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1.
Nature ; 627(8004): 620-627, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38448595

RESUMEN

The fungus Candida albicans frequently colonizes the human gastrointestinal tract, from which it can disseminate to cause systemic disease. This polymorphic species can transition between growing as single-celled yeast and as multicellular hyphae to adapt to its environment. The current dogma of C. albicans commensalism is that the yeast form is optimal for gut colonization, whereas hyphal cells are detrimental to colonization but critical for virulence1-3. Here, we reveal that this paradigm does not apply to multi-kingdom communities in which a complex interplay between fungal morphology and bacteria dictates C. albicans fitness. Thus, whereas yeast-locked cells outcompete wild-type cells when gut bacteria are absent or depleted by antibiotics, hyphae-competent wild-type cells outcompete yeast-locked cells in hosts with replete bacterial populations. This increased fitness of wild-type cells involves the production of hyphal-specific factors including the toxin candidalysin4,5, which promotes the establishment of colonization. At later time points, adaptive immunity is engaged, and intestinal immunoglobulin A preferentially selects against hyphal cells1,6. Hyphal morphotypes are thus under both positive and negative selective pressures in the gut. Our study further shows that candidalysin has a direct inhibitory effect on bacterial species, including limiting their metabolic output. We therefore propose that C. albicans has evolved hyphal-specific factors, including candidalysin, to better compete with bacterial species in the intestinal niche.


Asunto(s)
Candida albicans , Proteínas Fúngicas , Microbioma Gastrointestinal , Hifa , Intestinos , Micotoxinas , Simbiosis , Animales , Femenino , Humanos , Masculino , Ratones , Bacterias/crecimiento & desarrollo , Bacterias/inmunología , Candida albicans/crecimiento & desarrollo , Candida albicans/inmunología , Candida albicans/metabolismo , Candida albicans/patogenicidad , Proteínas Fúngicas/metabolismo , Microbioma Gastrointestinal/inmunología , Hifa/crecimiento & desarrollo , Hifa/inmunología , Hifa/metabolismo , Inmunoglobulina A/inmunología , Intestinos/inmunología , Intestinos/microbiología , Micotoxinas/metabolismo , Virulencia
2.
Sci Adv ; 9(51): eadh8310, 2023 Dec 22.
Artículo en Inglés | MEDLINE | ID: mdl-38134275

RESUMEN

Environmental influences on immune phenotypes are well-documented, but our understanding of which elements of the environment affect immune systems, and how, remains vague. Behaviors, including socializing with others, are central to an individual's interaction with its environment. We therefore tracked behavior of rewilded laboratory mice of three inbred strains in outdoor enclosures and examined contributions of behavior, including associations measured from spatiotemporal co-occurrences, to immune phenotypes. We found extensive variation in individual and social behavior among and within mouse strains upon rewilding. In addition, we found that the more associated two individuals were, the more similar their immune phenotypes were. Spatiotemporal association was particularly predictive of similar memory T and B cell profiles and was more influential than sibling relationships or shared infection status. These results highlight the importance of shared spatiotemporal activity patterns and/or social networks for immune phenotype and suggest potential immunological correlates of social life.


Asunto(s)
Sistema Inmunológico , Conducta Social , Ratones , Animales , Fenotipo
3.
Cell Host Microbe ; 31(9): 1450-1468.e8, 2023 09 13.
Artículo en Inglés | MEDLINE | ID: mdl-37652008

RESUMEN

Loss of antimicrobial proteins such as REG3 family members compromises the integrity of the intestinal barrier. Here, we demonstrate that overproduction of REG3 proteins can also be detrimental by reducing a protective species in the microbiota. Patients with inflammatory bowel disease (IBD) experiencing flares displayed heightened levels of secreted REG3 proteins that mediated depletion of Enterococcus faecium (Efm) from the gut microbiota. Efm inoculation of mice ameliorated intestinal inflammation through activation of the innate immune receptor NOD2, which was associated with the bacterial DL-endopeptidase SagA that generates NOD2-stimulating muropeptides. NOD2 activation in myeloid cells induced interleukin-1ß (IL-1ß) secretion to increase the proportion of IL-22-producing CD4+ T helper cells and innate lymphoid cells that promote tissue repair. Finally, Efm was unable to protect mice carrying a NOD2 gene variant commonly found in IBD patients. Our findings demonstrate that inflammation self-perpetuates by causing aberrant antimicrobial activity that disrupts symbiotic relationships with gut microbes.


Asunto(s)
Antiinfecciosos , Enterococcus faecium , Enfermedades Inflamatorias del Intestino , Animales , Ratones , Inmunidad Innata , Linfocitos , Inflamación
4.
Chem Commun (Camb) ; 59(56): 8711-8714, 2023 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-37350153

RESUMEN

A highly regio-, chemo-, and stereoselective cascade process initiated by enantioselective iminium-catalyzed conjugate addition of 2-hydroxycinnamaldehydes and 2-oxocarboxylic esters is presented. Normal cinnamaldehydes are not reactive under the same reaction conditions. Bridged bicyclic ketals rather than acetals bearing stereocenters on both the bridge carbon and bridgehead ketal carbon are synthesized.

5.
Sci Immunol ; 8(84): eadd6910, 2023 06 23.
Artículo en Inglés | MEDLINE | ID: mdl-37352372

RESUMEN

The paucity of blood granulocyte populations such as neutrophils in laboratory mice is a notable difference between this model organism and humans, but the cause of this species-specific difference is unclear. We previously demonstrated that laboratory mice released into a seminatural environment, referred to as rewilding, display an increase in blood granulocytes that is associated with expansion of fungi in the gut microbiota. Here, we find that tonic signals from fungal colonization induce sustained granulopoiesis through a mechanism distinct from emergency granulopoiesis, leading to a prolonged expansion of circulating neutrophils that promotes immunity. Fungal colonization after either rewilding or oral inoculation of laboratory mice with Candida albicans induced persistent expansion of myeloid progenitors in the bone marrow. This increase in granulopoiesis conferred greater long-term protection from bloodstream infection by gram-positive bacteria than by the trained immune response evoked by transient exposure to the fungal cell wall component ß-glucan. Consequently, introducing fungi into laboratory mice may restore aspects of leukocyte development and provide a better model for humans and free-living mammals that are constantly exposed to environmental fungi.


Asunto(s)
Granulocitos , Hematopoyesis , Ratones , Humanos , Animales , Neutrófilos , Candida albicans , Médula Ósea , Mamíferos
6.
bioRxiv ; 2023 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-36993484

RESUMEN

The relative and synergistic contributions of genetics and environment to inter-individual immune response variation remain unclear, despite its implications for understanding both evolutionary biology and medicine. Here, we quantify interactive effects of genotype and environment on immune traits by investigating three inbred mouse strains rewilded in an outdoor enclosure and infected with the parasite, Trichuris muris. Whereas cytokine response heterogeneity was primarily driven by genotype, cellular composition heterogeneity was shaped by interactions between genotype and environment. Notably, genetic differences under laboratory conditions can be decreased following rewilding, and variation in T cell markers are more driven by genetics, whereas B cell markers are driven more by environment. Importantly, variation in worm burden is associated with measures of immune variation, as well as genetics and environment. These results indicate that nonheritable influences interact with genetic factors to shape immune variation, with synergistic impacts on the deployment and evolution of defense mechanisms.

7.
bioRxiv ; 2023 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-36778381

RESUMEN

Loss of antimicrobial proteins such as REG3 family members compromises the integrity of the intestinal barrier. Here, we demonstrate that overproduction of REG3 proteins can also be detrimental by reducing a protective species in the microbiota. Patients with inflammatory bowel disease (IBD) experiencing flares displayed heightened levels of secreted REG3 proteins that mediated depletion of Enterococcus faecium ( Efm ) from the gut microbiota. Efm inoculation of mice ameliorated intestinal inflammation through activation of the innate immune receptor NOD2, which was associated with the bacterial DL-endopeptidase SagA. Microbiota sensing by NOD2 in myeloid cells mediated IL-1ß secretion and increased the proportion of IL-22-producing CD4 + T helper cells and innate lymphoid cells. Finally, Efm was unable to protect mice carrying a NOD2 gene variant commonly found in IBD patients. Our findings demonstrate that inflammation self-perpetuates by causing aberrant antimicrobial activity that disrupts symbiotic relationships with gut microbes.

9.
PLoS Biol ; 20(3): e3001592, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35358182

RESUMEN

Gastrointestinal effects associated with Coronavirus Disease 2019 (COVID-19) are highly variable for reasons that are not understood. In this study, we used intestinal organoid-derived cultures differentiated from primary human specimens as a model to examine interindividual variability. Infection of intestinal organoids derived from different donors with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) resulted in orders of magnitude differences in virus replication in small intestinal and colonic organoid-derived monolayers. Susceptibility to infection correlated with angiotensin I converting enzyme 2 (ACE2) expression level and was independent of donor demographic or clinical features. ACE2 transcript levels in cell culture matched the amount of ACE2 in primary tissue, indicating that this feature of the intestinal epithelium is retained in the organoids. Longitudinal transcriptomics of organoid-derived monolayers identified a delayed yet robust interferon signature, the magnitude of which corresponded to the degree of SARS-CoV-2 infection. Interestingly, virus with the Omicron variant spike (S) protein infected the organoids with the highest infectivity, suggesting increased tropism of the virus for intestinal tissue. These results suggest that heterogeneity in SARS-CoV-2 replication in intestinal tissues results from differences in ACE2 levels, which may underlie variable patient outcomes.


Asunto(s)
COVID-19 , Enzima Convertidora de Angiotensina 2/genética , Humanos , Organoides , SARS-CoV-2
10.
Chem Commun (Camb) ; 57(14): 1762-1765, 2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33470263

RESUMEN

An organocatalytic vinylogous Michael addition triggered triple-cascade reaction has been developed. 2-Hydroxycinnamaldehydes worked under iminium activation with either acyclic or cyclic ketone-derived α,α-dicyanoalkenes, yielding the benzofused oxabicyclo[3.3.1]nonanes bearing one quaternary stereocenter with excellent stereoselectivities.

11.
Blood ; 135(26): 2388-2401, 2020 06 25.
Artículo en Inglés | MEDLINE | ID: mdl-32232483

RESUMEN

A goal in precision medicine is to use patient-derived material to predict disease course and intervention outcomes. Here, we use mechanistic observations in a preclinical animal model to design an ex vivo platform that recreates genetic susceptibility to T-cell-mediated damage. Intestinal graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation. We found that intestinal GVHD in mice deficient in Atg16L1, an autophagy gene that is polymorphic in humans, is reversed by inhibiting necroptosis. We further show that cocultured allogeneic T cells kill Atg16L1-mutant intestinal organoids from mice, which was associated with an aberrant epithelial interferon signature. Using this information, we demonstrate that pharmacologically inhibiting necroptosis or interferon signaling protects human organoids derived from individuals harboring a common ATG16L1 variant from allogeneic T-cell attack. Our study provides a roadmap for applying findings in animal models to individualized therapy that targets affected tissues.


Asunto(s)
Enfermedad Injerto contra Huésped/prevención & control , Enfermedades Intestinales/prevención & control , Organoides , Linfocitos T/inmunología , Acrilamidas/farmacología , Animales , Autofagia , Proteínas Relacionadas con la Autofagia/deficiencia , Proteínas Relacionadas con la Autofagia/genética , Trasplante de Médula Ósea/efectos adversos , Técnicas de Cocultivo , Colon/anomalías , Femenino , Predisposición Genética a la Enfermedad , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/patología , Humanos , Imidazoles/farmacología , Indoles/farmacología , Enfermedades Inflamatorias del Intestino/patología , Enfermedades Intestinales/inmunología , Enfermedades Intestinales/patología , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Necroptosis/efectos de los fármacos , Nitrilos , Células de Paneth/patología , Medicina de Precisión , Pirazoles/farmacología , Pirimidinas , Quimera por Radiación , Proteína Serina-Treonina Quinasas de Interacción con Receptores/deficiencia , Sulfonamidas/farmacología , Linfocitos T/trasplante
12.
Cell Host Microbe ; 27(5): 830-840.e4, 2020 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-32209431

RESUMEN

The relative contributions of genetic and environmental factors to variation in immune responses are poorly understood. Here, we performed a phenotypic analysis of immunological parameters in laboratory mice carrying susceptibility genes implicated in inflammatory bowel disease (IBD) (Nod2 and Atg16l1) upon exposure to environmental microbes. Mice were released into an outdoor enclosure (rewilded) and then profiled for immune responses in the blood and lymph nodes. Variations of immune cell populations were largely driven by the environment, whereas cytokine production elicited by microbial antigens was more affected by the genetic mutations. We identified transcriptional signatures in the lymph nodes associated with differences in T cell populations. Subnetworks associated with responses against Clostridium perfringens, Candida albicans, and Bacteroides vulgatus were also coupled with rewilding. Therefore, exposing laboratory mice with genetic mutations to a natural environment uncovers different contributions to variations in microbial responses and immune cell composition.


Asunto(s)
Enfermedades Inflamatorias del Intestino , Animales , Proteínas Relacionadas con la Autofagia , Bacteroides , Proteínas Portadoras , Ambiente , Ratones
13.
Cell Host Microbe ; 27(5): 809-822.e6, 2020 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-32209432

RESUMEN

Free-living mammals, such as humans and wild mice, display heightened immune activation compared with artificially maintained laboratory mice. These differences are partially attributed to microbial exposure as laboratory mice infected with pathogens exhibit immune profiles more closely resembling that of free-living animals. Here, we examine how colonization by microorganisms within the natural environment contributes to immune system maturation by releasing inbred laboratory mice into an outdoor enclosure. In addition to enhancing differentiation of T cell populations previously associated with pathogen exposure, outdoor release increased circulating granulocytes. However, these "rewilded" mice were not infected by pathogens previously implicated in immune activation. Rather, immune system changes were associated with altered microbiota composition with notable increases in intestinal fungi. Fungi isolated from rewilded mice were sufficient in increasing circulating granulocytes. These findings establish a model to investigate how the natural environment impacts immune development and show that sustained fungal exposure impacts granulocyte numbers.


Asunto(s)
Ambiente , Hongos/crecimiento & desarrollo , Hongos/fisiología , Microbioma Gastrointestinal/inmunología , Animales , Proteínas Relacionadas con la Autofagia/genética , Linfocitos T CD8-positivos , Heces/microbiología , Femenino , Hongos/genética , Hongos/aislamiento & purificación , Granulocitos/inmunología , Sistema Inmunológico , Intestinos/microbiología , Intestinos/patología , Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Micobioma/inmunología , Micobioma/fisiología , Proteína Adaptadora de Señalización NOD2/genética
14.
Org Lett ; 21(20): 8358-8363, 2019 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-31580692

RESUMEN

By introducing a carbon functionality at 2-position of chromane, the formal asymmetric functionalization of the 3-position of 2-substituted chromane has been realized via a highly chemo-, regio-, and stereoselective organocatalytic cascade reaction in a sequential one-pot manner involving an E1cB mechanism governed ring-opening process. Critical to our success was the design of a chiral dipeptide-based bifunctional acid-base organocatalyst, which exhibited high catalytic activity at low catalyst loading (1-0.1 mol %), leading to biologically interesting polyheterocyclic compounds.

15.
Org Lett ; 21(17): 6750-6755, 2019 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-31433194

RESUMEN

The asymmetric organocatalytic cascade reaction of cyclic ß-oxo aldehydes to 2-hydroxycinnamaldehydes is developed. The bifunctional tertiary amine-thiourea catalyst was used in a rationally designed multiple catalysis where the asymmetric iminium catalysis and thiourea anion-binding catalysis were combined by carboxylate anion as a ternary catalytic system to form a quinary catalyst-substrate complex, providing an efficient protocol for the construction of enantioenriched spiro-bridged or cagelike polyheterocyclic compounds. The reuse of catalysts was also successfully realized.

16.
Org Lett ; 21(14): 5556-5561, 2019 07 19.
Artículo en Inglés | MEDLINE | ID: mdl-31244090

RESUMEN

A highly efficient asymmetric organocatalysis-triggered reaction sequence is developed. 2-Hydroxy cinnamaldehydes and cyclic N-sulfonyl ketimines were both used as multisite substrates (more than two reactive sites) to access structurally diverse chiral bridged and spiro-bridged benzofused aminal derivatives, where an inseparable equilibrating mixture of isomers can be regioselectively converted into bridged benzofused aminals with different ring connectivities via divergent pathways. Several stereoselective transformations of the resulted bridged aminals are presented.

17.
Ultrasound Q ; 35(1): 54-60, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30789487

RESUMEN

The aim of this study was to compare the effectiveness of physical examination, transvaginal sonography, magnetic resonance imaging, and rectal endoscopic sonography for the identification of rectovaginal endometriosis and potential rectal infiltration. Women with suspected rectovaginal endometriosis underwent physical examination, transvaginal sonography, magnetic resonance imaging, and rectal endoscopic sonography. Evaluation was performed for the presence of rectovaginal endometriotic foci and rectal infiltration. The findings obtained with these methods were compared with those of surgical and histopathological examination. Sensitivity, specificity, positive predictive values, and negative predictive values were evaluated for each method. Rectovaginal endometriosis was histologically confirmed in 21 (72.4%) of 29 women. With respect to diagnosis of rectovaginal endometriosis, the sensitivity, specificity, and accuracy of physical examination were 95.2%, 62.5%, and 86.2%; those of transvaginal sonography were 42.9%, 87.5%, and 55.2%; those of magnetic resonance imaging were 90.5%, 87.5%, and 89.7%; and those of rectal endoscopic sonography were 81.0%, 75.0%, and 79.3%, respectively. With respect to identification of rectal infiltration, the sensitivity, specificity, and accuracy of transvaginal sonography were 26.7%, 85.7%, and 55.2%; those of magnetic resonance imaging were 73.3%, 92.9%, and 82.8%; and those of rectal endoscopic sonography were 86.7%, 85.7%, and 86.2%, respectively. Magnetic resonance imaging combined with physical examination seem to be the main approach for the presurgical assessment of rectovaginal endometriosis. Rectal endoscopic sonography is a worthwhile method for the diagnosis of rectal infiltration.


Asunto(s)
Endometriosis/diagnóstico , Endosonografía/métodos , Imagen por Resonancia Magnética/métodos , Examen Físico/métodos , Cuidados Preoperatorios/métodos , Recto/diagnóstico por imagen , Adulto , Femenino , Humanos , Estudios Longitudinales , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Ultrasonografía/métodos , Vagina/diagnóstico por imagen
18.
Org Lett ; 21(1): 190-195, 2019 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-30576161

RESUMEN

The organocatalytic enantioselective synthesis of methanobenzodioxepine derivatives bearing a 6,6,5-bridged ring system is presented. The m-CPBA-triggered in situ α-oxidation of ß-oxoesters to provide the required but unstable α-hydroxy-ß-dicarbonyl substrates is the key to this three-step sequence, providing the desired cyclic acetals with excellent stereoselectivities containing two bridgehead and one fully substituted stereocenters. It is noteworthy that the absence of m-CPBA furnished the acetal products bearing a 6,6,6-bridged ring system with similar good results from the same starting materials.

19.
Org Lett ; 20(21): 6682-6686, 2018 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-30354166

RESUMEN

Following the reactivity inversion strategy, two different two-step sequences were designed and successfully applied to the asymmetric synthesis of spiro-bridged and spiro-fused heterocyclic compounds, which combined chromane, indole, and oxindole, three potential pharmacophores, in one molecule. The power of these two organocatalytic pathways is underscored by mild reaction conditions and high efficiency in the production of synthetically challenging, but biologically important heterocyclic products, which could be transformed into more biologically interesting heterocyclic structures.

20.
Org Lett ; 20(12): 3609-3612, 2018 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-29863888

RESUMEN

Structurally complex cyclic hemiacetals bearing a racemic tetrasubstituted stereocenter have been prepared in a concise manner and were successfully used in an organocatalytic enantioselective sequence to react with functionalized nitro-olefins, providing bicyclic acetal-containing compounds as two separable epimers with excellent stereoselectivity. The reaction showed broad substrate scope, with respect to the starting hemiacetals. Moreover, this protocol allows the synthetic transformation of the products to various interesting heterocyclic compounds with substantial structural diversity and broad functionality.

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