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1.
Nat Immunol ; 21(8): 857-867, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32601469

RESUMEN

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by homozygous or compound heterozygous gain-of-function mutations in MEFV, which encodes pyrin, an inflammasome protein. Heterozygous carrier frequencies for multiple MEFV mutations are high in several Mediterranean populations, suggesting that they confer selective advantage. Among 2,313 Turkish people, we found extended haplotype homozygosity flanking FMF-associated mutations, indicating evolutionarily recent positive selection of FMF-associated mutations. Two pathogenic pyrin variants independently arose >1,800 years ago. Mutant pyrin interacts less avidly with Yersinia pestis virulence factor YopM than with wild-type human pyrin, thereby attenuating YopM-induced interleukin (IL)-1ß suppression. Relative to healthy controls, leukocytes from patients with FMF harboring homozygous or compound heterozygous mutations and from asymptomatic heterozygous carriers released heightened IL-1ß specifically in response to Y. pestis. Y. pestis-infected MefvM680I/M680I FMF knock-in mice exhibited IL-1-dependent increased survival relative to wild-type knock-in mice. Thus, FMF mutations that were positively selected in Mediterranean populations confer heightened resistance to Y. pestis.


Asunto(s)
Resistencia a la Enfermedad/genética , Fiebre Mediterránea Familiar/genética , Peste , Pirina/genética , Selección Genética/genética , Animales , Proteínas de la Membrana Bacteriana Externa/inmunología , Proteínas de la Membrana Bacteriana Externa/metabolismo , Resistencia a la Enfermedad/inmunología , Haplotipos , Humanos , Inflamasomas/inmunología , Inflamasomas/metabolismo , Ratones , Ratones Endogámicos C57BL , Mutación , Peste/inmunología , Peste/metabolismo , Pirina/inmunología , Pirina/metabolismo , Turquía , Factores de Virulencia/inmunología , Factores de Virulencia/metabolismo , Yersinia pestis
2.
Nature ; 579(7797): 123-129, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32103176

RESUMEN

A mosaic of cross-phylum chemical interactions occurs between all metazoans and their microbiomes. A number of molecular families that are known to be produced by the microbiome have a marked effect on the balance between health and disease1-9. Considering the diversity of the human microbiome (which numbers over 40,000 operational taxonomic units10), the effect of the microbiome on the chemistry of an entire animal remains underexplored. Here we use mass spectrometry informatics and data visualization approaches11-13 to provide an assessment of the effects of the microbiome on the chemistry of an entire mammal by comparing metabolomics data from germ-free and specific-pathogen-free mice. We found that the microbiota affects the chemistry of all organs. This included the amino acid conjugations of host bile acids that were used to produce phenylalanocholic acid, tyrosocholic acid and leucocholic acid, which have not previously been characterized despite extensive research on bile-acid chemistry14. These bile-acid conjugates were also found in humans, and were enriched in patients with inflammatory bowel disease or cystic fibrosis. These compounds agonized the farnesoid X receptor in vitro, and mice gavaged with the compounds showed reduced expression of bile-acid synthesis genes in vivo. Further studies are required to confirm whether these compounds have a physiological role in the host, and whether they contribute to gut diseases that are associated with microbiome dysbiosis.


Asunto(s)
Ácidos y Sales Biliares/biosíntesis , Ácidos y Sales Biliares/química , Metabolómica , Microbiota/fisiología , Animales , Ácidos y Sales Biliares/metabolismo , Ácido Cólico/biosíntesis , Ácido Cólico/química , Ácido Cólico/metabolismo , Fibrosis Quística/genética , Fibrosis Quística/metabolismo , Fibrosis Quística/microbiología , Vida Libre de Gérmenes , Humanos , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/microbiología , Ratones , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo
3.
Semin Cell Dev Biol ; 88: 129-137, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-29432952

RESUMEN

The gastrointestinal tract is a complex environment in which the host immune system interacts with a diverse array of microorganisms, both symbiotic and pathogenic. As such, mobilizing a rapid and appropriate antimicrobial response depending on the nature of each stimulus is crucial for maintaining the balance between homeostasis and inflammation in the gut. Here we focus on the mechanisms by which intestinal antimicrobial peptides regulate microbial communities during dysbiosis and infection. We also discuss classes of bacterial peptides that contribute to reducing enteric pathogen outgrowth. This review aims to provide a comprehensive overview on the interplay of diverse antimicrobial responses with enteric pathogens and the gut microbiota.


Asunto(s)
Bacteriocinas/inmunología , Defensinas/inmunología , Disbiosis/prevención & control , Tracto Gastrointestinal/inmunología , Mucosa Intestinal/inmunología , Animales , Bacteriocinas/biosíntesis , Bacteriocinas/farmacología , Catelicidinas/biosíntesis , Catelicidinas/inmunología , Catelicidinas/farmacología , Defensinas/biosíntesis , Defensinas/farmacología , Disbiosis/inmunología , Disbiosis/microbiología , Microbioma Gastrointestinal/inmunología , Tracto Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/microbiología , Expresión Génica/inmunología , Humanos , Inmunidad Mucosa/efectos de los fármacos , Inflamación , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/microbiología , Lipocalina 2/biosíntesis , Lipocalina 2/inmunología , Lipocalina 2/farmacología , Muramidasa/biosíntesis , Muramidasa/inmunología , Muramidasa/farmacología , Simbiosis/inmunología
4.
Infect Immun ; 84(4): 1062-1072, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26810037

RESUMEN

Pathogenic Yersinia species utilize a type III secretion system to translocate Yop effectors into infected host cells. Yop effectors inhibit innate immune responses in infected macrophages to promote Yersinia pathogenesis. In turn,Yersinia-infected macrophages respond to translocation of Yops by activating caspase-1, but different mechanisms of caspase-1 activation occur, depending on the bacterial genotype and the state of phagocyte activation. In macrophages activated with lipopolysaccharide (LPS) prior to Yersinia pseudotuberculosis infection, caspase-1 is activated by a rapid inflammasome-dependent mechanism that is inhibited by translocated YopM. The possibility that other effectors cooperate with YopM to inhibit caspase-1 activation in LPS-activated macrophages has not been investigated. Toward this aim, epistasis analysis was carried out in which the phenotype of aY. pseudotuberculosis yopM mutant was compared to that of a yopJ yopM, yopE yopM, yopH yopM, yopT yopM, or ypkA yopM mutant. Activation of caspase-1 was measured by cleavage of the enzyme, release of interleukin-1ß (IL-1ß), and pyroptosis in LPS-activated macrophages infected with wild-type or mutant Y. pseudotuberculosis strains. Results show enhanced activation of caspase-1 after infection with the yopJ yopM mutant relative to infection by any other single or double mutant. Similar results were obtained with the yopJ, yopM, and yopJ yopM mutants ofY ersinia pestis Following intravenous infection of mice, theY. pseudotuberculosis yopJ mutant was as virulent as the wild type, while the yopJ yopM mutant was significantly more attenuated than the yopM mutant. In summary, through epistasis analysis this work uncovered an important role for YopJ in inhibiting caspase-1 in activated macrophages and in promoting Yersinia virulence.


Asunto(s)
Proteínas Bacterianas/metabolismo , Caspasa 1/metabolismo , Activación de Macrófagos/fisiología , Macrófagos/fisiología , Yersinia pseudotuberculosis/patogenicidad , Animales , Proteínas de la Membrana Bacteriana Externa/genética , Proteínas de la Membrana Bacteriana Externa/metabolismo , Proteínas Bacterianas/genética , Caspasa 1/genética , Células Cultivadas , Epistasis Genética , Femenino , Regulación Enzimológica de la Expresión Génica/fisiología , Inmunidad Innata , Lipopolisacáridos/toxicidad , Macrófagos/microbiología , Ratones , Mutación , Piroptosis , Virulencia
5.
J Interferon Cytokine Res ; 39(4): 214-223, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30855201

RESUMEN

CCL28 is a mucosal chemokine that has been involved in various responses, including IgA production. We have analyzed its production in human tissues using a comprehensive microarray database. Its highest expression is in the salivary gland, indicating that it is an important component of saliva. It is also expressed in the trachea, bronchus, and in the mammary gland upon onset of lactation. We have also characterized a Ccl28-/- mouse that exhibits very low IgA levels in milk, and the IgA levels in feces are also reduced. These observations confirm a role for the CCL28/CCR10 chemokine axis in the recruitment of IgA plasmablasts to the lactating mammary gland. CCL28 is also expressed in the vomeronasal organ. We also detected olfactory defects (anosmia) in a Ccl28-/- mouse suggesting that CCL28 is involved in the function/development of olfaction. Importantly, Ccl28-/- mice are highly susceptible to Salmonella enterica serovar Typhimurium in an acute model of infection, indicating that CCL28 plays a major role in innate immunity against Salmonella in the gut. Finally, microbiome studies revealed modest differences in the gut microbiota between Ccl28-/- mice and their cohoused wild-type littermates. The latter observation suggests that under homeostatic conditions, CCL28 plays a limited role in shaping the gut microbiome.


Asunto(s)
Quimiocinas CC/inmunología , Quimiocinas CC/fisiología , Inmunidad Innata/inmunología , Inmunidad Mucosa/inmunología , Inmunoglobulina A/inmunología , Salmonelosis Animal/inmunología , Olfato/fisiología , Inmunidad Adaptativa/inmunología , Animales , Microbioma Gastrointestinal/inmunología , Homeostasis/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Salmonelosis Animal/microbiología , Salmonella enterica/inmunología
6.
Cell Host Microbe ; 20(2): 128-9, 2016 08 10.
Artículo en Inglés | MEDLINE | ID: mdl-27512899

RESUMEN

Antibiotic therapy has been largely ineffective in improving clinical outcomes following Salmonellosis, yet the reasons why remain obscure. In this issue of Cell Host & Microbe, Dolowschiak et al. (2016) report that IFNγ produced by NK and T cells following antibiotic treatment of acute Salmonella infection limits mucosal remission.


Asunto(s)
Membrana Mucosa , Infecciones por Salmonella , Antibacterianos , Humanos , Salmonella , Linfocitos T
7.
Curr Opin Microbiol ; 29: 56-62, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26638030

RESUMEN

The human pathogenic Yersinia species cause diseases that represent a significant source of morbidity and mortality. Despite this, specific mechanisms underlying Yersinia pathogenesis and protective host responses remain poorly understood. Recent studies have shown that Yersinia disrupt cell death pathways, perturb inflammatory processes and exploit immune cells to promote disease. The ensuing host responses following Yersinia infection include coordination of innate and adaptive immune responses in an attempt to control bacterial replication. Here, we highlight current advances in our understanding of the interactions between the pathogenic yersiniae and host cells, as well as the protective host responses mobilized to counteract these pathogens. Together, these studies enhance our understanding of Yersinia pathogenesis and highlight the ongoing battle between host and microbe.


Asunto(s)
Evasión Inmune , Yersiniosis/inmunología , Yersinia/inmunología , Yersinia/patogenicidad , Inmunidad Adaptativa , Animales , Muerte Celular , Humanos , Inmunidad Innata , Pulmón/inmunología , Pulmón/microbiología , Transducción de Señal , Yersinia/crecimiento & desarrollo , Yersiniosis/microbiología , Yersinia pestis/inmunología , Yersinia pestis/patogenicidad
8.
Cell Host Microbe ; 20(3): 296-306, 2016 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-27569559

RESUMEN

Pathogenic Yersinia, including Y. pestis, the agent of plague in humans, and Y. pseudotuberculosis, the related enteric pathogen, deliver virulence effectors into host cells via a prototypical type III secretion system to promote pathogenesis. These effectors, termed Yersinia outer proteins (Yops), modulate multiple host signaling responses. Studies in Y. pestis and Y. pseudotuberculosis have shown that YopM suppresses infection-induced inflammasome activation; however, the underlying molecular mechanism is largely unknown. Here we show that YopM specifically restricts the pyrin inflammasome, which is triggered by the RhoA-inactivating enzymatic activities of YopE and YopT, in Y. pseudotuberculosis-infected macrophages. The attenuation of a yopM mutant is fully reversed in pyrin knockout mice, demonstrating that YopM inhibits pyrin to promote virulence. Mechanistically, YopM recruits and activates the host kinases PRK1 and PRK2 to negatively regulate pyrin by phosphorylation. These results show how a virulence factor can hijack host kinases to inhibit effector-triggered pyrin inflammasome activation.


Asunto(s)
Proteínas de la Membrana Bacteriana Externa/metabolismo , Interacciones Huésped-Patógeno , Evasión Inmune , Proteína Quinasa C/metabolismo , Pirina/antagonistas & inhibidores , Yersinia pseudotuberculosis/patogenicidad , Animales , Proteínas Bacterianas/metabolismo , Cisteína Endopeptidasas/metabolismo , Inflamasomas/antagonistas & inhibidores , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación , Procesamiento Proteico-Postraduccional , Pirina/metabolismo , Análisis de Supervivencia , Virulencia , Factores de Virulencia/metabolismo , Yersinia pseudotuberculosis/inmunología , Infecciones por Yersinia pseudotuberculosis/microbiología , Infecciones por Yersinia pseudotuberculosis/patología , Proteína de Unión al GTP rhoA/metabolismo
10.
mBio ; 5(4): e01402-14, 2014 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-24987096

RESUMEN

YopM is a leucine-rich repeat (LRR)-containing effector in several Yersinia species, including Yersinia pestis and Y. pseudotuberculosis. Different Yersinia strains encode distinct YopM isoforms with variable numbers of LRRs but conserved C-terminal tails. A 15-LRR isoform in Y. pseudotuberculosis YPIII was recently shown to bind and inhibit caspase-1 via a YLTD motif in LRR 10, and attenuation of YopM(-) YPIII was reversed in mice lacking caspase-1, indicating that caspase-1 inhibition is a major virulence function of YopM(YPIII). To determine if other YopM proteins inhibit caspase-1, we utilized Y. pseudotuberculosis strains natively expressing a 21-LRR isoform lacking the YLTD motif (YopM(32777)) or ectopically expressing a Y. pestis 15-LRR version with a functional (YopM(KIM)) or inactivated (YopM(KIM) D271A) YLTD motif. Results of mouse and macrophage infections with these strains showed that YopM(32777), YopM(KIM), and YopM(KIM) D271A inhibit caspase-1 activation, indicating that the YLTD motif is dispensable for this activity. Analysis of YopM(KIM) deletion variants revealed that LRRs 6 to 15 and the C-terminal tail are required to inhibit caspase-1 activation. YopM(32777), YopM(KIM), and YopM(KIM) deletion variants were purified, and binding partners in macrophage lysates were identified. Caspase-1 bound to YopM(KIM) but not YopM(32777). Additionally, YopM(KIM) bound IQGAP1 and the use of Iqgap1(-/-) macrophages revealed that this scaffolding protein is important for caspase-1 activation upon infection with YopM(-) Y. pseudotuberculosis. Thus, while multiple YopM isoforms inhibit caspase-1 activation, their variable LRR domains bind different host proteins to perform this function and the LRRs of YopM(KIM) target IQGAP1, a novel regulator of caspase-1, in macrophages. Importance: Activation of caspase-1, mediated by macromolecular complexes termed inflammasomes, is important for innate immune defense against pathogens. Pathogens can, in turn, subvert caspase-1-dependent responses through the action of effector proteins. For example, the Yersinia effector YopM inhibits caspase-1 activation by arresting inflammasome formation. This caspase-1 inhibitory activity has been studied in a specific YopM isoform, and in this case, the protein was shown to act as a pseudosubstrate to bind and inhibit caspase-1. Different Yersinia strains encode distinct YopM isoforms, many of which lack the pseudosubstrate motif. We studied additional isoforms and found that these YopM proteins inhibit caspase-1 activation independently of a pseudosubstrate motif. We also identified IQGAP1 as a novel binding partner of the Yersinia pestis YopM(KIM) isoform and demonstrated that IQGAP1 is important for caspase-1 activation in macrophages infected with Yersinia. Thus, this study reveals new insights into inflammasome regulation during Yersinia infection.


Asunto(s)
Proteínas Bacterianas/metabolismo , Caspasa 1/metabolismo , Macrófagos/enzimología , Yersinia pestis/metabolismo , Animales , Caspasa 1/genética , Células Cultivadas , Femenino , Ratones , Ratones Noqueados
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