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1.
Clin Infect Dis ; 61(12): 1831-4, 2015 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-26405147

RESUMEN

Four anatomical patterns of hydrocephalus secondary to congenital Toxoplasma gondii infection were identified and characterized for infants enrolled in the National Collaborative Chicago-based Congenital Toxoplasmosis Study. Analysis of parasite serotype revealed that different anatomical patterns associate with Type-II vs Not-Exclusively Type-II strains (NE-II) (P = .035).


Asunto(s)
Genotipo , Hidrocefalia/patología , Hidrocefalia/parasitología , Toxoplasma/clasificación , Toxoplasma/genética , Toxoplasmosis Congénita/complicaciones , Estudios de Cohortes , Humanos , Serogrupo , Toxoplasma/aislamiento & purificación
2.
Clin Infect Dis ; 61(12): 1815-24, 2015 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-26405150

RESUMEN

BACKGROUND: Family clusters and epidemics of toxoplasmosis in North, Central, and South America led us to determine whether fathers of congenitally infected infants in the National Collaborative Chicago-Based Congenital Toxoplasmosis Study (NCCCTS) have a high incidence of Toxoplasma gondii infection. METHODS: We analyzed serum samples collected from NCCCTS families between 1981 and 2013. Paternal serum samples were tested for T. gondii antibodies with immunoglobulin (Ig) G dye test and IgM enzyme-linked immunosorbent assay. Additional testing of paternal serum samples was performed with differential-agglutination and IgG avidity tests when T. gondii IgG and IgM results were positive and serum samples were collected by the 1-year visit of the congenitally infected child. Prevalence of paternal seropositivity and incidence of recent infection were calculated. We analyzed whether certain demographics, maternal parasite serotype, risk factors, or maternal/infant clinical manifestations were associated with paternal T. gondii infection status. RESULTS: Serologic testing revealed a high prevalence (29 of 81; 36%) of T. gondii infection in fathers, relative to the average seropositivity rate of 9.8% for boys and men aged 12-49 years in the United States between 1994 and 2004 (P < .001). Moreover, there was a higher-than-expected incidence of recent infections among fathers with serum samples collected by the 1-year visit of their child (6 of 45; 13%; P < .001). No demographic patterns or clinical manifestations in mothers or infants were associated with paternal infections, except for sandbox exposure. CONCLUSIONS: The high prevalence of chronic and incidence of recent T. gondii infections in fathers of congenitally infected children indicates that T. gondii infections cluster within families in North America. When a recently infected person is identified, family clustering and community risk factors should be investigated for appropriate clinical management.


Asunto(s)
Análisis por Conglomerados , Salud de la Familia , Padre , Toxoplasmosis/epidemiología , Adolescente , Pruebas de Aglutinación , Anticuerpos Antiprotozoarios/sangre , Chicago/epidemiología , Niño , Preescolar , Estudios de Cohortes , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Incidencia , Lactante , Recién Nacido , Masculino , Embarazo , Prevalencia
3.
iScience ; 27(1): 108477, 2024 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-38205261

RESUMEN

Toxoplasma gondii causes morbidity, mortality, and disseminates widely via cat sexual stages. Here, we find T. gondii ornithine aminotransferase (OAT) is conserved across phyla. We solve TgO/GABA-AT structures with bound inactivators at 1.55 Å and identify an inactivator selective for TgO/GABA-AT over human OAT and GABA-AT. However, abrogating TgO/GABA-AT genetically does not diminish replication, virulence, cyst-formation, or eliminate cat's oocyst shedding. Increased sporozoite/merozoite TgO/GABA-AT expression led to our study of a mutagenized clone with oocyst formation blocked, arresting after forming male and female gametes, with "Rosetta stone"-like mutations in genes expressed in merozoites. Mutations are similar to those in organisms from plants to mammals, causing defects in conception and zygote formation, affecting merozoite capacitation, pH/ionicity/sodium-GABA concentrations, drawing attention to cyclic AMP/PKA, and genes enhancing energy or substrate formation in TgO/GABA-AT-related-pathways. These candidates potentially influence merozoite's capacity to make gametes that fuse to become zygotes, thereby contaminating environments and causing disease.

4.
mBio ; 14(2): e0352422, 2023 04 25.
Artículo en Inglés | MEDLINE | ID: mdl-36786582

RESUMEN

Quorum sensing (QS) is a highly conserved microbial communication mechanism based on the production and sensing of secreted signaling molecules. The recalcitrant pathogen Pseudomonas aeruginosa is a problematic nosocomial pathogen with complex interconnected QS systems controlling multiple virulence functions. The relevance of QS in P. aeruginosa pathogenesis is well established; however, the regulatory interrelationships of the three major QS systems, LasR/LasI, MvfR (PqsR)/PqsABCD, and RhlR/RhlI, have been studied primarily in vitro. It is, therefore, unclear how these relationships translate to the host environment during infection. Here, we use a collection of P. aeruginosa QS mutants of the three major QS systems to assess the interconnections and contributions in intestinal inflammation and barrier function in vivo. This work reveals that MvfR, not LasR or RhlR, promotes intestinal inflammation during infection. In contrast, we find that P. aeruginosa-driven murine intestinal permeability is controlled by an interconnected QS network involving all three regulators, with MvfR situated upstream of LasR and RhlR. This study demonstrates the importance of understanding the interrelationships of the QS systems during infection and provides critical insights for developing successful antivirulence strategies. Moreover, this work provides a framework to interrogate QS systems in physiologically relevant settings. IMPORTANCE Pseudomonas aeruginosa is a common multidrug-resistant bacterial pathogen that seriously threatens critically ill and immunocompromised patients. Intestinal colonization by this pathogen is associated with elevated mortality rates. Disrupting bacterial communication is a desirable anti-infective approach since these systems coordinate multiple acute and chronic virulence functions in P. aeruginosa. Here, we investigate the role of each of the three major communication systems in the host intestinal functions. This work reveals that P. aeruginosa influences intestinal inflammation and permeability through distinct mechanisms.


Asunto(s)
Infecciones por Pseudomonas , Percepción de Quorum , Humanos , Animales , Ratones , Pseudomonas aeruginosa/metabolismo , Proteínas Bacterianas/metabolismo , Regulación Bacteriana de la Expresión Génica , Factores de Virulencia/genética , Inflamación , Infecciones por Pseudomonas/microbiología
5.
NPJ Biofilms Microbiomes ; 9(1): 11, 2023 03 23.
Artículo en Inglés | MEDLINE | ID: mdl-36959210

RESUMEN

Human microbiome composition is closely tied to health, but how the host manages its microbial inhabitants remains unclear. One important, but understudied, factor is the natural host environment: mucus, which contains gel-forming glycoproteins (mucins) that display hundreds of glycan structures with potential regulatory function. Leveraging a tractable culture-based system to study how mucins influence oral microbial communities, we found that mucin glycans enable the coexistence of diverse microbes, while resisting disease-associated compositional shifts. Mucins from tissues with unique glycosylation differentially tuned microbial composition, as did isolated mucin glycan libraries, uncovering the importance of specific glycan patterns in microbiome modulation. We found that mucins shape microbial communities in several ways: serving as nutrients to support metabolic diversity, organizing spatial structure through reduced aggregation, and possibly limiting antagonism between competing taxa. Overall, this work identifies mucin glycans as a natural host mechanism and potential therapeutic intervention to maintain healthy microbial communities.


Asunto(s)
Microbiota , Mucinas , Humanos , Mucinas/química , Mucinas/metabolismo , Glicosilación , Moco/metabolismo , Polisacáridos/metabolismo
6.
Clin Infect Dis ; 62(6): 812-4, 2016 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-26689955
7.
Curr Biol ; 31(1): 90-102.e7, 2021 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-33125866

RESUMEN

Mucus is a densely populated ecological niche that coats all non-keratinized epithelia, and plays a critical role in protecting the human body from infections. Although traditionally viewed as a physical barrier, emerging evidence suggests that mucus can directly suppress virulence-associated traits in opportunistic pathogens including Pseudomonas aeruginosa. However, the molecular mechanisms by which mucus affords this protection are unclear. Here, we show that mucins, and particularly their associated glycans, signal through the Dismed2 domain of the sensor kinase RetS in P. aeruginosa. We find that this RetS-dependent signaling leads to the direct inhibition of the GacS-GacA two-component system, the activity of which is associated with a chronic infection state. This signaling includes downregulation of the type VI secretion system (T6SS), and prevents T6SS-dependent bacterial killing by P. aeruginosa. Overall, these results shed light on how mucus impacts P. aeruginosa behavior, and may inspire novel approaches for controlling P. aeruginosa infections.


Asunto(s)
Proteínas Bacterianas/metabolismo , Mucina 5AC/metabolismo , Polisacáridos/metabolismo , Infecciones por Pseudomonas/inmunología , Pseudomonas aeruginosa/inmunología , Animales , Proteínas Bacterianas/genética , Modelos Animales de Enfermedad , Regulación hacia Abajo , Mucosa Gástrica/inmunología , Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiología , Regulación Bacteriana de la Expresión Génica/inmunología , Interacciones Huésped-Patógeno/inmunología , Humanos , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/metabolismo , Pseudomonas aeruginosa/patogenicidad , RNA-Seq , Porcinos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Sistemas de Secreción Tipo VI/genética , Sistemas de Secreción Tipo VI/metabolismo , Virulencia/genética
8.
Nat Microbiol ; 6(5): 574-583, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33737747

RESUMEN

Mucus barriers accommodate trillions of microorganisms throughout the human body while preventing pathogenic colonization1. In the oral cavity, saliva containing the mucins MUC5B and MUC7 forms a pellicle that coats the soft tissue and teeth to prevent infection by oral pathogens, such as Streptococcus mutans2. Salivary mucin can interact directly with microorganisms through selective agglutinin activity and bacterial binding2-4, but the extent and basis of the protective functions of saliva are not well understood. Here, using an ex vivo saliva model, we identify that MUC5B is an inhibitor of microbial virulence. Specifically, we find that natively purified MUC5B downregulates the expression of quorum-sensing pathways activated by the competence stimulating peptide and the sigX-inducing peptide5. Furthermore, MUC5B prevents the acquisition of antimicrobial resistance through natural genetic transformation, a process that is activated through quorum sensing. Our data reveal that the effect of MUC5B is mediated by its associated O-linked glycans, which are potent suppressors of quorum sensing and genetic transformation, even when removed from the mucin backbone. Together, these results present mucin O-glycans as a host strategy for domesticating potentially pathogenic microorganisms without killing them.


Asunto(s)
Caries Dental/metabolismo , Mucina 5B/metabolismo , Polisacáridos/metabolismo , Percepción de Quorum , Streptococcus mutans/fisiología , Caries Dental/genética , Caries Dental/microbiología , Interacciones Huésped-Patógeno , Humanos , Mucina 5B/química , Mucina 5B/genética , Polisacáridos/química , Saliva/metabolismo , Saliva/microbiología , Streptococcus mutans/genética , Streptococcus mutans/patogenicidad , Transformación Bacteriana , Virulencia
9.
Nat Microbiol ; 4(12): 2146-2154, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31611643

RESUMEN

A slimy, hydrated mucus gel lines all wet epithelia in the human body, including the eyes, lungs, and gastrointestinal and urogenital tracts. Mucus forms the first line of defence while housing trillions of microorganisms that constitute the microbiota1. Rarely do these microorganisms cause infections in healthy mucus1, suggesting that mechanisms exist in the mucus layer that regulate virulence. Using the bacterium Pseudomonas aeruginosa and a three-dimensional (3D) laboratory model of native mucus, we determined that exposure to mucus triggers downregulation of virulence genes that are involved in quorum sensing, siderophore biosynthesis and toxin secretion, and rapidly disintegrates biofilms-a hallmark of mucosal infections. This phenotypic switch is triggered by mucins, which are polymers that are densely grafted with O-linked glycans that form the 3D scaffold inside mucus. Here, we show that isolated mucins act at various scales, suppressing distinct virulence pathways, promoting a planktonic lifestyle, reducing cytotoxicity to human epithelia in vitro and attenuating infection in a porcine burn model. Other viscous polymer solutions lack the same effect, indicating that the regulatory function of mucin does not result from its polymeric structure alone. We identify that interactions with P. aeruginosa are mediated by mucin-associated glycans (mucin glycans). By isolating glycans from the mucin backbone, we assessed the collective activity of hundreds of complex structures in solution. Similar to their grafted counterparts, free mucin glycans potently regulate bacterial phenotypes even at relatively low concentrations. This regulatory function is likely dependent on glycan complexity, as monosaccharides do not attenuate virulence. Thus, mucin glycans are potent host signals that 'tame' microorganisms, rendering them less harmful to the host.


Asunto(s)
Interacciones Huésped-Patógeno , Mucinas/química , Moco/microbiología , Polisacáridos/química , Pseudomonas aeruginosa/patogenicidad , Animales , Biopelículas , Quemaduras/microbiología , Células Epiteliales/microbiología , Femenino , Células HT29 , Humanos , Moco/química , Pseudomonas aeruginosa/efectos de los fármacos , Percepción de Quorum , Porcinos , Virulencia/genética , Heridas y Lesiones/microbiología
10.
Artículo en Inglés | MEDLINE | ID: mdl-30323945

RESUMEN

Mucus is a biological gel that lines all wet epithelia in the body, including the mouth, lungs, and digestive tract, and has evolved to protect the body from pathogenic infection. However, microbial pathogenesis is often studied in mucus-free environments that lack the geometric constraints and microbial interactions in physiological three-dimensional mucus gels. We developed fluid-flow and static test systems based on purified mucin polymers, the major gel-forming constituents of the mucus barrier, to understand how the mucus barrier influences bacterial virulence, particularly the integrity of Pseudomonas aeruginosa biofilms, which can become resistant to immune clearance and antimicrobial agents. We found that mucins separate the cells in P. aeruginosa biofilms and disperse them into suspension. Other viscous polymer solutions did not match the biofilm disruption caused by mucins, suggesting that mucin-specific properties mediate the phenomenon. Cellular dispersion depended on functional flagella, indicating a role for swimming motility. Taken together, our observations support a model in which host mucins are key players in the regulation of microbial virulence. These mucins should be considered in studies of mucosal pathogenesis and during the development of novel strategies to treat biofilms.

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