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1.
Blood ; 144(8): 809-821, 2024 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-38875504

RESUMEN

ABSTRACT: Epidemiological studies report opposing influences of infection on childhood B-cell acute lymphoblastic leukemia (B-ALL). Although infections in the first year of life appear to exert the largest impact on leukemia risk, the effect of early pathogen exposure on the fetal preleukemia cells (PLC) that lead to B-ALL has yet to be reported. Using cytomegalovirus (CMV) infection as a model early-life infection, we show that virus exposure within 1 week of birth induces profound depletion of transplanted E2A-PBX1 and hyperdiploid B-ALL cells in wild-type recipients and in situ-generated PLC in Eµ-ret mice. The age-dependent depletion of PLC results from an elevated STAT4-mediated cytokine response in neonates, with high levels of interleukin (IL)-12p40-driven interferon (IFN)-γ production inducing PLC death. Similar PLC depletion can be achieved in adult mice by impairing viral clearance. These findings provide mechanistic support for potential inhibitory effects of early-life infection on B-ALL progression and could inform novel therapeutic or preventive strategies.


Asunto(s)
Modelos Animales de Enfermedad , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Animales , Ratones , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Infecciones por Citomegalovirus , Preleucemia/genética , Preleucemia/patología , Ratones Endogámicos C57BL , Animales Recién Nacidos , Diploidia
2.
Toxicol Appl Pharmacol ; 478: 116709, 2023 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-37797845

RESUMEN

Arsenic occurs naturally in the environment and humans can be exposed through food, drinking water and inhalation of air-borne particles. Arsenic exposure is associated with cardiovascular, pulmonary, renal, immunologic, and developmental toxicities as well as carcinogenesis. Arsenic displays dose-depen toxicities in target organs or tissues with elevated levels of arsenic. Zinc is an essential micronutrient with proposed protective benefits due to its antioxidant properties, integration into zinc-containing proteins and zinc-related immune signaling. In this study, we tested levels of arsenic and zinc in plasma, kidney, liver, and spleen as model tissues after chronic (42-day) treatment with either arsenite, zinc, or in combination. Arsenite exposure had minimal impact on tissue zinc levels with the exception of the kidney. Conversely, zinc supplementation of arsenite-exposed mice reduced the amount of arsenic detected in all tissues tested. Expression of transporters associated with zinc or arsenic influx and efflux were evaluated under each treatment condition. Significant effects of arsenite exposure on zinc transporter expression displayed tissue selectivity for liver and kidney, and was restricted to Zip10 and Zip14, respectively. Arsenite also interacted with zinc co-exposure for Zip10 expression in liver tissue. Pairwise comparisons show neither arsenite nor zinc supplementation alone significantly altered expression of transporters utilized by arsenic. However, significant interactions between arsenite and zinc were evident for Aqp7 and Mrp1 in a tissue selective manner. These findings illustrate interactions between arsenite and zinc leading to changes in tissue metal level and suggest a potential mechanism by which zinc may offer protection from arsenic toxicities.


Asunto(s)
Arsénico , Arsenitos , Humanos , Ratones , Animales , Arsénico/toxicidad , Arsenitos/toxicidad , Zinc/metabolismo , Distribución Tisular , Suplementos Dietéticos
3.
Toxicol Appl Pharmacol ; 454: 116252, 2022 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-36152676

RESUMEN

Uranium is a naturally occurring element found in the environment as a mixture of isotopes with differing radioactive properties. Enrichment of mined material results in depleted uranium waste with substantially reduced radioactivity but retains the capacity for chemical toxicity. Uranium mine and milling waste are dispersed by wind and rain leading to environmental exposures through soil, air, and water contamination. Uranium exposure is associated with numerous adverse health outcomes in humans, yet there is limited understanding of the effects of depleted uranium on the immune system. The purpose of this review is to summarize findings on uranium immunotoxicity obtained from cell, rodent and human population studies. We also highlight how each model contributes to an understanding of mechanisms that lead to immunotoxicity and limitations inherent within each system. Information from population, animal, and laboratory studies will be needed to significantly expand our knowledge of the contributions of depleted uranium to immune dysregulation, which may then inform prevention or intervention measures for exposed communities.


Asunto(s)
Uranio , Animales , Exposición a Riesgos Ambientales/efectos adversos , Humanos , Minería , Suelo , Uranio/toxicidad , Agua
4.
Pediatr Allergy Immunol ; 33(1): e13658, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34467574

RESUMEN

BACKGROUND: The "old friends" hypothesis posits that reduced exposure to previously ubiquitous microorganisms is one factor involved in the increased rates of allergic diseases. Cytomegalovirus (CMV) may be one of the "old friends" hypothesized to help prevent allergic diseases. We sought to elucidate whether early-life CMV infection is associated with childhood atopy via perturbations of the gut microbiota. METHODS: Participants were recruited from a population-based birth cohort (CHILD study) and followed prospectively until age 5 years in four Canadian cities. A total of 928 participants provided stool microbiome data, urine for CMV testing, skin prick tests, and questionnaire-based detailed environmental exposures. Cytomegalovirus infection was assessed in the first year of life while the main outcome was defined by persistent sensitization to any allergen at ages 1, 3, and 5 years. RESULTS: Early CMV infection was associated with increased beta and decreased alpha diversity of the gut microbiota. Both changes in diversity measures and early CMV infection were associated with persistent allergic sensitization at age 5 years (aOR = 2.08; 95% CI: 1, 4.33). Mediation analysis demonstrated that perturbation of gut microbial composition explains 30% of the association. CONCLUSIONS: Early-life CMV infection is associated with an alteration in the intestinal microbiota, which mediates the effect of the infection on childhood atopy. This work indicates that preventing CMV infection would not put children at increased risk of developing atopy. Rather, a CMV vaccine, in addition to preventing CMV-associated morbidity and mortality, might reduce the risk of childhood allergic diseases.


Asunto(s)
Infecciones por Citomegalovirus , Microbioma Gastrointestinal , Hipersensibilidad Inmediata , Canadá/epidemiología , Preescolar , Citomegalovirus , Infecciones por Citomegalovirus/epidemiología , Humanos , Hipersensibilidad Inmediata/epidemiología , Lactante
5.
J Virol ; 91(12)2017 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-28381570

RESUMEN

Cytomegalovirus (CMV) is acquired by the oral route in children, and primary infection is associated with abundant mucosal replication, as well as the establishment of latency in myeloid cells that results in lifelong infection. The efficiency of primary CMV infection in humans following oral exposure, however, is unknown. We consistently detected self-limited, low-level oral CMV shedding events, which we termed transient CMV infections, in a prospective birth cohort of 30 highly exposed CMV-uninfected infants. We estimated the likelihood of transient oral CMV infections by comparing their observed frequency to that of established primary infections, characterized by persistent high-level shedding, viremia, and seroconversion. We developed mathematical models of viral dynamics upon initial oral CMV infection and validated them using clinical shedding data. Transient infections comprised 76 to 88% of oral CMV shedding events. For this high percentage of transient infections to occur, we identified two mathematical prerequisites: a very small number of initially infected oral cells (1 to 4) and low viral infectivity (<1.5 new cells infected/cell). These observations indicate that oral CMV infection in infants typically begins with a single virus that spreads inefficiently to neighboring cells. Thus, although the incidence of CMV infection is high during infancy, our data provide a mechanistic framework to explain why multiple CMV exposures are typically required before infection is successfully established. These findings imply that a sufficiently primed immune response could prevent CMV from establishing latent infection in humans and support the achievability of a prophylactic CMV vaccine.IMPORTANCE CMV infects the majority of the world's population and is a major cause of birth defects. Developing a vaccine to prevent CMV infection would be extremely valuable but would be facilitated by a better understanding of how natural human CMV infection is acquired. We studied CMV acquisition in infants and found that infections are usually brief and self-limited and are successfully established relatively rarely. Thus, although most people eventually acquire CMV infection, it usually requires numerous exposures. Our analyses indicate that this is because the virus is surprisingly inefficient, barely replicating well enough to spread to neighboring cells in the mouth. Greater knowledge of why CMV infection usually fails may provide insight into how to prevent it from succeeding.


Asunto(s)
Citomegalovirus/fisiología , Boca/virología , Esparcimiento de Virus , Niño , Preescolar , Infecciones por Citomegalovirus/transmisión , Infecciones por Citomegalovirus/virología , Femenino , Humanos , Lactante , Masculino , Modelos Teóricos , Estudios Prospectivos , Seroconversión , Uganda , Viremia , Latencia del Virus , Replicación Viral
6.
Proc Biol Sci ; 282(1810)2015 Jul 07.
Artículo en Inglés | MEDLINE | ID: mdl-26108631

RESUMEN

Animals live in close association with microorganisms, mostly prokaryotes, living in or on them as commensals, mutualists or parasites, and profoundly affecting host fitness. Most animal-microbe studies focus on microbial community structure; for this project, allometry (scaling of animal attributes with animal size) was applied to animal-microbe relationships across a range of species spanning 12 orders of magnitude in animal mass, from nematodes to whales. Microbial abundances per individual animal were gleaned from published literature and also microscopically counted in three species. Abundance of prokaryotes/individual versus animal mass scales as a nearly linear power function (exponent = 1.07, R(2) = 0.94). Combining this power function with allometry of animal abundance indicates that macrofauna have an outsized share of animal-associated microorganisms. The total number of animal-associated prokaryotes in Earth's land animals was calculated to be 1.3-1.4 × 10(25) cells and the total of marine animal-associated microbes was calculated to be 8.6-9.0 × 10(24) cells. Animal-associated microbes thus total 2.1-2.3 × 10(25) of the approximately 10(30) prokaryotes on the Earth. Microbes associated with humans comprise 3.3-3.5% of Earth's animal-associated microbes, and domestic animals harbour 14-20% of all animal-associated microbes, adding a new dimension to the scale of human impact on the biosphere. This novel allometric power function may reflect underlying mechanisms involving the transfer of energy and materials between microorganisms and their animal hosts. Microbial diversity indices of animal gut communities and gut microbial species richness for 60 mammals did not indicate significant scaling relationships with animal body mass; however, further research in this area is warranted.


Asunto(s)
Invertebrados/microbiología , Microbiota , Vertebrados/microbiología , Animales , Peso Corporal , Invertebrados/fisiología , Vertebrados/fisiología
7.
Appl Environ Microbiol ; 80(6): 1941-8, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24441160

RESUMEN

Escherichia fergusonii is an emerging pathogen that has been isolated from a wide range of infections in animals and humans. Primers targeting specific genes, including yliE (encoding a conserved hypothetical protein of the cellulose synthase and regulator of cellulose synthase island), EFER_1569 (encoding a hypothetical protein, putative transcriptional activator for multiple antibiotic resistance), and EFER_3126 (encoding a putative triphosphoribosyl-dephospho-coenzyme A [CoA]), were designed for the detection of E. fergusonii by conventional and real-time PCR methods. Primers were screened by in silico PCR against 489 bacterial genomic sequences and by both PCR methods on 55 reference and field strains. Both methods were specific and sensitive for E. fergusonii, showing amplification only for this bacterium. Conventional PCR required a minimum bacterial concentration of approximately 10(2) CFU/ml, while real-time PCR required a minimum of 0.3 pg of DNA for consistent detection. Standard curves showed an efficiency of 98.5%, with an R(2) value of 0.99 for the real-time PCR assay. Cecal and cloacal contents from 580 chickens were sampled from broiler farms located in the Fraser Valley (British Columbia, Canada). Presumptive E. fergusonii isolates were recovered by enrichment and plating on differential and selective media. Of 301 total presumptive isolates, 140 (46.5%) were identified as E. fergusonii by biochemical profiling with the API 20E system and 268 (89.0%) using PCR methods. E. fergusonii detection directly from cecal and cloacal samples without preenrichment was achieved with both PCR methods. Hence, the PCR methods developed in this work significantly improve the detection of E. fergusonii.


Asunto(s)
Técnicas Bacteriológicas/métodos , Pollos/microbiología , Escherichia/clasificación , Escherichia/aislamiento & purificación , Técnicas de Diagnóstico Molecular/métodos , Reacción en Cadena de la Polimerasa Multiplex/métodos , Animales , Colombia Británica , Ciego/microbiología , Cloaca/microbiología , Cartilla de ADN/genética , Escherichia/genética , Proteínas de Escherichia coli/genética , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos
8.
Sci Rep ; 14(1): 8926, 2024 04 18.
Artículo en Inglés | MEDLINE | ID: mdl-38637558

RESUMEN

To evaluate immune responses to COVID-19 vaccines in adults aged 50 years and older, spike protein (S)-specific antibody concentration, avidity, and function (via angiotensin-converting enzyme 2 (ACE2) inhibition surrogate neutralization and antibody dependent cellular phagocytosis (ADCP)), as well as S-specific T cells were quantified via activation induced marker (AIM) assay in response to two-dose series. Eighty-four adults were vaccinated with either: mRNA/mRNA (mRNA-1273 and/or BNT162b2); ChAdOx1-S/mRNA; or ChAdOx1-S/ChAdOx1-S. Anti-S IgG concentrations, ADCP scores and ACE2 inhibiting antibody concentrations were highest at one-month post-second dose and declined by four-months post-second dose for all groups. mRNA/mRNA and ChAdOx1-S/mRNA schedules had significantly higher antibody responses than ChAdOx1-S/ChAdOx1-S. CD8+ T-cell responses one-month post-second dose were associated with increased ACE2 surrogate neutralization. Antibody avidity (total relative avidity index) did not change between one-month and four-months post-second dose and did not significantly differ between groups by four-months post-second dose. In determining COVID-19 correlates of protection, a measure that considers both antibody concentration and avidity should be considered.


Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Adulto , Humanos , Persona de Mediana Edad , Anciano , Enzima Convertidora de Angiotensina 2 , Vacuna BNT162 , Estudios Prospectivos , COVID-19/prevención & control , Canadá/epidemiología , Anticuerpos , ChAdOx1 nCoV-19 , ARN Mensajero , Anticuerpos Antivirales , Vacunación
9.
Hum Vaccin Immunother ; 18(1): 1879580, 2022 12 31.
Artículo en Inglés | MEDLINE | ID: mdl-33651972

RESUMEN

Potential conflicts of interest in vaccine research can lead to negative consequences that undermine public trust and thereby put communities at risk. However, collaborations that may give rise to potential conflicts between interests can also greatly facilitate appropriate, scientifically robust, and timely vaccine development, implementation, and evaluation. At present, policies regarding the management of potential conflicts between interests are not ideal. To optimally manage interests in vaccine research, we recommend acknowledging all forms of interests and treating them all as relevant, developing appropriate collaborations, referring to all "conflicts of interest" simply as "interests" or "declarations," and promoting transparency through developing consistent reporting mechanisms.


Asunto(s)
Investigación Biomédica , Vacunas , Conflicto de Intereses , Revelación , Inmunización
10.
Toxicol Rep ; 8: 1917-1929, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34926170

RESUMEN

Communities in the western region of the United States experience environmental exposure to metal mixtures from living in proximity to numerous unremediated abandoned uranium mines. Metals including arsenic and uranium co-occur in and around these sites at levels higher than the United States Environmental Protection Agency maximum contaminant levels. To address the potential effect of these metals on the activation of CD4+ T-cells, we used RNA sequencing methods to determine the effect of exposure to sodium arsenite (1 µM and 10 µM), uranyl acetate (3 µM and 30 µM) or a mixture of sodium arsenite and uranyl acetate (1 µM sodium arsenite + 3 µM uranyl acetate). Sodium arsenite induced a dose dependent effect on activation associated gene expression; targeting immune response genes at the lower dose. Increases in oxidative stress gene expression were observed with both sodium arsenite doses. While uranyl acetate alone did not significantly alter activation associated gene expression, the mixture of uranyl acetate with sodium arsenite demonstrated a combined effect relative to sodium arsenite alone. The results demonstrate the need to investigate metal and metalloid mixtures at environmentally relevant concentrations to better understand the toxicological impact of these mixtures on T-cell activation, function and immune dysregulation.

11.
Toxicol Lett ; 333: 269-278, 2020 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-32866568

RESUMEN

Elevated levels of arsenic and uranium have been detected in water sources near abandoned uranium mines in the Southwest. Evidence suggests uranium exposure increases the likelihood of immune dysfunction and this study investigates the impact of arsenic and uranium on human immune cell lines. Concentration-dependent cytotoxicity occurred following exposure to arsenite, whereas cells remained viable after 48 -h treatment with up to 100 µM uranyl acetate despite uptake of uranium into cells. Arsenite stimulated an oxidative stress response as detected by Nrf-2 nuclear accumulation and induction of HMOX-1 and NQO1, which was not detected with up to 30 µM uranyl acetate. Cellular oxidative stress can promote DNA damage and arsenite, but not uranium, stimulated DNA damage as measured by pH2AX. Arsenic enhanced the cytotoxic response to etoposide suggesting an inhibition of DNA repair, unlike uranium. Similarly, uranium did not inhibit PARP-1 activity. Because uranium reportedly stimulates oxidative stress, DNA damage and cytotoxicity in adherent epithelial cells, the current study suggests distinct cell type differences in response to uranium that may relate to generation of oxidative stress and associated downstream consequences. Delineating the actions of uranium across different cell targets will be important for understanding the potential health effects of uranium exposures.


Asunto(s)
Arsenitos/toxicidad , Daño del ADN , Compuestos Organometálicos/toxicidad , Estrés Oxidativo/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Monitoreo Biológico/métodos , Técnicas de Cultivo de Célula , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Reparación del ADN , Relación Dosis-Respuesta a Droga , Expresión Génica/efectos de los fármacos , Humanos , Células Jurkat , Minería , Compuestos Organometálicos/metabolismo , Estrés Oxidativo/genética , Linfocitos T/metabolismo , Linfocitos T/patología , Células THP-1
12.
PLoS One ; 13(1): e0190953, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29329319

RESUMEN

Rock salt represents a potential host rock formation for the final disposal of radioactive waste. The interactions between indigenous microorganisms and radionuclides, e.g. uranium, need to be investigated to better predict the influence of microorganisms on the safety assessment of the repository. Hence, the association process of uranium with two microorganisms isolated from rock salt was comparatively studied. Brachybacterium sp. G1, which was isolated from the German salt dome Gorleben, and Halobacterium noricense DSM15987T, were selected as examples of a moderately halophilic bacterium and an extremely halophilic archaeon, respectively. The microorganisms exhibited completely different association behaviors with uranium. While a pure biosorption process took place with Brachybacterium sp. G1 cells, a multistage association process occurred with the archaeon. In addition to batch experiments, in situ attenuated total reflection Fourier-transform infrared spectroscopy was applied to characterize the U(VI) interaction process. Biosorption was identified as the dominating process for Brachybacterium sp. G1 with this method. Carboxylic functionalities are the dominant interacting groups for the bacterium, whereas phosphoryl groups are also involved in U(VI) association by the archaeon H. noricense.


Asunto(s)
Bacterias/metabolismo , Halobacterium/metabolismo , Uranio/metabolismo , Bacterias/clasificación , Bacterias/crecimiento & desarrollo , Halobacterium/clasificación , Halobacterium/crecimiento & desarrollo , Microscopía Electrónica de Rastreo , Filogenia , Residuos Radiactivos , Espectrometría por Rayos X , Espectroscopía Infrarroja por Transformada de Fourier
13.
J Food Prot ; 79(6): 929-38, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27296596

RESUMEN

The objective of this study was to investigate the antibiotic resistance of Escherichia fergusonii isolated from commercial broiler chicken farms. A total of 245 isolates from cloacal and cecal samples of 28- to 36-day-old chickens were collected from 32 farms. Isolates were identified using PCR, and their susceptibility to 16 antibiotics was determined by disk diffusion assay. All isolates were susceptible to meropenem, amikacin, and ciprofloxacin. The most common resistances were against ampicillin (75.1%), streptomycin (62.9%), and tetracycline (57.1%). Of the 184 ampicillin-resistant isolates, 127 were investigated using a DNA microarray carrying 75 probes for antibiotic resistance genetic determinants. Of these 127 isolates, the ß-lactamase blaCMY2, blaTEM, blaACT, blaSHV, and blaCTX-M-15 genes were detected in 120 (94.5%), 31 (24.4%), 8 (6.3%), 6 (4.7%), and 4 (3.2%) isolates, respectively. Other detected genes included those conferring resistance to aminoglycosides (aadA1, strA, strB), trimethoprims (dfrV, dfrA1), tetracyclines (tetA, tetB, tetC, tetE), and sulfonamides (sul1, sul2). Class 1 integron was found in 35 (27.6%) of the ampicillin-resistant isolates. However, our data showed that the tested E. fergusonii did not carry any carbapenemase blaOXA genes. Pulsed-field gel electrophoresis revealed that the selected ampicillin-resistant E. fergusonii isolates were genetically diverse. The present study indicates that the monitoring of antimicrobial-resistant bacteria should include enteric bacteria such as E. fergusonii, which could be a reservoir of antibiotic resistance genes. The detection of isolates harboring extended-spectrum ß-lactamase genes, particularly blaCTX-M-15, in this work suggests that further investigations on the occurrence of such genes in broilers are warranted.


Asunto(s)
Pollos/microbiología , Farmacorresistencia Bacteriana Múltiple/genética , Animales , Antibacterianos/farmacología , Antiinfecciosos , Proteínas Bacterianas , Farmacorresistencia Bacteriana/genética , Escherichia coli/aislamiento & purificación , Pruebas de Sensibilidad Microbiana , beta-Lactamasas/genética
14.
J Pediatr Adolesc Gynecol ; 18(5): 343-5, 2005 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-16202938

RESUMEN

PURPOSE: To determine the yield of routine vaginal cultures for Neisseria gonorrhoeae and Chlamydia trachomatis from girls evaluated following sexual abuse. METHODS: Retrospective chart review evaluating results of cultures that were obtained from 2008 prepubertal girls seen within 72 hours following an assault over two periods of 3 years each. RESULTS: It was found that only 16 (0.8%) of cultures were positive for either gonorrhea or chlamydia. All but one of the prepubertal girls who had positive vaginal cultures for sexually transmitted disease had signs of acute vulvovaginitis. CONCLUSION: Routine vaginal cultures in asymptomatic pre-pubertal girls have a very low yield. Prospective studies are required to change current protocols for the evaluation of child victims of sexual abuse.


Asunto(s)
Abuso Sexual Infantil , Infecciones por Chlamydia/diagnóstico , Gonorrea/diagnóstico , Tamizaje Masivo , Enfermedades de Transmisión Sexual/diagnóstico , Vagina/microbiología , Niño , Preescolar , Infecciones por Chlamydia/transmisión , Chlamydia trachomatis/aislamiento & purificación , Femenino , Gonorrea/transmisión , Humanos , Neisseria gonorrhoeae/aislamiento & purificación , Estudios Retrospectivos
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