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Abdullah, M.

Publications and source records attributed to Abdullah, M..

18 recordsLinked to original sources

Contextual Biomedical Language Models for Imbalance-Aware Drug-Food Interaction Classification

Drug-food interactions (DFIs) are essential to patient safety because they can alter drug effectiveness or cause side effects. Automated classification of DFIs is difficult because of unstructured textual data, semantic ambiguity, and class imbalance, especially when separating neutral interactions. This paper presents an imbalance-aware deep learning approach for classifying drug-food interactions into three classes: safe, neutral, and unsafe. A structured dataset is created from textual drug interaction descriptions by extracting drug-food pairs and labeling them using rule-based heuristics. To address class imbalance, we apply class weighting and focal loss while fine-tuning the context-aware BioBERT language model. Our experiments show that the approach reaches an accuracy of 85% and a macro-averaged F1-score of 0.77, with a notable improvement on the minority neutral class (F1-score of 0.56). The main novelty of this work is the combination of contextual biomedical language modeling with imbalance-aware deep learning, enabling more effective classification of DFI datasets.

bioinformatics↗

Kinematics to Kinetics: Evaluating OpenGRF for Scalable Ground Reaction Force Estimation in Healthy and Pathological Gait

Ground reaction forces (GRFs) are important markers of gait impairment and rehabilitation, but direct measurement with force plates is expensive and limited to laboratory settings. OpenGRF is an open-source framework that estimates GRFs from motion-capture data using musculoskeletal modeling, yet its validity in pathological gait remains uncertain. This study evaluated the accuracy of OpenGRF for estimating three-dimensional GRFs during gait in healthy adults and in people with Parkinsons disease (PD), stroke, hip osteoarthritis (HOA), and total hip arthroplasty, and assessed its ability to reproduce clinically relevant GRF peak magnitudes and timings. OpenGRF estimates were compared with force-plate measurements in healthy participants and in cohorts with PD (OFF/ON medication), stroke, and HOA before surgery (M0) and 6 months after surgery (M6). Accuracy was quantified using root mean square error (RMSE), normalized RMSE (NRMSE), and Pearson correlation coefficients (PCC). Peak analyses examined biases in anterior-posterior (AP) braking and propulsive peaks, first and second vertical peaks (V1, V2), and the main mediolateral peak, as well as timing shifts across the gait cycle. One-dimensional statistical parametric mapping tested waveform differences (p = 0.01). OpenGRF reproduced overall GRF profiles across groups. Vertical GRF showed the best agreement (PCC 0.84-0.94; NRMSE 0.14-0.23), whereas mediolateral GRF showed low absolute error (RMSE 1.45-1.95 %BW) and moderate-to-good agreement (PCC 0.70-0.82). AP GRF was least accurate (PCC 0.61-0.73), especially during propulsion in PD (NRMSE up to 0.39). OpenGRF can reasonably estimate GRFs in healthy and pathological gait and may support kinetic gait assessment when force plates are unavailable.

bioengineering↗

Proteomic characterization of neuronal extracellular vesicle interactomes in Alzheimer's disease mouse model through TurboID-based proximity labeling

Extracellular vesicles (EVs) are critical mediators of neuronal communication and have been implicated in propagating pathological processes in neurodegenerative diseases, including Alzheimers disease (AD). However, the molecular interactome of neuronal EVs in vivo remains poorly defined. Here, we employed TurboID-CD9-based proximity biotinylation to label and capture EV-interacting proteins in the hippocampus of wild-type (WT) and APPNLGF knock-in AD mouse models. Adeno-associated viral delivery of hSyn1 promoter-driven TurboID-CD9 enabled neuron-specific EV tagging, followed by in vivo biotinylation and affinity purification of labeled proteins. Proteomic analysis using data independent acquisition liquid chromatography - mass spectrometry identified 5,502 proteins, with enriched pathways involving synaptic transmission, vesicle trafficking, and inhibitory neurotransmission. Comparative analyses revealed robust enrichment of GABAergic signaling components, including GABAA receptor subunits (Gabrb3, Gabra1, Gabbr2), Ncam1, and chloride transporters, in both WT and APPNLGF EV interactomes, with additional disease-associated proteins (Mapt, Snca) and potassium channel enrichment observed in APPNLGF mice. Proximity ligation assays validated direct EV-associated biotinylation of Ncam1, Gabrb3, and Gad1, with Gad1 showing significant upregulation in the APPNLGF cohort. In silico HADDOCK docking supported stable interactions between CD9 and these target proteins, revealing plausible EV-protein interfaces. These findings define the in vivo neuronal EV interactome and its remodeling in amyloid pathology, implicating EV-associated GABAergic and ion channel proteins in network excitability regulation. This work establishes a proteomic and structural framework for understanding EV-mediated signaling in health and disease, providing candidate targets for therapeutic modulation of excitatory / inhibitory balance in AD.

neuroscience↗

The Viral AlphaFold Database of monomers and homodimers reveals conserved protein folds in viruses of bacteria, archaea, and eukaryotes

Viruses are among the most abundant and genetically diverse entities on Earth, yet the functions and evolutionary origins of most viral proteins remain poorly understood. Their rapid evolution often obscures evolutionary relationships, making it difficult to assign functions using sequence-based methods alone. Although conservation of protein fold can reveal deep homologies undetectable by sequence comparison, viral proteins remain vastly underrepresented in structural databases, limiting our ability to explore them at the structural level. Here, we address this gap by clustering all unique viral sequences from the NCBI RefSeq database and predicting the structures of [~]27,000 representative proteins using AlphaFold2, creating a large-scale viral structural resource, the Viral AlphaFold Database (VAD). We uncover [~]10,000 proteins belonging to clusters that share folds across viruses infecting bacteria, archaea, and eukaryotes, revealing shared protein folds across diverse host-infecting viruses. We also predict oligomeric states using AlphaFold2-based homodimer modelling, alongside structural comparisons to the Protein Data Bank, providing valuable new data on the potential for viral proteins to oligomerise. We further reveal that large regions of the viral protein universe remain functionally dark and report the discovery and experimental validation of a previously uncharacterised antiviral toxin-antitoxin (TA) system. VAD is a resource that provides a foundation for exploring viral structure-function relationships, including ancient folds that shape viral interactions across all life. Predicted structures used in this study are available at data-sharing.atkinson-lab.com/vad/.

molecular biology↗

Weighted gene co-expression network analysis reveals key genes and lncRNAs in desi cattle chronically infected with Johne's disease

Johnes disease (JD), caused by Mycobacterium avium subsp. paratuberculosis (MAP), is a chronic enteric disease with significant economic impacts on the dairy industry. To elucidate molecular mechanisms underlying MAP infection in desi cattle (Bos indicus), we conducted a comprehensive transcriptomic study. This revealed 1,905 protein-coding and 3,123 lncRNA genes as differentially expressed in MAP-infected samples, alongside the first comprehensive annotation of 45,947 lncRNAs in desi cattle. Weighted Gene Co-expression Network Analysis identified 11 co-expressed gene modules, with the turquoise module comprising 870 protein- coding genes and 934 lncRNAs, highly correlated with clinical traits. Functional enrichment analysis of this key module revealed significant involvement in defense response, inflammatory processes, and NK cell-mediated immunity and cytotoxicity. GSE analysis revealed suppressed pathways, including NK cell immunity and lectin response, facilitating bacterial persistence in chronic infection, while activated pathways included G-protein-coupled receptor signaling and metabolic pathways. Network approach identified 12 hub genes (IL7R, TLR4, KLRK1, IFNG, TGFB1, CD68, CXCR6, GZMB, KLRG1, MMP9, GZMA, SELL) associated with immune suppression, inflammation, and tissue remodeling. Additionally, 22 lncRNAs co-expressed with hub genes suggesting roles in modulating immune regulation. By identifying critical genes and lncRNAs, our study offers potential targets for developing innovative diagnostic and therapeutic strategies for JD.

systems biology↗

Valosin-containing Protein is Cargo in Amyloid Precursor Protein Extracellular Vesicles

The Amyloid Precursor Protein (APP), a genetic cause of Alzheimers disease (AD), is a type-I transmembrane protein that is metabolized by proteolysis in the endolysomal system. APP and its metabolites are secreted by cells in extracellular vesicles (EVs). To study the function of APP-containing EVs, we isolated App-EVs from rat primary neuronal conditioned media and proteomic analysis identified the Valosin-containing protein (Vcp) as molecular cargo. Pharmacological modulation of Vcp activity was found to alter App processing and global EV secretion in rat primary neurons. AD-associated knock-in App mutations were found to alter the abundance of App-EVs and the trafficking of App metabolites within App-EVs, in a manner related to the epitopes generated by the nonamyloidogenic processing of App. The presence of Vcp suggests a role for App-EVs in the clearance of protein aggregates.

cell biology↗

Genomic characterization of Escherichia coli harbor a polyketide synthase (pks) island associated with colorectal cancer (CRC) development

The E. coli strain harboring the polyketide synthase (Pks) island encodes the genotoxin colibactin, a secondary metabolite reported to have severe implications for human health and for the progression of colorectal cancer. The present study involved whole-genome-wide comparison and phylogenetic analysis of pks harboring E. coli isolates to gain insight into the distribution and evolution of these organism. Fifteen E. coli strains isolated from patients with ulcerative colitis were sequenced, 13 of which harbored pks islands. In addition, 2,654 genomes from the public database were also screened for pks harboring E. coli genomes, 158 of which were pks-positive isolates. Whole-genome-wide comparison and phylogenetic analysis revealed that 171 (158+13) pks-positive isolates belonged to phylogroup B2, and most of the isolates associated to sequence types ST73 and ST95. One isolate from an ulcerative colitis (UC) patient was of the sequence type ST8303. The maximum likelihood tree based on the core genome of pks-positive isolates revealed horizontal gene transfer across sequence types and serotypes. Virulome and resistome analyses revealed the preponderance of virulence genes and a reduced number of antimicrobial genes in Pks-positive isolates. This study strongly contributes to understanding the evolution of pks islands in E. coli.

immunology↗

An improved haplotype resolved genome reveals more rice genes

The rice reference genome (Oryza sativa ssp. japonica cv. Nipponbare) has been an important resource in plant science. We now report an improved and haplotype resolved genome sequence based upon more accurate sequencing technology. This improved assembly includes regions missing in earlier genomes sequences and the annotation of more than 3,000 new genes due to greater sequence accuracy.

genomics↗

What is hidden in the darkness? Deep-learning assisted large-scale protein family curation uncovers novel protein families and folds

Driven by the development and upscaling of fast genome sequencing and assembly pipelines, the number of protein-coding sequences deposited in public protein sequence databases is increasing exponentially. Recently, the dramatic success of deep learning-based approaches applied to protein structure prediction has done the same for protein structures. We are now entering a new era in protein sequence and structure annotation, with hundreds of millions of predicted protein structures made available through the AlphaFold database. These models cover most of the catalogued natural proteins, including those difficult to annotate for function or putative biological role based on standard, homology-based approaches. In this work, we quantified how much of such "dark matter" of the natural protein universe was structurally illuminated by AlphaFold2 and modelled this diversity as an interactive sequence similarity network that can be navigated at https://uniprot3d.org/atlas/AFDB90v4. In the process, we discovered multiple novel protein families by searching for novelties from sequence, structure, and semantic perspectives. We added a number of them to Pfam, and experimentally demonstrate that one of these belongs to a novel superfamily of translation-targeting toxin-antitoxin systems, TumE-TumA. This work highlights the role of large-scale, evolution-driven protein comparison efforts in combination with structural similarities, genomic context conservation, and deep-learning based function prediction tools for the identification of novel protein families, aiding not only annotation and classification efforts but also the curation and prioritisation of target proteins for experimental characterisation.

bioinformatics↗

Species-specific protein-protein interactions govern the humanization of the 20S proteasome in yeast

Yeast and humans share thousands of genes despite a billion years of evolutionary divergence. While many human genes can functionally replace their yeast counterparts, nearly half of the tested shared genes cannot. For example, most yeast proteasome subunits are humanizable, except subunits comprising the {beta}-ring core, including {beta}2 (HsPSMB7). We developed a high-throughput pipeline to humanize yeast proteasomes by generating a large library of Hs{beta}2 mutants and screening them for complementation of yeast {beta}2 (ScPup1). Variants capable of replacing ScPup1 included (1) those impacting local protein-protein interactions (PPIs), with most affecting interactions between the {beta}2 C-terminal tail and the adjacent {beta}3 subunit, and (2) those affecting {beta}2 proteolytic activity. Exchanging the full-length tail of human {beta}2 with that of ScPup1 enabled complementation. Moreover, wild-type human {beta}2 replaced yeast {beta}2 if the adjacent human {beta}3 subunit was also provided. Unexpectedly, yeast proteasomes bearing a catalytically inactive HsPSMB7-T44A variant blocking precursor autoprocessing were viable, suggesting an intact propeptide stabilizes late assembly intermediates. Our data reveal roles for specific PPIs governing functional replaceability across vast evolutionary distances.

genetics↗

Rapid, scalable, combinatorial genome engineering by Marker-less Enrichment and Recombination of Genetically Engineered loci (MERGE)

Large-scale genome engineering in yeast is feasible primarily due to prodigious homology-directed DNA repair (HDR), a plethora of genetic tools, and simple conversion between haploid and diploid forms. However, a major challenge to rationally building multi-gene processes in yeast arises due to the combinatorics of combining all of the individual edits into the same strain. Here, we present an approach for scalable, precise, multi-site genome editing that combines all edits into a single strain without the need for selection markers by using CRISPR-Cas9 and gene drives. First, we show that engineered loci become resistant to the corresponding CRISPR reagent, allowing the enrichment of distinct genotypes. Next, we demonstrate a highly efficient gene drive that selectively eliminates specific loci by integrating CRISPR-Cas9 mediated Double-Strand Break (DSB) generation and homology-directed recombination with yeast sexual assortment. The method enables Marker-less Enrichment and Recombination of Genetically Engineered loci (MERGE) in yeast. We show that MERGE converts single heterologous yeast loci to homozygous loci at [~]100% efficiency, independent of chromosomal location. Furthermore, MERGE is equally efficient at converting and combining loci, thus identifying viable intermediate genotypes. Finally, we establish the feasibility of MERGE by engineering a fungal carotenoid biosynthesis pathway and most of the human proteasome core into yeast. MERGE, therefore, lays the foundation for marker-less, highly efficient, and scalable combinatorial genome editing in yeast.

synthetic biology↗

Designing of multiepitope-based vaccine against Leptospirosis using Immuno-Informatics approaches.

Leptospira is a zoonotic pathogen causing significant morbidity and mortality both in animals and humans. Although several surface proteins have been identified as vaccine candidate, they failed to induce sterilizing immunity and cross protection against different serovars. Thus, identification of highly immunogenic antigens that are conserved among pathogenic serovars would be first step towards development of universal vaccine for Leptospirosis. Here we used reverse vaccinology pipeline to screen core genome of pathogenic Leptospira spp.in order to identify suitable vaccine candidates. Based on properties like sub cellular localization, adhesin, homology to human proteins, antigenicity and allergenicity, 18 antigenic proteins were identified and were further investigated for immunological properties. Based on immunogenicity, Protegenicity, Antigenicity, B-cell and promiscuous T-cell epitopes, 6 Potential Vaccine Candidates (PVCs) were finally selected which covered most of the affected world population. For designing a Multi-Epitope Vaccine (MEV), 6 B-cell and 6 promiscuous MHC-I and MHC-II epitopes from each candidate were clustered with linkers in between and stitched along with a TLR4 adjuvant (APPHALS) at the N-terminal to form a construct of 361 amino acids. The physiochemical properties, secondary and tertiary structure analysis revealed that MEV was highly stable. Molecular docking analysis revealed the deep binding interactions of the MEV construct within the grooves of human TLR4 (4G8A). In-silico codon optimization and cloning of the vaccine construct assured good expression. Further, immune simulations have shown that MEV could induce strong and diverse B and T cell responses. Taken together our results indicate that the designed MEV could be a promising subunit vaccine candidate against Leptospirosis, however it requires experimental validation.

bioinformatics↗

Comparative analysis of whole genome sequences of Leptospira spp. from RefSeq database provide interspecific divergence and repertoire of virulence factors

Leptospirosis is an emerging zoonotic and neglected disease across the world causing huge loss of life and economy. The disease is caused by Leptospira of which 605 sequenced genomes representing 72 species are available in RefSeq database. A comparative genomics approach based on Average Amino acid Identity (AAI), Average Nucleotide Identity (ANI), and Insilco DNA-DNA hybridization provide insight that taxonomic and evolutionary position of few genomes needs to be changed and reclassified. Clustering on the basis of AAI of core and pan-genome contradict clustering pattern on basis of ANI into 4 clusters. Amino acid identity based hierarchical clustering clearly established 3 clusters of Leptospira correlating with level of virulence. Whole genome tree supported three cluster classifications and grouped Leptospira into three clades termed as pathogenic, intermediate and saprophytic. Leptospira genus consist of diverse species and exist in heterogeneous environment, it contains relatively large and closed core genome of 1038 genes. Analysis provided pan genome remains open with 20822 genes. COG analysis revealed that mobilome related genes were found mainly in pan-genome of pathogenic clade. Clade specific genes mined in the study can be used as marker for determining clade and associating level of virulence of any new Leptospira species. Many known Leptospira virulent genes were absent in set of 78 virulent factors mined using Virulence Factor database. A deep search approach provided a repertoire of 496 virulent genes in pan-genome. Further validation of virulent genes will help in accurately targeting pathogenic Leptospira and controlling leptospirosis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/426470v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@104babborg.highwire.dtl.DTLVardef@17f727dorg.highwire.dtl.DTLVardef@35a6c1org.highwire.dtl.DTLVardef@56fd53_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

Enrichment of neurodegenerative microglia signature in brain-derived extracellular vesicles isolated from Alzheimer's disease mouse model

Extracellular vesicles (EVs) are secreted by any neuronal cells in the central nervous system (CNS) for molecular clearance, cellular communications and disease spread in multiple neurodegenerative diseases, including Alzheimers disease (AD), although their exact molecular mechanism is poorly understood. We hypothesize that high-resolution proteomic profiling of EVs separated from animal models of AD would determine the composition of EV contents and their cellular origin. Here, we examined recently developed transgenic mice (CAST.APP/PS1), which express familial AD-linked mutations of amyloid precursor protein (APP) and presenilin-1 (PS1) in the CAST/EiJ mouse strain and develop hippocampal neurodegeneration. Quantitative proteomics analysis of EVs separated from CAST.APP/PS1 and age-matched control mice by tandem mass tag-mass spectrometry identified a total of 3,444 unique proteins, which are enriched in neuron, astrocyte, oligodendrocyte and microglia-specific molecules. CAST.APP/PS1-derived EVs show significant enrichment of Psen1, APP, Itgax, and reduction of Wdr61, Pmpca, Aldh1a2, Calu, Anp32b, Actn4 and Ndufv2 compared to WT-derived EVs, suggesting the involvement of A{beta}-processing complex and disease-associated / neurodegenerative microglia (DAM/MGnD) in EV secretion. In addition, Itgax and Apoe, the DAM/MGnD markers, in EV show a positive correlation with Itgax and Apoe mRNA expression from brain tissue in CAST.APP/PS1 mice. These datasets indicate the significant contribution of A{beta} plaque and neurodegeneration-induced DAM/MGnD microglia for EV secretion in CAST.APP/PS1 mice and shed light on understanding the AD pathogenesis.

neuroscience↗

Leptospira surface protein LigA plays a multifaceted role in modulating the host innate immune response

Leptospira, a zoonotic pathogen, is known to infect various hosts and can establish persistent infection. This remarkable ability of bacteria is attributed to its potential to modulate the host immune response by exploiting its surface proteins. We have identified and characterized the domain of the variable region of Leptospira immunoglobulin-like protein A (LAV) involved in immune modulation. The 11th domain (A11) of the variable region of LigA (LAV) induces a strong TLR4 dependent innate response leading to subsequent induction of humoral and cellular immune responses in mice. A11 is also involved in acquiring complement regulator FH and binds to host protease Plasminogen (PLG), there by mediating functional activity to escape from complement-mediated killing. The deletion of A11 domain significantly impaired TLR4 signaling and subsequent reduction in the innate and adaptive immune response. It also inhibited the binding of FH and PLG thereby mediating killing of bacteria. Our study discovered an unprecedented role of LAV as a nuclease capable of degrading Neutrophil Extracellular Traps (NETs). This nuclease activity was primarily mediated by A11. These results highlighted the moonlighting function of LigA and demonstrated that a single domain of a surface protein is involved in evading a myriad of host innate immune defenses, which might allow the persistence of Leptospira in different hosts for a long term without clearance.

immunology↗

Obtaining deeper insights into microbiome diversity using a simple method to block host and non-targets in amplicon sequencing

Microbiome profiling is revolutionizing our understanding of biological mechanisms such as metaorganismal (host+microbiome) assembly, functions and adaptation. Amplicon sequencing of multiple conserved, phylogenetically informative loci is an instrumental tool for characterization of the highly diverse microbiomes of natural systems. Investigations in many study systems are hindered by loss of essential sequencing depth due to amplification of non-target DNA from hosts or overabundant microorganisms. This issue requires urgent attention to address ecologically relevant problems using high throughput, high resolution microbial profiling. Here, we introduce a simple, low cost and highly flexible method using standard oligonucleotides ("blocking oligos") to block amplification of non-targets and an R package to aid in their design. They can be dropped into practically any two-step amplicon sequencing library preparation pipeline. We apply them in leaves, a system presenting exceptional challenges with host and non-target microbial amplification. Blocking oligos designed for use in eight target loci reduce undesirable amplification of host and non-target microbial DNA by up to 90%. In addition, 16S and 18S "universal" plant blocking oligos efficiently block most plant hosts, leading to increased microbial alpha diversity discovery without biasing beta diversity measurements. By blocking only chloroplast 16S amplification, we show that blocking oligos do not compromise quantitative microbial load information inherent to plant-associated amplicon sequencing data. Using these tools, we generated a near-complete survey of the Arabidopsis thaliana leaf microbiome based on diversity data from eight loci and discuss complementarity of commonly used amplicon sequencing regions for describing leaf microbiota. The blocking oligo approach has potential to make new questions in a variety of study systems more tractable by making amplicon sequencing more targeted, leading to deeper, systems-based insights into microbial discovery.

microbiology↗

Measuring the spatial heterogeneity on the reduction of vaginal fistula burden in Ethiopia between 2005 and 2016

Vaginal fistula is a shattering maternal complication characterized by an anomalous opening between the bladder and/or rectum and vagina resulting in continuous leakage of urine or stool. Although prevalent in Ethiopia, its magnitude and distribution is not well studied. We used statistical mapping models using 2005 and 2016 Ethiopia Demographic Health Surveys data combined with a suite of potential risk factors to estimate the burden of vaginal fistula among women of childbearing age. The estimated number of women of childbearing age with lifetime and untreated vaginal fistula in 2016 were 72,533 (95% CI 38,235-124,103) and 31,961 (95% CI 11,596-70,309) respectively. These figures show reduction from the 2005 estimates: 98,098 (95% CI 49,819-170,737) lifetime and 59,114 (95% CI 26,580-118,158) untreated cases of vaginal fistula. The number of districts having more than 200 untreated cases declined drastically from 54 in 2005 to 6 in 2016. Our results show a significant subnational variation in the burden of vaginal fistula. Overall, between 2005 and 2016 there was substantial reduction in the prevalence of vaginal fistula in Ethiopia. Our results help guide local level tracking, planning, spatial targeting of resources and implementation of interventions against vaginal fistula.

bioinformatics↗

Receptor guanylyl cyclase C confers protection during oral Salmonella Typhimurium infection by attenuating ileal damage and enhancing cytokine and antimicrobial peptide production

Non-typhoidal Salmonella disease contributes towards significant morbidity and mortality across the world. Host factors including IFN-{gamma}, TNF- and gut microbiota, significantly influence the outcome of Salmonella pathogenesis. However, the entire repertoire of host protective mechanisms contributing to Salmonella pathogenicity is not completely appreciated. Here, we have investigated the roles of receptor guanylyl cyclase C (GC-C) that is predominantly expressed in the intestine, and regulates intestinal cell proliferation and fluid-ion homeostasis. Mice deficient in GC-C (Gucy2c-/-) displayed accelerated mortality following infection via the oral route, in spite of possessing comparative systemic Salmonella infection burden. Survival following intra-peritoneal infection remained similar, indicating that GC-C offered protection via a gut-mediated response. Serum cortisol was higher in Gucy2c-/- mice, in comparison to wild type (Gucy2c+/+) mice, and an increase in infection-induced thymic atrophy, with loss in immature CD4+CD8+ double positive thymocytes, was observed. Accelerated and enhanced damage in the ileum, including submucosal edema, epithelial cell damage, focal tufting and distortion of villus architecture, was seen in Gucy2c-/- mice, concomitant with a larger number of ileal tissue-associated bacteria. Transcription of key mediators in Salmonella-induced inflammation (IL-22/Reg3{beta}) were altered in Gucy2c-/- mice in comparison to Gucy2c+/+ mice. A reduction in fecal Lactobacilli, which are protective against Salmonella infection, was observed in Gucy2c-/- mice. Gucy2c-/- mice cohoused with wild type mice continued to show reduced Lactobacilli and increased susceptibility to infection. Our study therefore suggests that receptor GC-C confers a survival advantage during gut-mediated S. Typhimurium pathogenesis, presumably by regulating Salmonella-effector mechanisms and maintaining a beneficial microbiome.

microbiology↗