells of the brain, initiate a robust response to Rift Valley fever virus infection and identified a key immune pathway that is critical for the ability of microglia to respond to infection. When this immune pathway is rendered non-functional, mice have a dysregulated response to infection in the brain. This study provides insight into how the immune response can control Rift Valley fever virus infection of the brain.

immunology↗