Biology subjects

Kaur, R.

Publications and source records attributed to Kaur, R..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

The Liver-Enriched Long Non-Coding RNA FAM99A Suppresses Tumorigenesis through Negative Regulation of Protein Synthesis

Primary liver cancer represents a significant global health burden, with limited therapeutic options for advanced disease. Long non-coding RNAs (lncRNAs) are increasingly found to play crucial roles in hepatic biology and disease progression. Here, we identify FAM99A as a highly liver-specific lncRNA that is systematically downregulated across liver malignancies, with reduced expression correlating with poor clinical outcomes. FAM99A exhibits remarkable tissue specificity with minimal expression outside the liver, and its levels rapidly decline during primary hepatocyte dedifferentiation in culture. Through isoform analysis, we establish FAM99A-203 as the predominant transcript in normal liver tissue and observe altered isoform distribution in liver cancers. Functionally, FAM99A overexpression inhibits anchorage-independent growth in liver cancer cell lines. Transcriptomic analysis reveals that FAM99A negatively regulates translation-related pathways in both liver cancer cells and primary hepatocytes. This is corroborated by protein synthesis assays showing that FAM99A overexpression substantially reduces global translation rates. Targeted RNase H-mediated extraction coupled with mass spectrometry identifies multiple components of the translation machinery as direct FAM99A binding partners, including eukaryotic translation initiation factors and RNA helicases involved in ribosome biogenesis. Clinical data analysis demonstrates significant inverse correlations between FAM99A expression and ribosomal protein genes in liver cancer patients. Additionally, hepatitis B virus appears to downregulate FAM99A expression, potentially contributing to its oncogenic properties. Our findings establish FAM99A as a liver-specific translational regulator that exerts tumor-suppressive effects by restraining protein synthesis rates, offering insights into hepatocarcinogenesis and the potential of FAM99A as both a biomarker and agent in new therapeutic avenues.

cancer biology↗

bioRxiv2025

Development and validation of KASP markers for a novel powdery mildew resistance gene in wheat using BSR-Seq analysis

Wheat powdery mildew occurs as a devastating infection caused by the pathogenic fungi Blumeeria graminis f. sp. tritici (Bgt). The management of disease becomes much more effective when host resistance methods are employed. The WL711-2U/2B line served as the introgressed line to identify genes linked with powdery mildew resistance. This allowed us to look into the potential resistance components in response to powdery mildew infection. The resistance status of the line towards powdery mildew developed from a single dominant gene named PmAT. Bulked segregant RNA-Seq (BSR-Seq) together with previous QTL-Seq SNP markers helped identify strong candidate regions in chromosome arm 2B extending from 531114848 bp to 530235618 bp. The LOD score from this region reached 72.4 with a PVE% of 64.7, thus proving its main role in resistance. The physical position was subsequently locked up, which was different from the previously identified genes on the same chromosome arm in its position, suggesting that it is most likely a new Pm gene. The QTL interval contained five potential genes that we identified during this research. The five candidate genes directs the protein production, which performs functions linked to the pentatricopeptide repeat family as well as B-box-type zinc finger domain, P-loop-containing nucleoside triphosphate hydrolase, and plant peroxidase. HighlightThe identification of a new wheat powdery mildew resistance gene (PmAT) using a combination of BSR-Seq and QTL-Seq analysis, which located five candidate genes specifically on chromosome 2B.

genetics↗

bioRxiv2025

Mapping the dimerization specificity of bZIP transcription factors in bread wheat

Dimerization plays a pivotal role in target-binding interactions among various transcription factors (TFs), including bZIPs, bHLHs, MYBs, and zinc finger TFs. The bZIP family is defined by an -helix class of TFs containing a basic region that binds to the major groove of double-stranded DNA (dsDNA), followed by a leucine zipper motif that mediates dimerization through coiled-coil structures, forming homo- or heterodimers. In polyploid bread wheat (Triticum aestivum cv.), bZIPs and their homeologs interact through the dimerization motifs to form specific bZIP pairs with distinct regulatory functions. The dimerization pattern of bZIPs is critical for gene regulation, however, the mechanisms underlying their specificity remain poorly understood. Here, we focus on the dimerization specificity of coiled-coil - helical bZIP proteins in bread wheat, highlighting the leucine zipper region as a key dimerization motif. We identified 265 bZIPs containing the bZIP motif, following dimerization criteria established in humans, Drosophila, and Arabidopsis based on the presence of specific amino acids at the a, d, e, and g positions in heptads. Eight key bZIP TFs were cloned, expressed, and purified for the structural analysis. This study not only provides the dimerization trend exhibited by bZIPs during thermal stability analysis but also provides the reversibility pattern followed by the thermal denaturation exposure at 85{degrees}C. Our study also points towards that how amino acid substitutions and the length of the leucine zipper influence the formation of coiled-coil structures among bZIP homeologs of polyploid wheat. Overall, the study advances our understanding of the role of leucine zippers, in determining the specificity and stability of bZIP dimers, which in turn governs DNA binding and gene regulation in plants.

biochemistry↗

bioRxiv2025

HKU5 bat merbecoviruses use divergent mechanisms to engage bat and mink ACE2 as entry receptors

Identifying receptors for bat coronaviruses is critical for spillover risk assessment, countermeasure development, and pandemic preparedness. While Middle East respiratory syndrome coronavirus (MERS-CoV) uses DPP4 for entry, the receptors of many MERS-related betacoronaviruses remain unknown. The bat merbecovirus HKU5 was previously shown to have an entry restriction in human cells. Using both pseudotyped and full-length virus, we show that HKU5 uses Pipistrellus abramus bat ACE2 but not human ACE2 or DPP4 as a receptor. Cryo-electron microscopy (cryo-EM) analysis of the virus-receptor complex and structure-guided mutagenesis reveal a spike and ACE2 interaction that is distinct from other ACE2-using coronaviruses. MERS-CoV vaccine sera poorly neutralize HKU5 informing pan-merbecovirus vaccine design. Notably, HKU5 can also engage American mink and stoat ACE2, revealing mustelids as potential intermediate hosts. These findings highlight the versatility of merbecovirus receptor use and underscore the need for continued surveillance of bat and mustelid species.

microbiology↗

bioRxiv2025

CD4+ Mucosal-associated Invariant T (MAIT) cells express highly diverse T cell receptors

Mucosal-associated invariant T cells are highly conserved innate-like T cells in mammals recognized for their high baseline frequency in human blood and cytotoxic effector functions during infectious diseases, autoimmunity, and cancer. While the majority of these cells express a conserved CD8{beta}+ TRAV1-2 T cell receptor recognizing microbially-derived Vitamin B2 intermediates presented by the evolutionarily conserved major histocompatibility complex I-related molecule, MR1, there is an emerging appreciation for diverse subsets that may be selected for in humans with distinct functions, including subpopulations that co-express CD4. Prior work has not examined T cell receptor (TCR) heterogeneity in CD4+ MAIT cells, largely due to bias of identifying human MAIT cells as CD8+ TRAV1-2+ cells. In this study, we adopted an unbiased single-cell TCR-sequencing approach of total MR1-5-OP-RU-tetramer-reactive T cells and discovered that CD4+ MAIT cells express highly diverse TRAV1-2 negative TCRs. To specifically characterize this TCR repertoire, we analyzed VDJ sequences of single MR1-5-OP-RU tetramer+ MAIT cells across two datasets and identified distinct TCR usage among CD4+ MAIT cells including TRAV21, TRAV8 (TRAV8-1, TRAV8-2, TRAV8-3), and TRAV12 families (TRAV12-2, TRAV12-3), as well as more variable J chain and CDR3 sequences. Non-TRAV1-2 MAIT cell TCRs were also enriched after in vitro expansion, including with Mycobacterial tuberculosis. These results indicate that mature human CD4+ MAIT cells adopt distinct TCR usage from the canonical TRAV1-2+ CD8+ subset and suggest that alternative MR1 ligands in addition to riboflavin intermediates may select them.

genomics↗

bioRxiv2025

A highly efficient CRISPR-Cas9-based gene editing system in oat (Avena sativa)

Cultivated oat (Avena sativa) is an emerging cereal for healthy lives owing to its unique characteristics, such as high {beta}-glucan and oil content, distinctive fatty acid composition, and gluten-free nature. The recent unravelling of the 12.5 Gb hexaploid oat genome underlined breeding barriers caused by ancestral translocations and inversions, leading to recombination suppression and pseudo-linkage further hindering conventional trait introgression. Over the past decade, the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 system has been extensively used for crop improvement and functional genomics in all other cereals except oats. Its large repetitive genome with three sub-genomes, lack of efficient transformation, recalcitrant nature, and complex molecular screening due to gene redundancy have been major obstacles to gene editing success in oat. We report the first successful CRISPR-Cas9-based gene editing in oat in three genes -- AsTLP8, AsVRN3 and AsVRN3D with gene-editing efficiency of up to 41.1%. The gene-edited plants for all the genes carried deletions and/or one base insertion. Further analysis of VRN3 T1 and T2 mutants revealed bent leaves in heterozygous knockouts (AACCdD), while an extended vegetative growth phase was seen in the T1 homozygous and biallelic mutants (aaccdd), accentuating the important role of VRN3 in oat development. We are confident that this highly efficient oat gene editing system will pave the way for a deeper molecular understanding of this healthy cereal, deciphering oats functional genomics, and creating genetic diversity at the cold spots of recombination in oat.

plant biology↗

bioRxiv2024

A pangenome and pantranscriptome of hexaploid oat

Oat grain is a traditional human food rich in dietary fiber that contributes to improved human health. Interest in the crop has surged in recent years owing to its use as the basis for plant-based milk analogs. Oat is an allohexaploid with a large, repeat-rich genome that was shaped by subgenome exchanges over evolutionary timescales. In contrast to many other cereal species, genomic research in oat is still at an early stage, and surveys of structural genome diversity and gene expression variability are scarce. Here, we present annotated chromosome-scale sequence assemblies of 33 wild and domesticated oats along with an atlas of gene expression across six tissues of different developmental stages in 23 accessions. We describe the interplay of gene expression diversity across subgenomes, accessions and tissues. Gene loss in the hexaploid is accompanied by compensatory up-regulation of the remaining homeologs, but this process is constrained by subgenome divergence. Chromosomal rearrangements have significantly impacted recent oat breeding. A large pericentric inversion associated with early flowering explains distorted segregation on chromosome 7D and a homeologous sequence exchange between chromosomes 2A and 2C in a semidwarf mutant has risen to prominence in Australian elite varieties. The oat pangeome will promote the adoption of genomic approaches to understanding the evolution and adaptation of domesticated oats and will accelerate their improvement.

genomics↗

bioRxiv2024

Syzygium cumini (L.) Skeels has Thermostable and Selective Anti-Bacillus anthracis Activity

IntroductionGastrointestinal (GI) anthrax caused by Bacillus anthracis remains a neglected disease in many parts of the Americas, Asia, and Africa. The symptoms include dysentery, stomachache, bloating of the stomach, vomiting, fever, chills, etc. Current study evaluated several edible plants traditionally indicated for GI disease/symptoms in the Indian subcontinent for their anti-B. anthracis activity. Materials & MethodsAqueous extracts of plant parts were assessed for anti-B. anthracis activity using standard antimicrobial susceptibility testing assays. Most promising extracts were evaluated for desirable activity under conditions relevant to their usage, including extremes of temperature, pH, presence of bile salt, impact on gut microflora, and interaction with FDA-approved drugs for anthrax treatment. The bioactive components separated by bioactivity-guided thin-layer-chromatography were subjected to GC-MS characterization. ResultsAqueous Syzygium cumini (L.) Skeels or Jamun extract (AJE) was most potent and reduced the viable colony-forming units (CFU) by 6-logs within 2 hours of exposure at [≥]1.9%w/v concentration. It displayed both desirable selectivity towards gut microflora and thermostability (>90% and [~]80% of anti-B. anthracis activity were retained on incubation at 50{degrees}C for 20 days and at 95{degrees}C for 12h, respectively). AJE and FDA-approved antibiotics for anthrax displayed synergy. GC-MS analysis of AJE identified various previously-identified antimicrobials belonging to categories of alkaloids, flavonoids, phenols, etc. ConclusionAJE has potent and selective anti-B. anthracis activity with the desired degree of thermotolerance, compatibility with gut microflora, and recommended antibiotics. Further studies exploring the bioactive components in AJE and their potential application in preventing anthrax and anthrax-like diseases may be undertaken.

microbiology↗

bioRxiv2024

The holobiont's extracellular microbiome modulates the adaptation of an intracellular endosymbiont

Holobionts contain spatially separated microbes whose interorgan effects are a neglected source of potential, functional variation. Here we show the extracellular gut microbiome modulates the transcriptome and adaptation of the endosymbiont Wolbachia in Drosophila melanogaster testes. Gut bacteria suppress cytoplasmic incompatibility (CI), a sperm-egg lethality trait, by altering endosymbiont pathogenicity gene expression. Transgenic assays identify the enchancer of cytoplasmic incompatibility gene eci as causal to the variation. Restoring the gut microbiome in laboratory and wild-caught, germ-free flies recapitulates CI attenuation and shifts host fitness. Intact holobionts sustain higher densities of the two symbiont types versus isolated rearing, revealing a synergistic, replication interaction between the symbiont classes. The gut-germline axis on symbiont functions has far-reaching implications for the study of holobiont trait variation.

microbiology↗

bioRxiv2024

Nutrient Challenges in a Changing Atmosphere: Investigating Biomass Growth and Mineral Concentration Changes in Soybean Plants under Elevated CO2

Rising atmospheric CO2 levels, projected to reach [~]650 ppm by 2050, threaten the nutritional value of food crops. This rise is expected to increase biomass yield in C3 plants through enhanced photosynthesis and water-use efficiency. However, elevated CO2 (eCO2) reduces protein, nitrogen, and essential minerals like zinc (Zn) and iron (Fe) in plant leaves and seeds, posing a global nutrition risk. We conducted an experiment using Open Top Chambers to examine the response of three soybean cultivars (Clark, Flyer, and Loda) to ambient ([~]410 ppm) and eCO2 ([~]610 ppm) conditions. These cultivars were selected due to their contrasting responses to eCO2. Measurements of physiological parameters (i.e., biomass, and nutrient concentration) were taken at different growth stages. Our results showed that eCO2 increased carbon assimilation, leading to higher aboveground biomass and seed yield (through increased seed number) while root biomass remained unchanged. eCO2 also reduced stomatal conductance and transpiration. There was a significant decrease in seed nutrient concentration at maturity, particularly iron (Fe), phosphorous (P), potassium (K), and magnesium (Mg), in plants grown in eCO2. These findings suggest that increased yield, reduced transpiration, and unchanged root biomass are key drivers of nutrient dilution in seeds under eCO2.

plant biology↗

bioRxiv2024

Targeting dendritic cell-specific TNFR2 improves skin and joint inflammation by inhibiting IL-12/ IFN-γ pathways in a mouse model of psoriatic arthritis.

Psoriasis (PsO) and Psoriatic arthritis (PsA) are immune-mediated inflammatory diseases affecting the skin and joints. Approximately, 30% of patients with PsO develop PsA over time with both conditions being associated with elevated tumor necrosis factor-alpha (TNF-) expression. TNF- mediates its effect through two membrane receptors, TNFR1 and TNFR2. While current TNF--neutralizing agents, targeting both TNFR1 and TNFR2 receptors, constitute the primary treatment for psoriatic diseases, their long-term use is limited due to an increase in opportunistic infections, tuberculosis reactivation and malignancies likely attributed to TNFR1 inactivation. Recent findings suggest a pivotal role of TNFR2 in psoriatic disease, as evidenced by its amelioration in global TNFR2-knockout (TNFR2KO) mice, but not in TNFR1KO mice. The diminished disease phenotype in TNFR2KO mice is accompanied by a decrease in DC populations. However, the specific contribution of TNFR2 in dendritic cells (DCs) remains unclear. Here, utilizing a mannan-oligosaccharide (MOS)-induced PsA model, we demonstrate a significant reduction in PsA-like skin scaling and joint inflammation in dendritic cell-specific TNFR2 knockout mice (DC-TNFR2KO). Notably, MOS treatment in control mice (TNFR2 fl/fl) led to an increase in conventional type 1 dendritic cells (cDC1) population in the spleen, a response inhibited in DC-TNFR2KO mice. Furthermore, DC-TNFR2KO mice exhibited reduced levels of interleukin-12 (IL-12), a Th1 cell activator, as well as diminished Th1 cells, and interferon-gamma (IFN-{gamma}) levels in the serum compared to controls following MOS stimulation. In summary, our study provides compelling evidence supporting the role of TNFR2 in promoting PsA-like inflammation through cDC1/Th1 activation pathways.

immunology↗

bioRxiv2024

Impact of Species-Specific Plant Growth-Promoting Rhizobacteria (PGPR) on Maize (Zea mays) Phenotypic and Biochemical Diversity

Maize (Zea mays) is a vital cereal crop used as a staple diet in many countries. In contemporary farming practises, inoculation with plant-growth-promoting rhizobacteria (PGPR) can be promoted as a sustainable alternative to chemical fertilizers and pesticides in cereal crops including maize. For experimental verification of the above-mentioned hypothesis, four PGPR inoculants Pseudomonas fluorescens, P. putida, Azospirillum lipoferum and Bacillus subtilis were applied to three maize genotypes (AXE*, PMH1 and PMH10) and their effects were studied by measurement of various morphological and biochemical paramters. Substantial increase in the amount of chlorophyll a (45%), chlorophyll b (100%), total chlorophyll (95%), nitrate reductase (22%), superoxide dismutase (52%), protein content (16%), methionine content (31.8%), grain protein content (69%) were recorded over the control (non-treated or mock) plants. Morphological parameters also exhibited an increase in leaf number (53%), fresh weight (41%) and dry weight (62%) in test plants. Comparable outcome was observed for whole cob weight showing an increase of 42%, cob weight (60%), hundred-grain weight (25.9%), maize grain yield m-2 (18%) and yield ha-1 (18%) over the control. This study highlights the efficacy of the aforementioned four PGPR species as the most effective for maize crops. Bacillus subtilis and Azospirillum lipoferum may be considered species-specific PGPRs due to their superior performance compared to other strains. The considerable growth-promoting advantages observed in maize plants treated with bacterial inoculation indicated that PGPRs have the potential to be employed as sustainable solutions in maize production.

plant biology↗

bioRxiv2024

Loss of circulating CD8α+ NK cells during human Mycobacterium tuberculosis infection

Natural Killer (NK) cells can recognize and kill Mtb-infected cells in vitro, however their role after natural human exposure has not been well-studied. To identify Mtb-responsive NK cell populations, we analyzed the peripheral blood of healthy household contacts of active Tuberculosis (TB) cases and source community donors in an endemic region of Port-au-Prince, Haiti by flow cytometry. We observed higher CD8 expression on NK cells in putative resistors (IGRA-contacts) with a progressive loss of these circulating cells during household-associated latent infection and disease. In vitro assays and CITE-seq analysis of CD8+ NK cells demonstrated enhanced maturity, cytotoxic gene expression, and response to cytokine stimulation relative to CD8- NK cells. CD8+ NK cells also displayed dynamic surface expression dependent on MHC I in contrast to conventional CD8+ T cells. Together, these results support a specialized role for CD8+ NK cell populations during Mtb infection correlating with disease resistance.

immunology↗

bioRxiv2024

Highly conserved brain vascular receptor ALPL mediates transport of engineered viral vectors across the blood-brain barrier

Delivery of systemically administered therapeutics to the central nervous system (CNS) is restricted by the blood-brain barrier (BBB). Bioengineered Adeno-Associated Virus (AAV) capsids have been shown to penetrate the BBB with great efficacy in mouse and non-human primate models, but their translational potential is often limited by species selectivity and undefined mechanisms of action. Here, we apply our RNA-guided TRACER AAV capsid evolution platform to generate VCAP-102, an AAV9 variant with markedly increased brain tropism following intravenous delivery in both rodents and primates. VCAP-102 demonstrates a similar CNS tropism in cynomolgus macaque, african green monkey, marmoset and mouse, showing 20- to 400-fold increased transgene expression across multiple brain regions relative to AAV9. We demonstrate that the enhanced CNS tropism of VCAP-102 results from direct interaction with alkaline phosphatase (ALPL), a highly conserved membrane-associated protein expressed on the brain vasculature. VCAP-102 interacts with human, primate and murine ALPL isoforms, and ectopic expression of ALPL is sufficient to initiate receptor-mediated transcytosis of VCAP-102 in an in vitro transwell model. Our work identifies VCAP-102 as a cross-species CNS gene delivery vector with a strong potential for clinical translation and establishes ALPL as a brain delivery shuttle capable of efficient BBB transport to maximize CNS delivery of biotherapeutics.

neuroscience↗

bioRxiv2024

Identifying the genetic and epigenetic basis for asymmetric bZIP expression in temperature-stressed bread wheat

Asymmetric expression in the bread wheat (Triticum aestivum) genome refers to the differential expression of genes from A, B, and D parental genomes. Bread wheat is a hexaploid crop with six copies of each chromosome. This complexity can result in unequal expression of genes from each parental genome, leading to asymmetry in gene expression. In other polyploid crops like cotton, transcription factors (TF) exhibit genome-biased expression; however, there are no comparable studies for bread wheat. One of the most prominent TFs families in plants is the basic Leucine Zippers (bZIP) which are eukaryote-specific proteins and regulate various biological processes, including stress-related responses. bZIP proteins are dimeric and several heptads long. They exhibit typical coiled-coil structures with strategically placed amino acids in each heptad, responsible for their stability and specificity. Here, we aim to decipher the structural basis of the asymmetric expression of the bZIP TFs in wheat under low and high-temperature conditions. Furthermore, 19 highly expressed stress-related TabZIP TFs were analysed for their asymmetric expression profiles as plants were exposed to temperature-stress conditions. Two benchmarks were used to analyse the asymmetric gene expression of bZIPs, i.e., a) the promoters occupancy by the epigenetic marker histones, namely, H3K4me3, H3k9ac (active) and H3K27me3 (repressive), b) density and diversity of cis-regulatory elements in the promoters. Notably, the genetic basis of the differences in protein sequences of bZIP triads was explored, which may impart structural stability to a specific homeolog enabling the plant to endure the stress conditions better.

plant biology↗

bioRxiv2023

Germline transformation of the West Nile Virus and avian malaria vector Culex quinquefasciatus Say using the piggyBac transposon system

Culex quinquefasciatus Say is a mosquito which acts as a vector for numerous diseases including West Nile Virus, lymphatic filariasis and avian malaria, over a broad geographical range. As the effectiveness of insecticidal mosquito control methods declines, the need has grown to develop genetic control methods to curb the spread of disease. The piggyBac transposon system - the most widely used genetic transformation tool in insects, including mosquitoes - generates quasi-random insertions of donor DNA into the host genome. However, despite the broad reported species range of piggyBac, previous attempts to use this tool to transform Culex quinquefasciatus mosquitoes have failed. Here we report the first successful transformation of Culex quinquefasciatus with the piggyBac transposon system. Using commercially synthesised piggyBac mRNA as a transposase source, we were able to generate three independent insertions of a ZsGreen fluorescent marker gene, with transformation efficiencies of up to 5%. Through this work, we have expanded the genetic toolkit available for the genetic manipulation of Culex mosquitoes and thus removed a barrier to developing novel genetic control methods in this important disease vector.

synthetic biology↗

bioRxiv2023

SARS-CoV-2 infection triggers pro-atherogenic inflammatory 1 responses in human coronary vessels

COVID-19 patients present higher risk for myocardial infarction (MI), acute coronary syndrome, and stroke for up to 1 year after SARS-CoV-2 infection. While the systemic inflammatory response to SARS-CoV-2 infection likely contributes to this increased cardiovascular risk, whether SARS-CoV-2 directly infects the coronary vasculature and attendant atherosclerotic plaques to locally promote inflammation remains unknown. Here, we report that SARS-CoV-2 viral RNA (vRNA) is detectable and replicates in coronary atherosclerotic lesions taken at autopsy from patients with severe COVID-19. SARS-CoV-2 localizes to plaque macrophages and shows a stronger tropism for arterial lesions compared to corresponding perivascular fat, correlating with the degree of macrophage infiltration. In vitro infection of human primary macrophages highlights that SARS-CoV-2 entry is increased in cholesterol-loaded macrophages (foam cells) and is dependent, in part, on neuropilin-1 (NRP-1). Furthermore, although viral replication is abortive, SARS-CoV-2 induces a robust inflammatory response that includes interleukins IL-6 and IL-1{beta}, key cytokines known to trigger ischemic cardiovascular events. SARS-CoV-2 infection of human atherosclerotic vascular explants recapitulates the immune response seen in cultured macrophages, including pro-atherogenic cytokine secretion. Collectively, our data establish that SARS-CoV-2 infects macrophages in coronary atherosclerotic lesions, resulting in plaque inflammation that may promote acute CV complications and long-term risk for CV events.

immunology↗

bioRxiv2023

SWI/SNF complex-mediated chromatin remodelling is vital for cell surface adhesin repression and immune evasion

Immune evasion is critical for fungal virulence. However, how the human opportunistic pathogen Candida glabrata (Cg) accomplishes this is unknown. Here, using micrococcal nuclease-sequencing, RNA-sequencing, macrophage-signalling and genetic analyses, we demonstrate that chromatin reorganization in macrophage-internalized Cg, via CgSnf2 (ATPase subunit of the SWI/SNF chromatin remodelling complex), leads to upregulation and downregulation of immunosuppressive seven mannosyltransferase-cluster (CgMT-C) and immunostimulatory cell surface adhesin EPA1 genes, respectively. Consistently, EPA1 overexpression and CgMT-C deletion led to increased IL-1{beta} (pro-inflammatory cytokine) production and reduced Cg proliferation in macrophages. Further, CgSNF2 deletion evoked increased IL-1{beta} secretion, and the consequent killing of macrophage-internalized Cg, with elevated IL-1{beta} levels being partially reversed in Akt-, p38-, NF-{kappa}B- or NLRP3 inflammasome-inhibited macrophages. Importantly, macrophages respond to multiple Candida pathogens via NF-{kappa}B-dependent IL-1{beta} production, underscoring NF-{kappa}B signallings role in fungal diseases. Finally, we present the first genome-wide nucleosome map of macrophage-internalized Cg consisting of [~]12,000 dynamic and 70,000 total nucleosomes. Altogether, our findings directly link the nucleosome positioning-based chromatin remodelling to fungal immunomodulatory molecule expression, which dictates Cg fate in host immune cells.

microbiology↗