RESUMEN
Poly(ADP-ribose) polymerases (PARPs) synthesize and bind branched polymers of ADP-ribose to acceptor proteins using NAD as a substrate and participate in the control of gene transcription and DNA repair. PARP1, the most abundant isoform, regulates the expression of proinflammatory mediator cytokines, chemokines, and adhesion molecules, and inhibition of PARP1 enzymatic activity reduced or ameliorated autoimmune diseases in several experimental models, including colitis. However, the mechanism(s) underlying the protective effects of PARP1 inhibition in colitis and the cell types in which Parp1 deletion has the most significant impact are unknown. The objective of the current study was to determine the impact of Parp1 deletion on the innate immune response to mucosal injury and on the gut microbiome composition. Parp1 deficiency was evaluated in DSS-induced colitis in WT, Parp1(-/-), Rag2(-/-), and Rag2(-/-)×Parp1(-/-) double knock-out mice. Genome-wide analysis of the colonic transcriptome and fecal 16S amplicon profiling was performed. Compared with WT, we demonstrated that Parp1(-/-) were protected from dextran-sulfate sodium-induced colitis and that this protection was associated with a dramatic transcriptional reprogramming in the colon. PARP1 deficiency was also associated with a modulation of the colonic microbiota (increases relative abundance of Clostridia clusters IV and XIVa) and a concomitant increase in the frequency of mucosal CD4(+)CD25(+) Foxp3(+) regulatory T cells. The protective effects conferred by Parp1 deletion were lost in Rag2(-/-) × Parp1(-/-) mice, highlighting the role of the adaptive immune system for full protection.
Asunto(s)
Inmunidad Adaptativa , Colitis/inmunología , Colon/inmunología , Inmunidad Innata , Inmunidad Mucosa , Mucosa Intestinal/inmunología , Poli(ADP-Ribosa) Polimerasas/deficiencia , Animales , Colitis/inducido químicamente , Colitis/genética , Colitis/patología , Colon/lesiones , Colon/patología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Sulfato de Dextran/toxicidad , Mucosa Intestinal/lesiones , Mucosa Intestinal/patología , Ratones , Ratones Noqueados , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patologíaRESUMEN
Azoles are frequently used to treat systemic mycoses but have been associated with a number of adverse effects of the skin and skin appendages. Herein we describe two cases of chronic paronychia in pediatric patients receiving fluconazole for coccidioidomycosis. Their clinical characteristics are described, and the literature reviewed.
RESUMEN
Chronic inflammation and enteric infections are frequently associated with epithelial Na(+)/H(+) exchange (NHE) inhibition. Alterations in electrolyte transport and in mucosal pH associated with inflammation may represent a key mechanism leading to changes in the intestinal microbial composition. NHE3 expression is essential for the maintenance of the epithelial barrier function. NHE3(-/-) mice develop spontaneous distal chronic colitis and are highly susceptible to dextran sulfate (DSS)-induced mucosal injury. Spontaneous colitis is reduced with broad-spectrum antibiotics treatment, thus highlighting the importance of the microbiota composition in NHE3 deficiency-mediated colitis. We herein characterized the colonic microbiome of wild-type (WT) and NHE3(-/-) mice housed in a conventional environment using 454 pyrosequencing. We demonstrated a significant decrease in the phylogenetic diversity of the luminal and mucosal microbiota of conventional NHE3(-/-) mice compared with WT. Rederivation of NHE3(-/-) mice from conventional to a barrier facility eliminated the signs of colitis and decreased DSS susceptibility. Reintroduction of the conventional microflora into WT and NHE3(-/-) mice from the barrier facility resulted in the restoration of the symptoms initially described in the conventional environment. Interestingly, qPCR analysis of the microbiota composition in mice kept in the barrier facility compared with reconventionalized mice showed a significant reduction of Clostridia classes IV and XIVa. Therefore, the gut microbiome plays a prominent role in the pathogenesis of colitis in NHE3(-/-) mice, and, reciprocally, NHE3 also plays a critical role in shaping the gut microbiota. NHE3 deficiency may be a critical contributor to dysbiosis observed in patients with inflammatory bowel disease.
Asunto(s)
Bacterias/clasificación , Colitis/microbiología , Intercambiadores de Sodio-Hidrógeno/metabolismo , Animales , Colitis/inducido químicamente , Colitis/genética , Sulfato de Dextran/toxicidad , Heces/microbiología , Ratones , Ratones Noqueados , Reacción en Cadena de la Polimerasa , Intercambiador 3 de Sodio-Hidrógeno , Intercambiadores de Sodio-Hidrógeno/genéticaRESUMEN
Clostridioides difficile is a leading cause of healthcare-associated infections worldwide. Currently, there is a lack of consensus for an optimal diagnostic method for C. difficile infection (CDI). Multi-step diagnostic algorithms use enzyme immunosorbent analysis (EIA)-based detection of C. difficile toxins TcdA/TcdB in stool, premised on the rationale that EIA toxin-negative (Tox-) patients have less severe disease and shorter diarrhoea duration. The aim of this study was to characterize toxigenic (i.e. tcdA/tcdB-positive) C. difficile strains isolated from diarrheic patient stool with an EIA Tox- (i.e. "discrepant") CDI diagnostic test result. Recovered strains were DNA fingerprinted (ribotyped), subjected to multiple toxin, genome and proteome evaluations, and assessed for virulence. Overall, of 1243 C. difficile-positive patient stool specimens from Southern Arizona hospitals, 31% were discrepant. For RT027 (the most prevalent ribotype)-containing specimens, 34% were discrepant; the corresponding RT027 isolates were cytotoxic to cultured fibroblasts, but their total toxin levels were comparable to, or lower than, the historic low-toxin-producing C. difficile strain CD630. Nevertheless, these low-toxin RT027 strains (LT-027) exhibited similar lethality to a clade-matched high-toxin RT027 strain in Golden Syrian hamsters, and heightened colonization and persistence in mice. Genomics and proteomics analyses of LT-027 strains identified unique genes and altered protein abundances, respectively, relative to high-toxin RT027 strains. Collectively, our data highlight the robust virulence of LT-027 C. difficile, provide a strong argument for reconsidering the clinical significance of a Tox- EIA result, and underscore the potential limitations of current diagnostic protocols.
Asunto(s)
Toxinas Bacterianas , Clostridioides difficile , Infecciones por Clostridium , Animales , Proteínas Bacterianas/metabolismo , Toxinas Bacterianas/genética , Clostridioides , Clostridioides difficile/genética , Ratones , VirulenciaRESUMEN
Clostridioides difficile infection (CDI) is a major healthcare-associated diarrheal disease. Consistent with trends across the United States, C. difficile RT106 was the second-most prevalent molecular type in our surveillance in Arizona from 2015 to 2018. A representative RT106 strain displayed robust virulence and 100% lethality in the hamster model of acute CDI. We identified a unique 46 KB genomic island (GI1) in all RT106 strains sequenced to date, including those in public databases. GI1 was not found in its entirety in any other C. difficile clade, or indeed, in any other microbial genome; however, smaller segments were detected in Enterococcus faecium strains. Molecular clock analyses suggested that GI1 was horizontally acquired and sequentially assembled over time. GI1 encodes homologs of VanZ and a SrtB-anchored collagen-binding adhesin, and correspondingly, all tested RT106 strains had increased teicoplanin resistance, and a majority displayed collagen-dependent biofilm formation. Two additional genomic islands (GI2 and GI3) were also present in a subset of RT106 strains. All three islands are predicted to encode mobile genetic elements as well as virulence factors. Emergent phenotypes associated with these genetic islands may have contributed to the relatively rapid expansion of RT106 in US healthcare and community settings.
Asunto(s)
Clostridioides difficile/clasificación , Clostridioides difficile/genética , Genoma Bacteriano , Islas Genómicas , Genómica , Fenotipo , Filogenia , Ribotipificación , Animales , Antibacterianos/farmacología , Arizona/epidemiología , Clostridioides difficile/efectos de los fármacos , Clostridioides difficile/aislamiento & purificación , Infecciones por Clostridium/epidemiología , Infecciones por Clostridium/microbiología , Cricetinae , Infección Hospitalaria/epidemiología , Farmacorresistencia Bacteriana , Variación Genética , Genómica/métodos , Genotipo , Humanos , Pruebas de Sensibilidad Microbiana , Prevalencia , Vigilancia en Salud Pública , Ribotipificación/métodosRESUMEN
Balamuthia mandrillaris is a recently described ameba known to cause a subacute to chronic central nervous system infection called granulomatous amebic encephalitis. Evidence suggests that apparently immunocompetent persons are at risk for disease and show a similar nonspecific presentation to that of immunodeficient persons. However, evidence of hematogenous dissemination, which has been found in immunodeficient patients, has been lacking in immunocompetent patients. Here, we describe a previously healthy patient with B mandrillaris-associated granulomatous amebic encephalitis in whom both central nervous system and renal disease were found during autopsy, which suggests hematogenous dissemination. We also provide a comprehensive review of the pediatric literature on this disease and its clinical presentation in children.
Asunto(s)
Amebiasis/parasitología , Balamuthia mandrillaris , Granuloma/parasitología , Encefalitis Infecciosa/parasitología , Enfermedades Renales/parasitología , Adolescente , Amebiasis/inmunología , Amebiasis/patología , Encéfalo/parasitología , Encéfalo/patología , Resultado Fatal , Femenino , Granuloma/inmunología , Granuloma/patología , Humanos , Inmunocompetencia , Encefalitis Infecciosa/inmunología , Encefalitis Infecciosa/patología , Enfermedades Renales/inmunología , Enfermedades Renales/patología , Imagen por Resonancia Magnética , Factores de RiesgoRESUMEN
BACKGROUND: Intestinal microbiota influences the progression of colitis-associated colorectal cancer. With diet being a key determinant of the gut microbial ecology, dietary interventions are an attractive avenue for the prevention of colitis-associated colorectal cancer. Curcumin is the most active constituent of the ground rhizome of the Curcuma longa plant, which has been demonstrated to have anti-inflammatory, antioxidative, and antiproliferative properties. METHODS: Il10 mice on 129/SvEv background were used as a model of colitis-associated colorectal cancer. Starting at 10 weeks of age, wild-type or Il10 mice received 6 weekly intraperitoneal injections of azoxymethane (AOM) or phosphate-buffered saline (PBS) and were started on either a control or a curcumin-supplemented diet. Stools were collected every 4 weeks for microbial community analysis. Mice were killed at 30 weeks of age. RESULTS: Curcumin-supplemented diet increased survival, decreased colon weight/length ratio, and, at 0.5%, entirely eliminated tumor burden. Although colonic histology indicated improvement with curcumin, no effects of mucosal immune responses have been observed in PBS/Il10 mice and limited effects were seen in AOM/Il10 mice. In wild-type and in Il10 mice, curcumin increased bacterial richness, prevented age-related decrease in alpha diversity, increased the relative abundance of Lactobacillales, and decreased Coriobacterales order. Taxonomic profile of AOM/Il10 mice receiving curcumin was more similar to those of wild-type mice than those fed control diet. CONCLUSIONS: In AOM/Il10 model, curcumin reduced or eliminated colonic tumor burden with limited effects on mucosal immune responses. The beneficial effect of curcumin on tumorigenesis was associated with the maintenance of a more diverse colonic microbial ecology.