Biology subjects

Alvi, A.

Publications and source records attributed to Alvi, A..

3 recordsLinked to original sources

bioRxiv2024

Regulatory T cells crosstalk with tumor and endothelium through lymphotoxin signaling

Regulatory T cells (Tregs) are suppressors of anti-tumor immunity that exert multifaceted functions by signaling surrounding cells. We revealed Tregs use their high-level surface lymphotoxin (LT)1{beta}2 to preferentially stimulate LT{beta} receptor (LT{beta}R) nonclassical NF{kappa}B signaling on both tumor and lymphatic endothelial cells (LECs) to accelerate tumor growth and metastasis. Selectively targeting LT{beta}R nonclassical NF{kappa}B pathways on both tumors and LECs cocultured with Tregs, inhibited tumor growth and migration in vitro. Further, we identified protumorigenic chemokines and interferon-stimulated response genes selectively driven by LT{beta}R nonclassical NF{kappa}B in melanoma cells. Endothelial specific genes related to oncogenic process such as SOX18 and FLRT2 were identified to be driven under LT{beta}R nonclassical NF{kappa}B in LECs. Leveraging in vivo Treg LT1{beta}2 interactions with LT{beta}R on tumor and LECs, transfer of WT but not LT-deficient Tregs promoted transplanted WT B16F10 growth and tumor cell-derived CXCL1 and CXCL10 secretion in LT{beta}R-deficient host mice, and increased endothelial specific genes related to tumor angiogenesis and lymphangiogenesis, in WT mice bearing LT{beta}R-depleted melanoma. Selectively blocking LT{beta}R nonclassical NF{kappa}B pathways remarkably suppressed tumor growth and lymphatic metastasis by reducing tumor cell and LEC-derived CXCL1 and CXCL10 production, restricting Treg and myeloid-derived suppressor cell (MDSC) recruitment to tumor. It also retained intratumoral effector T cells, especially IFN{gamma}+ CD8 T cells by restraining Treg facilitated lymphatic vessel permeability. Our data revealed that Treg LT1{beta}2 promotes LT{beta}R nonclassical NF{kappa}B signaling in tumor cells and LECs providing a rational strategy to modulate Treg-mediated protumorigenic molecules to prevent tumor growth and metastasis.

cancer biology↗

bioRxiv2024

A biofilm-tropic Pseudomonas aeruginosa bacteriophage uses the exopolysaccharide Psl as receptor

Bacteria in nature can exist in multicellular communities called biofilms. Biofilms also form in the course of many infections. Pseudomonas aeruginosa infections frequently involve biofilms, which contribute materially to the difficulty to treat these infections with antibiotic therapy. Many biofilm-related characteristics are controlled by the second messenger, cyclic-di-GMP, which is upregulated on surface contact. Among these factors is the exopolysaccharide Psl, which is a critically important component of the biofilm matrix. Here we describe the discovery of a P. aeruginosa bacteriophage, which we have called Clew-1, that directly binds to and uses Psl as a receptor. While this phage does not efficiently infect planktonically growing bacteria, it can disrupt P. aeruginosa biofilms and replicate in biofilm bacteria. We further demonstrate that the Clew-1 can reduce the bacterial burden in a mouse model of P. aeruginosa keratitis, which is characterized by the formation of a biofilm on the cornea. Due to its reliance on Psl for infection, Clew-1 does not actually form plaques on wild-type bacteria under standard in vitro conditions. This argues that our standard isolation procedures likely exclude bacteriophage that are adapted to using biofilm markers for infection. Importantly, the manner in which we isolated Clew-1 can be easily extended to other strains of P. aeruginosa and indeed other bacterial species, which will fuel the discovery of other biofilm-tropic bacteriophage and expand their therapeutic use.

microbiology↗

bioRxiv2023

Polygenic adaptation to overnutrition reveals a role for cholinergic signaling in longevity

Overnutrition by high-sugar (HS) feeding reduces both the lifespan and healthspan across taxa. Pressuring organisms to adapt to overnutrition can highlight genes and pathways important for the healthspan in stressful environments. We used an experimental evolution approach to adapt four replicate, outbred population pairs of Drosophila melanogaster to a HS or control diet. Sexes were separated and aged on either diet until mid-life, then mated to produce the next generation, allowing enrichment for protective alleles over time. All HS-selected populations increased their lifespan and were therefore used as a platform to compare allele frequencies and gene expression. Pathways functioning in the nervous system were overrepresented in the genomic data and showed evidence for parallel evolution, although very few genes were the same across replicates. Acetylcholine-related genes, including the muscarinic receptor mAChR-A, showed significant changes in allele frequency in multiple selected populations and differential expression on a HS diet. Using genetic and pharmacological approaches, we show that cholinergic signaling affects Drosophila feeding in a sugar-specific fashion. Together, these results suggest that adaptation produces changes in allele frequencies that benefit animals under conditions of overnutrition and that it is repeatable at the pathway level.

genetics↗