Biology subjects

Cheong, K. N.

Publications and source records attributed to Cheong, K. N..

5 recordsLinked to original sources

bioRxiv2026

Maternal antiviral history synergizes with pregnancy and lactation to transfer intergenerational systemic immunity through IgG in milk

Maternal immune transfer is essential for early-life health, yet whether immune experiences before pregnancy shape maternal physiology to optimize immunity in subsequent offspring is unclear. Here, we show that respiratory viral infection before pregnancy confers robust protection against lethal neonatal influenza through antibodies transferred postpartum in milk. Despite the predominance of IgA in milk, antiviral IgG is indispensable for protection. Pregnancy amplifies pre-existing antiviral B cell responses, while prior infection durably reprograms the mammary gland to promote transfer of circulating antiviral IgG into milk. These antibodies retain their epitope specificity, are enriched for broadly protective influenza epitopes, remain functional after passage through the neonatal intestine, and enter offspring circulation through FcRn to provide protection beyond weaning. Natural transmission of virus from infected offspring to mothers establishes maternal immunity that protects future offspring, revealing a coordinated adaptive program that links maternal immune history, pregnancy, and lactation to optimize intergenerational immunity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=178 SRC="FIGDIR/small/744935v1_ufig1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@1f82cbeorg.highwire.dtl.DTLVardef@41ac81org.highwire.dtl.DTLVardef@1a4538aorg.highwire.dtl.DTLVardef@168bc21_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGRAPHICAL ABSTRACTC_FLOATNO C_FIG HIGHLIGHTSO_LIPreconceptual maternal intranasal influenza infection confers complete neonatal B cell mediated protection against lethal neonatal influenza infection that persists beyond weaning into early adulthood. C_LIO_LIProtection can be transmitted postnatally through milk and is fully dependent on maternal IgG. C_LIO_LIPregnancy enhances rather than suppresses antiviral B cell programs in the mother. C_LIO_LIMilk IgG targets a restricted set of conserved influenza Hemagglutinin epitopes, suggesting selective transfer of broadly protective antibody populations. C_LIO_LIProtective IgG in milk derives from maternal circulation, not from local B cell mammary gland production. C_LIO_LIRespiratory infection before pregnancy induces long-lived vascular, stromal, and epithelial transcriptional remodeling of the mammary gland. C_LIO_LINeonatal Fc Receptor (FcRn) mediated transport of milk IgG into circulation is required for protection. C_LIO_LIInfected neonates transmit virus back to mothers, extending protection to subsequent litters for multi-generation protection. C_LI

immunology↗

bioRxiv2025

WHEP Domain of Glycyl-tRNA Synthetase Regulates Neuropilin 1 Binding and Vascular Permeability

AbstractAminoacyl-tRNA synthetases (aaRSs) charge tRNAs with their cognate amino acids, ensuring accurate translation of the genetic code from mRNA to protein. During eukaryotic evolution, aaRSs acquired additional domains with unclear functions, including the WHEP domain, a two-helix bundle found in several eukaryotic aaRSs such as glycyl-tRNA synthetase (GlyRS, encoded by GARS1). We generated Gars1{Delta}WHEP mutant mice lacking exon 2, which disrupts most of the WHEP domain. Homozygous Gars1{Delta}WHEP/{Delta}WHEP mice exhibited late embryonic or neonatal lethality, with delayed lung development, characterized by reduced airway dilation (inflatability), and increased vascular leakage. Disruption of the WHEP domain did not impair tRNA aminoacylation but inhibited the free release of GlyRS from cells. Instead, GlyRS{Delta}WHEP was found in the membrane fractions and showed a stronger interaction with the extracellular region of neuropilin 1 (Nrp1) receptor compared to full-length GlyRS. This aberrant interaction enhanced Nrp1s endocytic activity and significantly reduced the localization of the Nrp1 interactor VE-cadherin at the adherens junctions of endothelial cells. A heterozygous knockout of Nrp1 in the Gars1 {Delta}WHEP/{Delta}WHEP mice partially rescued body weight and vascular permeability defects. This study establishes a physiological role for the GlyRS WHEP domain in lung development and its regulation of GlyRS-Nrp1 interaction and vascular permeability.

molecular biology↗

bioRxiv2024

Rebuilding the autoimmune-damaged corneal stroma through topical lubrication

Corneal lubrication is the most common treatment for relieving the signs and symptoms of dry eye and is considered to be largely palliative with no regenerative functions. Here we challenge this notion by demonstrating that wetting the desiccated cornea of an aqueous-deficient mouse model with the simplest form of lubrication, a saline-based solution, is sufficient to rescue the severely disrupted collagen-rich architecture of the stroma, the largest corneal compartment that is essential to transparency and vision. At the single cell level we show that stromal keratocytes responsible for maintaining stromal integrity are converted from an inflammatory state into unique reparative cell states by lubrication alone, thus revealing the extensive plasticity of these cells and the regenerative function of lubricating the surface. We further show that the generation of a reparative phenotype is due, in part, to disruption of an IL1{beta} autocrine amplification loop promoting chronic inflammation. Thus, our study uncovers the regenerative potential of topical lubrication in dry eye and represents a paradigm shift in our understanding of its therapeutic impact.

immunology↗

bioRxiv2022

A synthetic tear protein resolves dry eye through promoting corneal nerve regeneration.

Corneal architecture is essential for vision and is greatly perturbed by the absence of tears due to the highly prevalent disorder dry eye. With no regenerative therapies available, pathological alterations of the ocular surface in response to dryness, including persistent epithelial defects and poor wound healing, result in lifelong morbidity. Here, using a mouse model of aqueous-deficient dry eye, we reveal that topical application of the synthetic tear protein lacripep reverses the pathological outcomes of dry eye through restoring the extensive network of corneal nerves that are essential for tear secretion, barrier function, epithelial homeostasis and wound healing. Intriguingly, the restorative effects of lacripep occur despite extensive immune cell infiltration, suggesting tissue reinnervation and regeneration can be achieved under chronic inflammatory conditions. In summary, our data highlight lacripep as a first-in-class regenerative therapy for returning the cornea to a near homeostatic state in individuals who suffer from dry eye. TeaserTopical application of a synthetic tear protein repairs dry eye-mediated corneal damage through driving functional sensory reinnervation.

cell biology↗

bioRxiv2020

Sentinel p16INK4a+ cells in the basement membrane form a reparative niche in the lung

Senescent cells are recognized drivers of aging-related decline in organ function, but deciphering the biology of senescence in vivo has been hindered by the paucity of tools to track and isolate senescent cells in tissues1-4. Deleting senescent cells from transgenic murine models have demonstrated therapeutic benefits in numerous age-related diseases5-11, but the identity, behavior, and function of the senescent cells deleted in vivo remain elusive. We engineered an ultra-sensitive reporter of p16INK4a, a biomarker of senescence12, to isolate and track p16INK4a+ cells in vivo. Surprisingly, p16INK4a+ mesenchymal cells appear in the basement membrane adjacent to epithelial progenitors in the lung shortly after birth, and these cells demonstrate senescent characteristics in vivo and ex vivo. Transcriptomic analysis of p16INK4a+ mesenchymal cells from non-aged lungs demonstrates a transition to a secretory phenotype upon airway epithelial injury. Heterotypic 3D organoid assays show that injured p16INK4a+ mesenchymal cells enhance epithelial progenitor proliferation, and we identified EREG as a novel airway progenitor mitogen produced by the secretory p16INK4a+ mesenchymal cells. Mesenchymal-specific deletion of the p16INK4a gene abrogates features of senescence in vivo, but also attenuates normal epithelial repair. Thus, p16INK4a+ mesenchymal cells can act as sentinels for the airway epithelial stem cell niche, poised to transition to a senescence-associated secretory phenotype to support barrier repair. Our data identify possible cellular targets in vivo for a rapidly growing list of senolytic therapies, but also raises important questions about the hidden cost of targeting senescent cells present in normal organs.

cell biology↗