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At least 19 recordsLinked to original sources
PubMed2025

Strain-level differences in Gardnerella urinary tract persistence and pathogenesis are consistent with comparative phylogenomic analyses.

BACKGROUND: Gardnerella is a genus of gram variable anaerobic bacteria that is commonly present in the female urogenital tract, especially during bacterial vaginosis (BV). BV is linked with increased risk of urinary tract infections (UTI) and Gardnerella has been frequently detected in urine collected directly from the bladder. Understanding the contribution of Gardnerella to urogenital pathogenesis has been complicated by its genetic heterogeneity and a shortage of data from in vivo models. Recently, a clinical isolate of Gardnerella displayed covert pathogenesis in a mouse urinary tract inoculation model, triggering urothelial exfoliation and promoting UTI by uropathogenic E. coli. Data from clinical studies suggests differential association of Gardnerella phylogenetic clades with BV or urogenital infections. In vitro data has demonstrated heterogeneity in the presence and expression of putative virulence determinants between Gardnerella strains. This study was designed to compare diverse Gardnerella strains in vivo to identify genomic variation associated with urinary tract persistence and pathogenesis. METHODS: Eighteen Gardnerella clinical isolates from each of the four main phylogenetic clades were individually inoculated transurethrally into female C57BL/6 mice. Bacteriuria was monitored by quantitative culturing of Gardnerella in urine. Pathologic features were assessed by immunofluorescent and histological staining of bladder tissues. Pan-genome phylogenetic analyses were performed on the 18 Gardnerella isolates used for mouse infections to identify accessory genes that were associated with observable in vivo phenotypes, including long and short-term persistence, urothelial exfoliation and bladder edema. Genes that were significantly associated to phenotype were then matched against a pangenome analysis of 291 publicly available Gardnerella genomes to determine the conservation of these putative colonization and virulence factors across the genus. RESULTS: Gardnerella strains displayed clear differences in persistence and pathogenesis in the mouse bladder that were congruent with phylogeny. Clade 2 strains were more persistent in the urinary tract whereas strains from the other three clades either caused transient bacteriuria or were undetectable. Strains from clade 2 and 4 induced urothelial exfoliation while edema was triggered by strains from clades 2, 3 and 4. Pangenome analyses revealed 45 genes that were associated with in vivo persistence and pathogenicity. Among the wider 291 publicly available genomes, clade 2 strains encoded more of the genes associated with bacteriuria phenotypes compared to strains in the other three clades. Exfoliation-associated genes were present in most clade 4 strains. Clade 3 strains lack most of the in vivo-associated genes, whereas clade 1 strains were more heterogenous. CONCLUSIONS: This study provides in vivo evidence for differential urinary tract colonization and pathogenesis by strains from different clades/species within the genus Gardnerella and identifies new putative persistence and virulence factors. Utilizing the in vivo data from tested strains, pangenome analyses predicts that clade 2 Gardnerella are the most likely to persist in the urinary tract and that clades 2 and 4 have the highest uropathogenic potential. These findings inform future targeted screening and treatment approaches aimed at limiting harmful Gardnerella urinary tract exposures.

Journal Article↗
PubMed1979

The pathogenesis of hyperadrenergic postural hypotension in diabetic patients.

Patients with diabetes generally exhibit normal plasma catecholamine responses to standing. Some have blunted norepinephrine responses and postural hypotension-hypoadrenergic postural hypotension due to classic diabetic adrenergic neuropathy. Others, including some with postural hypotension, have exaggerated norepinephrine responses to standing. In order to clarify the pathogenesis of this hyperadrenergic state which occurs in a subset of diabetic patients, we studied aldosterone secretion, vascular and metabolic responsiveness to the administration of norepinephrine, and intravascular volumes in four diabetic patients who were selected for their exaggerated plasma norepinephrine responses to standing. Three of the four patients also exhibited (hyperadrenergic) postural hypotension. None of the hyperadrenergic diabetic patients had evidence of hypoaldosteronism or vascular resistance to norepinephrine, but all four patients had subnormal red blood cell masses and the mean (+/-SE) red blood cell mass (13.1 +/- 1.0 ml/kg) was approximately half of that of age- and sex-matched diabetic controls (26.5 +/- 2.7 ml/kg, p less than 0.01). Thus, intravascular volume contraction, specifically a reduction in the red blood cell mass, may play an important role in the pathogenesis of hyperadrenergic state observed in a subset of diabetic patients and in the pathogenesis of hyperadrenergic postural hypotension in affected diabetic patients.

Acetoacetates↗
PubMed2024

Acute MeCP2 loss in adult mice reveals transcriptional and chromatin changes that precede neurological dysfunction and inform pathogenesis.

Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene cause Rett syndrome, a severe childhood neurological disorder. MeCP2 is a well-established transcriptional repressor, yet upon its loss, hundreds of genes are dysregulated in both directions. To understand what drives such dysregulation, we deleted Mecp2 in adult mice, circumventing developmental contributions and secondary pathogenesis. We performed time series transcriptional, chromatin, and phenotypic analyses of the hippocampus to determine the immediate consequences of MeCP2 loss and the cascade of pathogenesis. We find that loss of MeCP2 causes immediate and bidirectional progressive dysregulation of the transcriptome. To understand what drives gene downregulation, we profiled genome-wide histone modifications and found that a decrease in histone H3 acetylation (ac) at downregulated genes is among the earliest molecular changes occurring well before any measurable deficiencies in electrophysiology and neurological function. These data reveal a molecular cascade that drives disease independent of any developmental contributions or secondary pathogenesis.

Animals↗
PubMed1975

The localisation of sorbitol pathway activity in the rat renal cortex and its relationship to the pathogenesis of the renal complications of diabetes mellitus.

A series of in vivo and in vitro investigations was performed to examine the localisation of sorbitol pathway activity in the rat renal cortex and to investigate the possible relation that the acculumation of sorbitol pathway intermediates in renal cortical tissue may have to the pathogenesis of renal complications in diabetes mellitus. Neither of the sorbitol pathway intermediates, sorbitol or fructose, were detected either in intact glomeruli which had been isolated from rats rendered chronically diabetic with streptozotocin, or in metabolically active glomeruli which had been incubated in vitro in high glucose media. Such data agreed with previously published observations that the enzyme aldose reductase is not present in renal glomeruli, and suggested that changes in sorbitol pathway activity cannot be directly related to the pathogenesis of diabetic glomerulosclerosis. Sorbitol was detected in low concentrations (3.1 mu-mol/g protein) in cortical tubules which had been isolated from the renal cortex of rats rendered chronically diabetic with streptozotocin. This concentration of sorbitol was higher than that in the intact renal cortex of the diabetic animal (0.3 mu-mol/g protein) or in the cortical tubules of non-diabetic animals (0.5 mu-mol/g protein). It is apparent that the renal cortical tubule is a major site of sorbitol pathway activity in the renal cortex. However, there is presently no obvious causal relationship between the accumulation of such relatively low concentrations of sorbitol in the renal cortical tubule and the pathogenesis of glomerulosclerosis or cortical tubular lesions in diabetes.

Animals↗
PubMed2026

Lineage-associated differences in adenine methylation patterns of mammalian-associated Campylobacter fetus isolates: a possible role for epigenetic factors in host tropism and pathogenesis.

Mammalian Campylobacter fetus (CF) is divided into two subspecies, C. fetus fetus (CFF) and C. fetus venerealis (CFV), the latter being bovine-adapted and responsible for the notifiable disease bovine genital campylobacteriosis (BGC). Differentiation between CF subspecies has traditionally been undertaken by a few biochemical tests, but these are complicated by the existence of a biotype, C. fetus venerealis intermedius (CFVi), which shares attributes of both CFF and CFV. Molecular methods targeting specific genes have gained acceptance for more accurate subtype identification and align well with whole-genome analysis. However, limited genomic diversity between subtypes has confounded efforts to understand the genetic basis for differential host tropism and pathogenesis of these organisms. A previous study of a small cohort of C. fetus isolates suggested that dam gene coding variations might correlate with CF subtype. Accordingly, this study examines a cohort of 331 C. fetus genomes, representative of all seven phylogenetic groups for their complement of adenine methylases and the genomic motifs they target in representative isolates. All CF isolates retained a cfeM1 gene, the presence of which correlates with RAATTY methylation, while seven other adenine methylase genes exhibited distinct cladal distributions. Notably, a cjeM1 gene appears to target the CCAN7TAG/CTAN7TGG motif in CFV and CFVi isolates only. Given the increasing recognition of the impact of adenine methylation on bacterial-host interactions, further exploration of the role of adenine methylation in C. fetus pathogenesis could reveal mechanisms contributing to BGC and thus aid in its eradication.IMPORTANCECampylobacter fetus remains an important zoonotic pathogen, for which a better understanding of its host tropism and pathogenesis is sought. However, the limited genomic variation observed between subtypes has to date confounded efforts in this regard. This study suggests that an alternative approach that examines epigenetic differences between subtypes, specifically adenine methylation patterns, may reveal mechanisms critical to the pathologies of these organisms.

Animals↗
PubMed1979

The role of the gallbladder in the pathogenesis of cholesterol gallstones.

During the past century, a variety of explanations have been proposed to explain the pathogenesis of cholesterol gallstones. Early attempts to account for the phenomenon of cholelithiasis focused on events in the gallbladder and stressed mucosal inflammatory changes, gallbladder stasis, stratification of bile, and absorption of bile salts from a damaged mucosa. The advent of the concept of "lithogenic bile" redirected attention to the liver and led to the proposal that an enzyme-mediated genetic and/or metabolic defect is the initiator of cholesterol cholelithiasis. While recognizing that the pathogenesis of gallstones is probably multifactorial, alterations in gallbladder and biliary ductal motor function constitute a plausible, but as yet unexplored, mechanism for alterations in enterohepatic circulation dynamics and subsequent cholesterol cholelithiasis. Gallbladder motor function is a complex phenomenon influenced by dynamic compliance, autonomic pharmacology, hormonal responses, and sphincter dynamics. Attempts to describe these aspects of biliary physiology may characterize the next phase in our understanding of the pathogenesis of cholesterol cholelithiasis.

Bile Acids and Salts↗
PubMed2022

A Multitrait Locus Regulates Sarbecovirus Pathogenesis.

Infectious diseases have shaped the human population genetic structure, and genetic variation influences the susceptibility to many viral diseases. However, a variety of challenges have made the implementation of traditional human Genome-wide Association Studies (GWAS) approaches to study these infectious outcomes challenging. In contrast, mouse models of infectious diseases provide an experimental control and precision, which facilitates analyses and mechanistic studies of the role of genetic variation on infection. Here we use a genetic mapping cross between two distinct Collaborative Cross mouse strains with respect to severe acute respiratory syndrome coronavirus (SARS-CoV) disease outcomes. We find several loci control differential disease outcome for a variety of traits in the context of SARS-CoV infection. Importantly, we identify a locus on mouse chromosome 9 that shows conserved synteny with a human GWAS locus for SARS-CoV-2 severe disease. We follow-up and confirm a role for this locus, and identify two candidate genes, CCR9 and CXCR6, that both play a key role in regulating the severity of SARS-CoV, SARS-CoV-2, and a distantly related bat sarbecovirus disease outcomes. As such we provide a template for using experimental mouse crosses to identify and characterize multitrait loci that regulate pathogenic infectious outcomes across species. IMPORTANCE Host genetic variation is an important determinant that predicts disease outcomes following infection. In the setting of highly pathogenic coronavirus infections genetic determinants underlying host susceptibility and mortality remain unclear. To elucidate the role of host genetic variation on sarbecovirus pathogenesis and disease outcomes, we utilized the Collaborative Cross (CC) mouse genetic reference population as a model to identify susceptibility alleles to SARS-CoV and SARS-CoV-2 infections. Our findings reveal that a multitrait loci found in chromosome 9 is an important regulator of sarbecovirus pathogenesis in mice. Within this locus, we identified and validated CCR9 and CXCR6 as important regulators of host disease outcomes. Specifically, both CCR9 and CXCR6 are protective against severe SARS-CoV, SARS-CoV-2, and SARS-related HKU3 virus disease in mice. This chromosome 9 multitrait locus may be important to help identify genes that regulate coronavirus disease outcomes in humans.

Animals↗
PubMed1977

Pathogenesis of reovirus type 1 hydrocephalus in mice. Significance of aqueductal changes.

The pathogenesis of hydrocephalus following reovirus type 1 inoculation of neonatal mice has been examined by light microscopy, radiology, immunofluorescence, and electron microscopy. The reovirus infection causes an acute ependymitis and leptomeningitis, followed by a fibrous arachnoiditis and arachnoid villitis. Hydrocephalus develops in proportion to the degree of inflammatory/fibrotic changes within the cerebrospinal fluid pathways. With the beginning of hydrocephalus there is radiographic evidence of basal cistern blockage. As the hydrocephalic state progresses, axial herniation and compression of the midbrain result in the appearance of aqueduct stenosis. We demonstrate that the stenosis of the aqueduct is a secondary phenomenon, not causally related to the pathogenesis of hydrocephalus, and discuss the significance of this finding to human aqueduct stenosis.

Animals↗
PubMed1977

Optic disc edema in raised intracranial pressure. V. Pathogenesis.

The pathogenesis of optic disc edema (ODE) in raised intracranial pressure is discussed in the light of recent observations on the subject. The findings indicate that ODE is a mechanical phenomenon. The raised cerebrospinal fluid pressure (CSFP) in the sheath of the optic nerve produces axoplasmic flow stasis in the optic nerve head. This results in swelling of the axons, which manifests as early ODE and secondarily produces the well-known optic disc and retinal vascular changes associated with ODE. The pathogenesis of ODE seen in different conditions without raised CSFP cannot be explained by any single mechanism in spite of the occurrence of axoplasmic flow stasis in most cases, because the stasis in different situations has different mechanisms.

Adolescent↗
PubMed2025

Development and Characterization of an Inducible Bacterial Artificial Chromosome System for Studying Lytic Replication and Pathogenesis of Kaposi's Sarcoma-Associated Herpesvirus.

Bacterial artificial chromosome (BAC) is widely used to manipulate herpesvirus genome and generate recombinant virus. Here, we developed a new KSHV BACmid, namely as iBAC, by replacing the EGFP with TET3G transactivator under EF1α promoter and inserted Tet response elements in the promoter of RTA in the original KSHV BAC16 clone and characterized KSHV lytic replication in SLK-iBAC cells. SLK-iBAC cells developed more efficient lytic replication and generated more progeny virus than iSLK-BAC16 cells upon the same conditions of doxycycline treatment. Since SLK-iBAC cells only occupied hygromycin selection marker, it is convenient to generate cellular gene knockout via lentivirus-mediated CRISPR-Cas9 or stably express viral or cellular gene via lentivirus followed by antibiotic selection, making iBAC system a better tool to identify cellular targets of viral proteins in the context of virus infection or study the role of viral or cellular genes for KSHV lytic replication and pathogenesis. In addition, iBAC is color-free and can be utilized to track subcellular localization of viral proteins or colocalization between different viral proteins by introducing fusing fluorescent proteins into the BAC backbone. Therefore, the new KSHV iBAC is a powerful inducible tool to study KSHV lytic replication and pathogenesis in cell model.

Chromosomes, Artificial, Bacterial↗