RESUMEN
RHOH, an atypical small GTPase predominantly expressed in hematopoietic cells, plays a vital role in immune function. A deficiency in RHOH has been linked to epidermodysplasia verruciformis, lung disease, Burkitt lymphoma and T cell defects. Here, we report a novel germline homozygous RHOH c.245G > A (p.Cys82Tyr) variant in a 21-year-old male suffering from recurrent, invasive, opportunistic infections affecting the lungs, eyes, and brain. His sister also succumbed to a lung infection during early adulthood. The patient exhibited a persistent decrease in CD4+ T, B, and NK cell counts, and hypoimmunoglobulinemia. The patient's T cell showed impaired activation upon in vitro TCR stimulation. In Jurkat T cells transduced with RHOHC82Y, a similar reduction in activation marker CD69 up-regulation was observed. Furthermore, the C82Y variant showed reduced RHOH protein expression and impaired interaction with the TCR signaling molecule ZAP70. Together, these data suggest that the newly identified autosomal-recessive RHOH variant is associated with T cell dysfunction and recurrent opportunistic infections, functioning as a hypomorph by disrupting ZAP70-mediated TCR signaling.
Asunto(s)
Homocigoto , Infecciones Oportunistas , Humanos , Masculino , Adulto Joven , Células Jurkat , Activación de Linfocitos/genética , Infecciones Oportunistas/genética , Infecciones Oportunistas/inmunología , Linaje , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Recurrencia , Linfocitos T/inmunología , Proteína Tirosina Quinasa ZAP-70/genética , Proteína Tirosina Quinasa ZAP-70/metabolismoRESUMEN
Serratia marcescens is an emerging opportunistic pathogen with high genetic diversity. This article describes the microbiological characteristics of isolates and the risk factors for infections caused by carbapenem-resistant S. marcescens. A retrospective study of patients colonized (n=43) and infected (n=20) with carbapenem-resistant S. marcescens over a 3-year period was conducted. Polymerase chain reaction for carbapenemase genes and molecular typing of all available strains was performed. Forty-two isolates were analysed, including three environmental samples identified during an outbreak. Thirty-five carbapenem-resistant S. marcescens carried blaKPC-2, one isolate was blaNDM-positive and four isolates carried blaOXA-101. The genomes were grouped into three clusters with 100% bootstrap; three patterns of mutations on ompC and ompF were found. The strains carried virulence genes related to invasion and haemolysis, and the environmental strains presented fewer mutations on the virulence genes than the clinical strains. Multi-variate analysis showed that previous use of polymyxin (P=0.008) was an independent risk factor for carbapenem-resistant S. marcescens infection. This study highlighted that blaKPC-2 in association with ompC or ompF mutation was the most common mechanism of resistance in the study hospital, and that previous use of polymyxin was an independent risk factor for carbapenem-resistant S. marcescens. There was a predominant clone, including the environmental isolates, suggesting that cross-transmission was involved in the dissemination of this pathogen.
Asunto(s)
Enterobacteriaceae Resistentes a los Carbapenémicos/genética , Infecciones Oportunistas/genética , Infecciones por Serratia/fisiopatología , Serratia marcescens/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Brotes de Enfermedades , Femenino , Variación Genética , Genotipo , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Tipificación Molecular , Fenotipo , Estudios Retrospectivos , Adulto JovenRESUMEN
Background: Infections are the major cause of morbidity and mortality in patients with primary immunodeficiency disease (PID). Timely and accurate microbiological diagnosis is particularly important in these patients. Metagenomic next-generation sequencing (mNGS) has been used for pathogen detection recently. However, few reports describe the use of mNGS for pathogen identification in patients with PID. Objective: To evaluate the utility of mNGS for detecting pathogens in patients with PID, and to compare it with conventional microbiological tests (CMT). Methods: This single center retrospective study investigated the diagnostic performance of mNGS for pathogens detection in PID patients and compared it with CMT. Sixteen PID patients with suspected infection were enrolled, and medical records were analyzed to extract detailed clinical characteristics such as gene variation, immune status, microbial distribution, time-consuming of mNGS and CMT, treatment, and outcomes. Results: mNGS identified pathogenic microbe in 93.75% samples, compared to 31.25% for culture and 68.75% for conventional methods, and detected an extra 18 pathogenic microorganisms including rare opportunistic pathogens and Mycobacterium tuberculosis. Pathogen identification by mNGS required 48 hours, compared with bacterial culture for 3-7 days and even longer for fungus and Mycobacterium tuberculosis culture. Conclusions: mNGS has marked advantages over conventional methods for pathogenic diagnosis, particularly opportunistic pathogens and mixed infections, in patients with PID. This method might enable clinicians to make more timely and targeted therapeutic decisions, thereby improving the prognosis of these patients.
Asunto(s)
Infecciones Bacterianas/diagnóstico , Secuenciación de Nucleótidos de Alto Rendimiento , Metagenoma/genética , Metagenómica , Micosis/diagnóstico , Infecciones Oportunistas/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/inmunología , Adolescente , Infecciones Bacterianas/genética , Infecciones Bacterianas/inmunología , Infecciones Bacterianas/microbiología , Técnicas Bacteriológicas , Niño , Preescolar , Femenino , Interacciones Huésped-Patógeno , Humanos , Huésped Inmunocomprometido , Lactante , Masculino , Metagenoma/inmunología , Micosis/genética , Micosis/inmunología , Micosis/microbiología , Infecciones Oportunistas/genética , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/microbiología , Valor Predictivo de las Pruebas , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/genética , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
The application of CLSI and EUCAST guidelines led to many discrepancies. Various doubts have already appeared in preliminary stages of microbiological diagnostics of Haemophilus spp. A total of 87 H. parainfluenzae isolates were obtained from throat or nasopharyngeal swabs from adults 18 to 70 years old, both healthy volunteers and patients with chronic diseases between 2013 to 2015 in eastern Poland. Haemophilus spp. were identified by colony morphology, Gram-staining, API NH and MALDI-TOF MS technique. Both susceptibility to various antimicrobials and phenotypes of Haemophilus spp. resistance to beta-lactams were determined. Statistically significant association between applied guidelines and drug resistance patterns were observed to as follows: ampicillin, cefuroxime, cefotaxime, amoxicillin-clavulanate, azithromycin, tetracycline and trimethoprim-sulfamethoxazole. Resistance phenotypes according to CLSI vs. EUCAST were as follows: 3.4% vs. 8.0% for BLNAR and 6.9% vs. 19.5% for BLPACR isolates. In conclusion, this is the first study that reports comparative analysis of drug susceptibility interpretation using CLSI and EUCAST of haemophili rods from human respiratory microbiota in Poland. In case of susceptible, increased exposure (formerly intermediate) category of susceptibility within H. parainfluenzae isolates we have observed EUCAST as more restrictive than CLSI. Moreover, BLNAI and BLPAI phenotype isolates have been observed, as well as BLPBR using only CLSI or EUCAST guidelines, respectively.
Asunto(s)
Antibacterianos/efectos adversos , Farmacorresistencia Bacteriana/genética , Haemophilus parainfluenzae/genética , Infecciones Oportunistas/tratamiento farmacológico , Mucosa Respiratoria/microbiología , Adolescente , Adulto , Anciano , Antibacterianos/uso terapéutico , Enfermedad Crónica/tratamiento farmacológico , Enfermedad Crónica/prevención & control , Femenino , Haemophilus parainfluenzae/efectos de los fármacos , Haemophilus parainfluenzae/patogenicidad , Voluntarios Sanos , Humanos , Macrólidos/efectos adversos , Macrólidos/uso terapéutico , Pruebas de Sensibilidad Microbiana , Microbiota/genética , Persona de Mediana Edad , Infecciones Oportunistas/genética , Infecciones Oportunistas/microbiología , Infecciones Oportunistas/patología , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/patología , Adulto JovenRESUMEN
Deficiencies in T regulatory (Treg) and Th17 cells attenuate peripheral tolerance and the IL-17 family of cytokines, contributing to autoimmune disorders and opportunistic (fungal) infections, respectively. Because of limited blood samples from patients with primary immunodeficiency diseases (PIDs), a positive correlation/linear relationship between Treg and Th17 cells and their respective expressions of transcription factors forkhead box P3 (FOXP3) and retinoic acid-related orphan receptor γ (RORγt) by real-time PCR (RT-PCR) amplification, was used to predict the percentages of Treg and Th17 cells in peripheral blood. Compared to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) expression, the percentages of Treg and Th17 cells were calculated as the linear relationship to the 2-ΔCT value (cycle threshold). Among 91 PIDs patients, 68 and 78 had predicted Treg and Th17 percentages below 5% of the normal ranges (0.859 and 0.734%, respectively), which expanded different categories beyond obvious T cell deficiency. Notably, FOXP3 was undetectable in one patient (CVID), RORγt was undetectable in six patients (one CVID, one CID, two neutropenia, one WAS, and one CMC), and both were undetectable in four patients (two SCID, one STAT1, and one periodic fever). In contrast, two patients with auto-IFNγ antibodies had increased susceptibility to intracellular mycobacterial infections, interrupted Th1 development and subsequent elevation in the Th17 cells. Both predicted Treg and Th17 percentages in the PIDs patients were more independent of age (months) than in the controls. The predicted Th17/Treg ratio in the PIDs patients, overall, was lower than that in the healthy controls (0.79 ± 0.075 vs. 1.16 ± 0.208; p = 0.038). In conclusion, lower predicted Treg and Th17 cell populations calculated by RT-PCR-amplified FOXP3 and RORγt in PIDs patients at diagnosis can explain the higher potential phenotypes of autoimmune disorders and opportunistic infections, although effective interventions in the early stage might have prevented such phenotypic development and caused a statistical bias in the comparisons.
Asunto(s)
Factores de Transcripción Forkhead/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/inmunología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Recuento de Linfocito CD4 , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Infecciones Oportunistas/genética , Infecciones Oportunistas/inmunología , Reacción en Cadena en Tiempo Real de la Polimerasa , Adulto JovenRESUMEN
The opportunistic pathogen Pseudomonas aeruginosa is responsible for much of the morbidity and mortality associated with cystic fibrosis (CF), a condition that predisposes patients to chronic lung infections. P. aeruginosa lung infections are difficult to treat because P. aeruginosa adapts to the CF lung, can develop multidrug resistance, and can form biofilms. Despite the clinical significance of P. aeruginosa, modeling P. aeruginosa infections in CF has been challenging. Here, we characterize Scnn1b-transgenic (Tg) BALB/c mice as P. aeruginosa lung infection models. Scnn1b-Tg mice overexpress the epithelial Na+ channel (ENaC) in their lungs, driving increased sodium absorption that causes lung pathology similar to CF. We intranasally infected Scnn1b-Tg mice and wild-type littermates with the laboratory P. aeruginosa strain PAO1 and CF clinical isolates and then assessed differences in bacterial clearance, cytokine responses, and histological features up to 12 days postinfection. Scnn1b-Tg mice carried higher bacterial burdens when infected with biofilm-grown rather than planktonic PAO1; Scnn1b-Tg mice also cleared infections more slowly than their wild-type littermates. Infection with PAO1 elicited significant increases in proinflammatory and Th17-linked cytokines on day 3. Scnn1b-Tg mice infected with nonmucoid early CF isolates maintained bacterial burdens and mounted immune responses similar to those of PAO1-infected Scnn1b-Tg mice. In contrast, Scnn1b-Tg mice infected with a mucoid CF isolate carried high bacterial burdens, produced significantly more interleukin 1ß (IL-1ß), IL-13, IL-17, IL-22, and KC, and showed severe immune cell infiltration into the bronchioles. Taken together, these results show the promise of Scnn1b-Tg mice as models of early P. aeruginosa colonization in the CF lung.
Asunto(s)
Fibrosis Quística/genética , Modelos Animales de Enfermedad , Canales Epiteliales de Sodio/genética , Infecciones Oportunistas/genética , Infecciones por Pseudomonas/genética , Pseudomonas aeruginosa/inmunología , Animales , Carga Bacteriana , Biopelículas/crecimiento & desarrollo , Fibrosis Quística/inmunología , Fibrosis Quística/microbiología , Fibrosis Quística/patología , Canales Epiteliales de Sodio/inmunología , Femenino , Regulación de la Expresión Génica , Humanos , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-13/genética , Interleucina-13/inmunología , Interleucina-17/genética , Interleucina-17/inmunología , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Interleucina-8/genética , Interleucina-8/inmunología , Interleucinas/genética , Interleucinas/inmunología , Transporte Iónico , Pulmón/inmunología , Pulmón/microbiología , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/microbiología , Infecciones Oportunistas/patología , Plancton/crecimiento & desarrollo , Plancton/inmunología , Plancton/patogenicidad , Infecciones por Pseudomonas/inmunología , Infecciones por Pseudomonas/patología , Pseudomonas aeruginosa/crecimiento & desarrollo , Pseudomonas aeruginosa/patogenicidad , Sodio/metabolismo , Interleucina-22RESUMEN
BACKGROUND: Talaromyces marneffei, also named Penicillium marneffei, is an opportunistic pathogen that can cause systemic or limited infection in human beings. This infection is especially common in human immunodeficiency virus (HIV)-infected hosts; however, it has also been recently reported in HIV-negative hosts. Here, we report a very rarely seen case of T. marneffei pulmonary infection in a non-HIV-infected patient with signal transducer and activator of transcription 3 (STAT3) mutation. CASE PRESENTATION: A 34-year-old woman was admitted to our hospital for uncontrollable nonproductive cough and dyspnea with exercise. She had been immunocompromised since infancy. Computerized tomography scan showed multiple ground glass opacities with multiple bullae in both lungs. Next generation sequencing (NGS) of the bronchoalveolar lavage fluid identified T. marneffei nucleotide sequences. Culture of bronchoscopy specimens further verified the results. The patient was HIV negative, and blood gene detection indicated STAT3 mutation. To date, following the application of itraconazole, the patient has recovered satisfactorily. CONCLUSION: In clinical practice, T. marneffei infection among HIV-negative individuals is relatively rare, and we found that patients who are congenitally immunocompromised due to STAT3 mutation may be potential hosts. Early diagnosis and timely treatment are expected to improve the prognosis of T. marneffei infection. NGS is a powerful technique that may play an important role in this progress. The reviews of this paper are available via the supplemental material section.
Asunto(s)
Análisis Mutacional de ADN , Huésped Inmunocomprometido/genética , Enfermedades Pulmonares Fúngicas/diagnóstico , Mutación , Micosis/diagnóstico , Infecciones Oportunistas/diagnóstico , Factor de Transcripción STAT3/genética , Talaromyces/patogenicidad , Adulto , Diagnóstico Precoz , Femenino , Prueba de VIH , Secuenciación de Nucleótidos de Alto Rendimiento , Interacciones Huésped-Patógeno , Humanos , Enfermedades Pulmonares Fúngicas/genética , Enfermedades Pulmonares Fúngicas/inmunología , Enfermedades Pulmonares Fúngicas/microbiología , Micosis/genética , Micosis/inmunología , Micosis/microbiología , Infecciones Oportunistas/genética , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/microbiología , Valor Predictivo de las Pruebas , Talaromyces/inmunologíaAsunto(s)
Virus BK/patogenicidad , Genes Codificadores de los Receptores de Linfocitos T , Rechazo de Injerto/diagnóstico , Trasplante de Riñón/efectos adversos , Infecciones Oportunistas/diagnóstico , Infecciones por Polyomavirus/diagnóstico , Análisis de Secuencia de ADN , Infecciones Tumorales por Virus/diagnóstico , Virus BK/inmunología , Diagnóstico Diferencial , Rechazo de Injerto/genética , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Huésped Inmunocomprometido , Inmunosupresores/efectos adversos , Masculino , Infecciones Oportunistas/genética , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/virología , Infecciones por Polyomavirus/genética , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/virología , Valor Predictivo de las Pruebas , Resultado del Tratamiento , Infecciones Tumorales por Virus/genética , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/virología , Carga Viral , Adulto JovenRESUMEN
Both the herpes zoster virus and suid herpesvirus type 1 (SuHV-1) belong to the Varicellovirus genus of the α-herpesviridae subfamily. They may cause opportunistic infections especially in patients with kidney diseases, varying from latent illness to overt lethality. Under these circumstances, impaired renal function is both the culprit for and victim of the infection. However, fulminant eruption of severe skin herpes zoster in lupus nephritis (LN) patients under prolonged immunosuppressive therapy is rare and even more rarely seen is the SuHV-1 encephalitis in human. Facing the evolution of these rare infections, we hence chose to review the clinical pathogenicity of these two viruses which were cognate in origin but distinct in virulence. As such, we began with the first of the two above viral diseases and proceeded with peculiar renal involvement, unique clinical symptoms and pertinent lethal risk. Of importance, LN was used to exemplify the reciprocally detrimental interactions between impaired renal function and suppressed immune response. Then in a manner similar to the gradient overlay, SuHV-1 encephalitis was discussed focusing on its neurotropic features, specific MRI findings and exclusive test of high throughput sequencing. Our report highlighted novel presentations of the Varicellovirus genus infection by providing a productive multidisciplinary communication with pointed disclosure of the renal involvement. It may therefore be of great medical relevance and educational value for clinicians, especially the unseasoned ones, to foresee and manage similar cases in susceptible patients.
Asunto(s)
Herpes Zóster/epidemiología , Herpesvirus Suido 1/patogenicidad , Encefalitis Infecciosa/epidemiología , Enfermedades Renales/epidemiología , Animales , Herpes Zóster/complicaciones , Herpes Zóster/genética , Herpes Zóster/virología , Infecciones por Herpesviridae/complicaciones , Infecciones por Herpesviridae/epidemiología , Infecciones por Herpesviridae/genética , Infecciones por Herpesviridae/virología , Humanos , Encefalitis Infecciosa/complicaciones , Encefalitis Infecciosa/genética , Encefalitis Infecciosa/virología , Enfermedades Renales/complicaciones , Enfermedades Renales/genética , Enfermedades Renales/virología , Nefritis Lúpica/complicaciones , Nefritis Lúpica/epidemiología , Nefritis Lúpica/genética , Nefritis Lúpica/virología , Infecciones Oportunistas/complicaciones , Infecciones Oportunistas/epidemiología , Infecciones Oportunistas/genética , Infecciones Oportunistas/virología , Porcinos/virología , Varicellovirus/patogenicidadRESUMEN
Patients with acute myeloid leukemia frequently present translocations of MLL gene. Rearrangements of MLL protein (MLL-r) in complexes that contain the histone methyltransferase DOT1L are common, which elicit abnormal methylation of lysine 79 of histone H3 at MLL target genes. Phase 1 clinical studies with pinometostat (EPZ-5676), an inhibitor of DOT1L activity, demonstrated the therapeutic potential for targeting DOT1L in MLL-r leukemia patients. We previously reported that down-regulation of DOT1L increases influenza and vesicular stomatitis virus replication and decreases the antiviral response. Here we show that DOT1L inhibition also reduces Sendai virus-induced innate response and its overexpression decreases influenza virus multiplication, reinforcing the notion of DOT1L controlling viral replication. Accordingly, genes involved in the host innate response against pathogens (RUBICON, TRIM25, BCL3) are deregulated in human lung epithelial cells treated with pinometostat. Concomitantly, deregulation of some of these genes together with that of the MicroRNA let-7B, may account for the beneficial effects of pinometostat treatment in patients with MLL-r involving DOT1L. These results support a possible increased vulnerability to infection in MLL-r leukemia patients undergoing pinometostat treatment. Close follow up of infection should be considered in pinometostat therapy to reduce some severe side effects during the treatment.
Asunto(s)
Antineoplásicos/efectos adversos , Bencimidazoles/efectos adversos , Inhibidores Enzimáticos/efectos adversos , Regulación Leucémica de la Expresión Génica , N-Metiltransferasa de Histona-Lisina/genética , Subtipo H1N1 del Virus de la Influenza A/genética , Infecciones Oportunistas/inducido químicamente , Células A549 , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/inmunología , Proteínas del Linfoma 3 de Células B/genética , Proteínas del Linfoma 3 de Células B/inmunología , Susceptibilidad a Enfermedades , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , N-Metiltransferasa de Histona-Lisina/inmunología , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Subtipo H1N1 del Virus de la Influenza A/crecimiento & desarrollo , Subtipo H1N1 del Virus de la Influenza A/metabolismo , Gripe Humana/inducido químicamente , Gripe Humana/genética , Gripe Humana/inmunología , Gripe Humana/virología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/patología , MicroARNs/genética , MicroARNs/inmunología , Infecciones Oportunistas/genética , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/virología , Virus Sendai/genética , Virus Sendai/crecimiento & desarrollo , Virus Sendai/metabolismo , Transducción de Señal , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Proteínas de Motivos Tripartitos/genética , Proteínas de Motivos Tripartitos/inmunología , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/inmunología , Replicación ViralRESUMEN
Here, we describe the creation of three integration vectors, pPEPX, pPEPY and pPEPZ, for use with the opportunistic human pathogen Streptococcus pneumoniae. The constructed vectors, named PEP for Pneumococcal Engineering Platform (PEP), employ an IPTG-inducible promoter and BglBrick and BglFusion compatible multiple cloning sites allowing for fast and interchangeable cloning. PEP plasmids replicate in Escherichia coli and harbor integration sites that have homology in a large set of pneumococcal strains, including recent clinical isolates. In addition, several options of antibiotic resistance markers are available, even allowing for selection in multidrug resistant clinical isolates. The transformation efficiency of these PEP vectors as well as their ability to be expressed simultaneously was tested. Two of the three PEP vectors share homology of the integration regions with over half of the S. pneumoniae genomes examined. Transformation efficiency varied among PEP vectors based on the length of the homology regions, but all were highly transformable and can be integrated simultaneously in strain D39V. Vectors used for pneumococcal cloning are an important tool for researchers for a wide range of uses. The PEP vectors described are of particular use because they have been designed to allow for easy transfer of genes between vectors as well as integrating into transcriptionally silent areas of the chromosome. In addition, we demonstrate the successful production of several new spectrally distinct fluorescent proteins (mTurquoise2, mNeonGreen and mScarlet-I) from the PEP vectors. The PEP vectors and newly described fluorescent proteins will expand the genetic toolbox for pneumococcal researchers and aid future discoveries.
Asunto(s)
Vectores Genéticos/genética , Infecciones Oportunistas/genética , Infecciones Neumocócicas/genética , Streptococcus pneumoniae/genética , Genoma Bacteriano/genética , Humanos , Proteínas Luminiscentes/genética , Infecciones Oportunistas/diagnóstico , Infecciones Oportunistas/microbiología , Plásmidos/genética , Infecciones Neumocócicas/diagnóstico , Infecciones Neumocócicas/microbiología , Regiones Promotoras Genéticas , Streptococcus pneumoniae/aislamiento & purificación , Streptococcus pneumoniae/patogenicidadRESUMEN
Recent discoveries in innate immunity together with improvements in the analysis of the human genome have led to the identification of factors that make certain individuals more susceptible to infections than other. We know understand why herpes simplex virus I, a virus with a minor burden in most individuals, is responsible for devastating encephalitis in children unable to detect primo-infection of neural cells. A growing number of patients are treated with immunosuppressive drugs in the field of oncology, organ transplantation and immunology. In such patients, opportunistic infections such invasive aspergillosis are clearly associated with genetic polymorphisms. Medical immune suppression represents a possible model for personalized approaches, in which infections could be prevented by individualized prophylactic strategies based on genetic testing.
Les progrès de la connaissance du système immunitaire inné et des techniques d'analyse du génome humain ont permis d'identifier des facteurs qui rendent certains individus susceptibles aux agents infectieux. C'est ainsi que l'on comprend depuis quelques années pourquoi le virus de l'herpès simplex I peut causer des encéphalites dévastatrices chez des enfants dont l'immunité est incapable de détecter la primo-infection. De plus en plus de patients subissent des traitements immunosuppresseurs dans le domaine de l'oncologie, des greffes d'organes ou de l'immunologie. Chez ces patients, certaines infections opportunistes, comme l'aspergillose pulmonaire invasive, sont clairement associées à des polymorphismes génétiques. L'immunosuppression Med représente un modèle possible d'infectiologie personnalisée, où les infections pourraient être prévenues par des prophylaxies individualisées, basées sur des tests génétiques.
Asunto(s)
Aspergilosis , Inmunogenética , Infecciones Oportunistas , Aspergilosis/genética , Aspergilosis/inmunología , Aspergilosis/terapia , Niño , Humanos , Inmunidad Innata , Terapia de Inmunosupresión , Infecciones Oportunistas/genética , Infecciones Oportunistas/terapiaRESUMEN
Schizophyllum commune is a well-known mushroom forming fungi which is an edible one due to its nutritive value. It exhibits a special wood degrading mechanism to grow in decay matters by releasing a series of enzymes. These enzymes might make them an opportunistic pathogen which has been reported to infect various animals and human beings too. Although these fungi were identified as human and animal pathogens, their mechanisms of pathogenesis and the key virulence factors involved in disease establishment are not known. In this study, we reported this fungal infection in freshwater fish for the first time and its morphological features. Further, we employed RNA-seq technique to identify the major virulence factors involved in the pathogenesis in fish and the network of interaction between the identified virulence factors were analysed. Also, we confirmed the virulence roles of this fungus during infection by qRT-PCR analysis. This study emphasizes the virulence nature of the common mushroom forming food fungus and the involvement of enzymes such as phosphoinositide phospholipase C, hexosaminidase and few toxins such as pesticidal and insecticidal crystal proteins which opened a new avenue in the virulence nature of edible mushrooms.
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Schizophyllum/genética , Schizophyllum/metabolismo , Animales , Peces/microbiología , Proteínas Fúngicas/genética , Perfilación de la Expresión Génica/métodos , Glicósido Hidrolasas , Micosis/genética , Micosis/patología , Infecciones Oportunistas/genética , Infecciones Oportunistas/metabolismo , Fosfoinositido Fosfolipasa C , Schizophyllum/patogenicidad , Transcriptoma/genética , Virulencia , Factores de Virulencia/metabolismoAsunto(s)
ARN Pequeño no Traducido/fisiología , Staphylococcus aureus/metabolismo , Metabolismo Energético/genética , Regulación Bacteriana de la Expresión Génica , Humanos , Infecciones Oportunistas/genética , Infecciones Oportunistas/metabolismo , Infecciones Oportunistas/microbiología , Staphylococcus aureus/genética , Staphylococcus aureus/patogenicidadRESUMEN
Streptococcus pneumoniae is an opportunistic human pathogen that typically colonizes the nasopharyngeal passage and causes lethal disease in other host niches, such as the lung or the meninges. The expression and regulation of pneumococcal genes at different life-cycle stages, such as commensal or pathogenic, are not entirely understood. To chart the transcriptional responses of S. pneumoniae, we used RNA-seq to quantify the relative abundance of the transcriptome under 22 different infection-relevant conditions. The data demonstrated a high level of dynamic expression and, strikingly, all annotated pneumococcal genomic features were expressed in at least one of the studied conditions. By computing the correlation values of every pair of genes across all studied conditions, we created a co-expression matrix that provides valuable information on both operon structure and regulatory processes. The co-expression data are highly consistent with well-characterized operons and regulons, such as the PyrR, ComE and ComX regulons, and have allowed us to identify a new member of the competence regulon. Lastly, we created an interactive data center named PneumoExpress (https://veeninglab.com/pneumoexpress) that enables users to access the expression data as well as the co-expression matrix in an intuitive and efficient manner, providing a valuable resource to the pneumococcal research community.
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Proteínas Bacterianas/genética , Infecciones Oportunistas/genética , Streptococcus pneumoniae/genética , Transcriptoma/genética , Secuencia de Bases/genética , Regulación Bacteriana de la Expresión Génica/genética , Humanos , Pulmón/microbiología , Pulmón/patología , Meninges/microbiología , Meninges/patología , Nasofaringe/microbiología , Operón/genética , Infecciones Oportunistas/microbiología , Streptococcus pneumoniae/patogenicidadRESUMEN
PURPOSE OF REVIEW: Many genetic conditions predispose affected individuals to opportunistic infections. A number of immunodeficiency diseases, including genetic defects termed Mendelian susceptibility to mycobacterial disease (MSMD), permit infection from many different strains of mycobacteria that would otherwise not cause disease. These include tuberculous and nontuberculous mycobacteria, and bacille Calmette-Guérin vaccine (BCG). Patients may present with infections from other organisms that depend on macrophage function for containment. Defects in multiple genes in the IL-12 and NFKB signaling pathways can cause the MSMD phenotype, some of which include IL12RB1, IL12B, IKBKG, ISG15, IFNGR1, IFNGR2, CYBB, TYK2, IRF8, and STAT1. RECENT FINDINGS: Multiple autosomal recessive and dominant, and 2 X-linked recessive gene defects resulting in the MSMD phenotype have been reported, and others await discovery. This review presents the known gene defects and describes clinical findings that result from the mutations. If MSMD is suspected, a careful clinical history and examination and basic immunodeficiency screening tests will narrow the differential diagnosis. A specific diagnosis requires more sophisticated laboratory investigation. Genetic testing permits a definitive diagnosis, permitting genetic counseling. Mild cases respond well to appropriate antibiotic therapy, whereas severe disease may require hematopoietic stem cell transplantation.
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Predisposición Genética a la Enfermedad , Infecciones por Mycobacterium/genética , Infecciones Oportunistas/genética , Niño , Humanos , Interleucina-12/genética , Infecciones por Mycobacterium/diagnóstico , Infecciones por Mycobacterium/terapia , FN-kappa B/genética , Infecciones Oportunistas/diagnóstico , Infecciones Oportunistas/terapia , RecurrenciaRESUMEN
BACKGROUND: The diagnosis of granulomatous amoebic encephalitis is challenging for clinicians because it is a rare and lethal disease. Previous reports have indicated that Acanthamoeba with some specific genotypes tend to cause the majority of human infections. We report a case of granulomatous amoebic encephalitis caused by Acanthamoeba spp. with genotype T18 in an immunodeficient patient in Japan after allogenic bone marrow transplantation, along with the morphological characteristics and genetic analysis. CASE PRESENTATION: A 52-year old man, who had undergone allogenic bone marrow transplantation, suffered from rapid-growing brain masses in addition to pneumonia and died within 1 month from the onset of the symptoms including fever, headache and disorientation. Infection with Acanthamoeba in the brain and lung was confirmed by histological evaluation; immunohistochemical staining and polymerase chain reaction analysis using autopsy samples also indicated the growth of Acanthamoeba in the brain. Gene sequence analysis indicated that this is the second documented case of infection with Acanthamoeba spp. with genotype T18 in a human host. Postmortem retrospective evaluation of cerebrospinal fluid sample in our case, as well as literature review, indicated that some cases of granulomatous amoebic encephalitis caused by Acanthamoeba may be diagnosable by cerebrospinal fluid examination. CONCLUSION: This case indicates that Acanthamoeba spp. with genotype T18 can also be an important opportunistic pathogen. For pathologists as well as physicians, increased awareness of granulomatous amoebic encephalitis is important for improving the poor prognosis along with the attempt to early diagnosis with cerebrospinal fluid.
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Amebiasis/diagnóstico , Encefalitis Infecciosa/diagnóstico , Infecciones Oportunistas/diagnóstico , Acanthamoeba/genética , Amebiasis/genética , Amebiasis/inmunología , Anemia Aplásica/cirugía , Genotipo , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Huésped Inmunocomprometido , Encefalitis Infecciosa/inmunología , Encefalitis Infecciosa/microbiología , Masculino , Persona de Mediana Edad , Infecciones Oportunistas/genética , Infecciones Oportunistas/inmunologíaAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Infecciones Bacterianas/tratamiento farmacológico , Exantema/tratamiento farmacológico , Inmunoglobulinas Intravenosas/uso terapéutico , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Infecciones Oportunistas/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Corticoesteroides/uso terapéutico , Infecciones Bacterianas/diagnóstico , Infecciones Bacterianas/genética , Infecciones Bacterianas/inmunología , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 4 , Exantema/inducido químicamente , Exantema/genética , Exantema/inmunología , Femenino , Humanos , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Recién Nacido , Metotrexato/efectos adversos , Infecciones Oportunistas/diagnóstico , Infecciones Oportunistas/genética , Infecciones Oportunistas/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Inducción de Remisión , Translocación Genética , Resultado del TratamientoRESUMEN
BACKGROUND: Primary immunodeficiency disorders (PID) include a wide spectrum of inherited disorders characterised by functional abnormalities of one or more components of the immune system. Recent updates from the genomic data have contributed significantly to its better understanding with identification of new entities. Diagnosis is always challenging due to their variable clinical presentation. With the evolution of molecular diagnosis, many of these children are being diagnosed early and offered appropriate therapy. However, in developing countries, early diagnosis is still not being made: as a result these patients succumb to their disease. Autopsy data on PID is notably lacking in the literature with histopathological evaluation of PID being limited to rare case reports. OBJECTIVE: To analyse the clinical, immunologic (including mutational) and morphologic features at autopsy in 10 proven and suspected cases of primary immunodeficiency disorders diagnosed at our Institute over the past decade. METHODS: Study includes a detailed clinico-pathological analysis of 10 proven and suspected cases of primary immunodeficiency disorders. RESULTS: A varied spectrum of infectious and non-infectious complications were identified in these cases of which fungal infections were found to be more frequent compared with viral or bacterial infections. Rare and novel morphological findings, like granulomatous involvement of the heart in a patient with chronic granulomatous disease, systemic amyloidosis in a teenage girl with X-linked agammaglobulinemia, are highlighted which is distinctly lacking in the literature. CONCLUSIONS: The present study is perhaps the first autopsy series on PID. Even in the molecular era, such analysis is still important, as correlation of pathological features with clinical symptoms provides clues for a timely diagnosis and appropriate therapeutic intervention.
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Amiloidosis/patología , Enfermedad Granulomatosa Crónica/patología , Huésped Inmunocomprometido , Síndromes de Inmunodeficiencia/patología , Infecciones Oportunistas/patología , Amiloidosis/genética , Amiloidosis/inmunología , Amiloidosis/mortalidad , Autopsia , Biopsia , Causas de Muerte , Niño , Preescolar , Análisis Mutacional de ADN , Países en Desarrollo , Diagnóstico Precoz , Femenino , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Enfermedad Granulomatosa Crónica/genética , Enfermedad Granulomatosa Crónica/inmunología , Enfermedad Granulomatosa Crónica/mortalidad , Humanos , Inmunohistoquímica , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/mortalidad , India , Lactante , Recién Nacido , Masculino , Mutación , Infecciones Oportunistas/genética , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/mortalidad , Fenotipo , Valor Predictivo de las Pruebas , PronósticoRESUMEN
Staphylococcus xylosus is a commensal bacterium found on the skin and mucosal surfaces of SPF mice. S. xylosus is rarely pathogenic, most often causing skin lesions and dermatitis in immunocompromised mice, particularly those with impaired NADPH oxidase function. Here we report spontaneous infection with S. xylosus in Rag1-/-Tpl2-/- mice. Infection was characterized by the presence of alopecia, crusts, and scaly skin. S. xylosus was detected in the feces, skin, lymph nodes, and lungs of Rag1-/-Tpl2-/- mice and led to mortality or euthanasia due to humane endpoints. C57BL/6 mice were culture-positive for S. xylosus on the skin, and Rag1-/- and Tpl2-/- mice were culture-positive on the skin and occasionally in the feces. However, S. xylosus did not cause clinical symptoms in C57BL/6, Rag1-/-, or Tpl2-/- mice. Compared with those in Rag1-/- mice, relative concentrations of circulating monocytes, but not neutrophils or lymphocytes, were increased in Rag1-/-Tpl2-/- mice, consistent with their increased incidence of clinical symptoms. Overall, this case study suggests a novel role for Tpl2 in T-cell-independent host resistance to the otherwise commensal organism S. xylosus.