kumar, R. | Search bioRxiv

bioRxiv2026

All-trans retinoic acid recalibrates macrophage transcriptional responses to drug-resistant Mycobacterium tuberculosis through strain-specific immunometabolic reprogramming

Tuberculosis (TB) caused by Mycobacterium tuberculosis (M.tb) remains the leading infectious cause of death worldwide, with multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains presenting an escalating therapeutic crisis. All-trans retinoic acid (ATRA), an active vitamin A metabolite with established immunomodulatory properties, has emerged as a candidate host-directed therapy, yet its genome-wide transcriptional effects on macrophage across strains of differing drug-resistance profiles remain uncharacterized. We performed RNA sequencing of murine peritoneal macrophages infected with drug-susceptible H37Rv, MDR-2261, or XDR-MCY M.tb strains, with and without ATRA treatment, validated by RT-PCR and flow cytometry. All three strains activated a conserved pro-inflammatory program dominated by Nos2, Il1b, and Acod1 induction with progressive suppression of host translational and mitochondrial machinery. XDR-MCY uniquely induced Ifnb1/IFN-{beta}, suppressed Prdx1 and Gpx4, the latter shared with MDR-2261 and showed selective downregulation of MHC-II processing genes, suggesting a multilayered immune evasion strategy. ATRA activated canonical retinoid signaling across all infection states and consistently induced Arg1-mediated resolution signaling, with Nos2 suppression observed in H37Rv- and MDR-infected macrophages. ATRA selectively restored Epas1/HIF-2 in H37Rv- and MDR-infected macrophages without disrupting the HIF-1-driven antimicrobial program or itaconate biosynthesis. ATRA responsiveness progressively attenuated with drug resistance, with XDR-MCY-infected macrophages largely refractory to transcriptional reprogramming. These findings provide a transcriptional rationale for evaluating ATRA as a host-directed adjunct in drug-resistant TB and identify Gpx4 suppression in drug-resistant strains and XDR-specific Ifnb1 induction as vulnerabilities necessitating further investigation.

microbiology↗

bioRxiv2024

Molecular and physiological characterization of tillering and shade tolerance of dwarf mutants of perennial ryegrass

Tillering and shade tolerance are important traits in turfgrass, influenced by environmental factors, nutrients, and hormones. Shade stress negatively affects tillering. In this study, two dwarf mutants, shadow-1 and shadow-2, developed via Gamma-ray and fast-neutron mutagenesis, respectively, showed significantly higher tillering than the wild-type under greenhouse conditions. Both mutants demonstrated shade tolerance in plant height, grass quality, and color under 85% and 95% shade conditions, while shade-induced inhibition of tillering was observed in both the mutants and the wild-type. In comparison to wild-type plants under 95% shade conditions, we observed that the cytokinin biosynthetic gene IPT8 is upregulated, while the cytokinin inactivating gene CKX2 is downregulated in shadow-1. Similarly, the GA biosynthetic genes CPS1, GA2ox3, and GA20ox1 are upregulated, while the GA inactivating gene GA20ox8 is downregulated in the shadow-1 mutant. Furthermore, the ethylene biosynthetic genes ACS and ACO are also downregulated in the shadow-1 mutant. Consistently, we observed that wild-type plants exhibit increased GA and reduced CK levels, while shadow-1 mutant plants have reduced GA but increased CK levels. This explains the shadow-1 mutants shade tolerance in terms of plant height, grass quality, and color. Conversely, the tillering inhibitor genes CRY1, MAX2, and SnRK1 are upregulated in both wild-type and shadow-1 mutant plants. Our results provide novel insights into the mechanisms behind tillering and shade tolerance in turfgrasses under shade conditions.

plant biology↗