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1.
Res Sq ; 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35313592

RESUMO

SARS-CoV-2 infection leads to a broad range of outcomes and immune responses, with the development of neutralizing antibodies generally correlated with protection against reinfection. Here, we have characterized both neutralizing activity and T cell responses in a cluster of subjects with mild disease linked to a single spreading event. Surprisingly, we observed sex-specific associations between spike- and particularly nucleoprotein-specific T cell responses and neutralization, with pro-inflammatory cytokines being linked to higher titers only in males. Using single cell immunoprofiling, which provided matched transcriptome and T-cell receptor (TCR) profiles in restimulated CD4 + and CD8 + cells from these subjects, we identified differences in type I IFN signaling that may underlie this difference in antibody generation. Finally, we also identified several TCRs associated with cytokine producing T cells. Altogether, our work maps the breadth of immunological outcomes of SARS-CoV2 infections and highlight the potential role of sex-specific feedback loops during the generation of neutralizing antibodies.

2.
J Prim Care Community Health ; 13: 21501319211067349, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34986694

RESUMO

INTRODUCTION: Disorders of serum sodium (SNa) are common in hospitalized patients with COVID-19 and may reflect underlying disease severity. However, the association of SNa with patient-reported outcomes is not clear. METHODS: The Brigham and Women's Hospital COVID-19 Registry is a prospective cohort study of consecutively admitted adult patients with confirmed SARS-CoV-2 infection (n = 809). We examined the associations of SNa (continuous and tertiles) on admission with: (1) patient symptoms obtained from detailed chart review; and (2) in-hospital mortality, length of stay, and intensive care unit (ICU) admission using unadjusted and adjusted logistic regression models. Covariates included demographic data and comorbidities. RESULTS: Mean age was 60 years, 48% were male, and 35% had diabetes. The most frequent symptoms were cough (64%), fever (60%), and shortness of breath (56%). In adjusted models, higher SNa (per mmol/L) was associated with lower odds of GI symptoms (OR 0.96; 95% CI 0.92-0.99), higher odds of confusion (OR 1.08; 95% CI 1.04-1.13), in-hospital mortality (OR 1.06; 95% CI 1.02-1.11), and ICU admission (OR 1.09; 95% CI 1.05-1.13). The highest sodium tertile (compared with the middle tertile) showed similar associations, in addition to lower odds of either anosmia or ageusia (OR 0.30; 95% CI 0.12-0.74). CONCLUSION: In this prospective cohort study of hospitalized patients with COVID-19, hypernatremia was associated with higher odds of confusion and in-hospital mortality. These findings may aid providers in identifying high-risk patients who warrant closer attention, thereby furthering patient-centered approaches to care.


Assuntos
COVID-19 , Adulto , Feminino , Hospitalização , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , SARS-CoV-2 , Sódio
3.
Sci Transl Med ; 13(598)2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34103408

RESUMO

Bacterial sepsis and severe COVID-19 share similar clinical manifestations and are both associated with dysregulation of the myeloid cell compartment. We previously reported an expanded CD14+ monocyte state, MS1, in patients with bacterial sepsis and validated expansion of this cell subpopulation in publicly available transcriptomics data. Here, using published datasets, we show that the gene expression program associated with MS1 correlated with sepsis severity and was up-regulated in monocytes from patients with severe COVID-19. To examine the ontogeny and function of MS1 cells, we developed a cellular model for inducing CD14+ MS1 monocytes from healthy bone marrow hematopoietic stem and progenitor cells (HSPCs). We found that plasma from patients with bacterial sepsis or COVID-19 induced myelopoiesis in HSPCs in vitro and expression of the MS1 gene program in monocytes and neutrophils that differentiated from these HSPCs. Furthermore, we found that plasma concentrations of IL-6, and to a lesser extent IL-10, correlated with increased myeloid cell output from HSPCs in vitro and enhanced expression of the MS1 gene program. We validated the requirement for these two cytokines to induce the MS1 gene program through CRISPR-Cas9 editing of their receptors in HSPCs. Using this cellular model system, we demonstrated that induced MS1 cells were broadly immunosuppressive and showed decreased responsiveness to stimulation with a synthetic RNA analog. Our in vitro study suggests a potential role for systemic cytokines in inducing myelopoiesis during severe bacterial or SARS-CoV-2 infection.


Assuntos
COVID-19 , Transplante de Células-Tronco Hematopoéticas , Sepse , Humanos , Células Mieloides , SARS-CoV-2
4.
bioRxiv ; 2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32908980

RESUMO

A recent estimate suggests that one in five deaths globally are associated with sepsis 1 . To date, no targeted treatment is available for this syndrome, likely due to substantial patient heterogeneity 2,3 and our lack of insight into sepsis immunopathology 4 . These issues are highlighted by the current COVID-19 pandemic, wherein many clinical manifestations of severe SARS-CoV-2 infection parallel bacterial sepsis 5-8 . We previously reported an expanded CD14+ monocyte state, MS1, in patients with bacterial sepsis or non-infectious critical illness, and validated its expansion in sepsis across thousands of patients using public transcriptomic data 9 . Despite its marked expansion in the circulation of bacterial sepsis patients, its relevance to viral sepsis and association with disease outcomes have not been examined. In addition, the ontogeny and function of this monocyte state remain poorly characterized. Using public transcriptomic data, we show that the expression of the MS1 program is associated with sepsis mortality and is up-regulated in monocytes from patients with severe COVID-19. We found that blood plasma from bacterial sepsis or COVID-19 patients with severe disease induces emergency myelopoiesis and expression of the MS1 program, which are dependent on the cytokines IL-6 and IL-10. Finally, we demonstrate that MS1 cells are broadly immunosuppressive, similar to monocytic myeloid-derived suppressor cells (MDSCs), and have decreased responsiveness to stimulation. Our findings highlight the utility of regulatory myeloid cells in sepsis prognosis, and the role of systemic cytokines in inducing emergency myelopoiesis during severe bacterial and SARS-CoV-2 infections.

6.
Nat Med ; 26(5): 705-711, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32284589

RESUMO

Among the most urgent public health threats is the worldwide emergence of carbapenem-resistant Enterobacteriaceae1-4, which are resistant to the antibiotic class of 'last resort'. In the United States and Europe, carbapenem-resistant strains of the Klebsiella pneumoniae ST258 (ref. 5) sequence type are dominant, endemic6-8 and associated with high mortality6,9,10. We report the global evolution of pathogenicity in carbapenem-resistant K. pneumoniae, resulting in the repeated convergence of virulence and carbapenem resistance in the United States and Europe, dating back to as early as 2009. We demonstrate that K. pneumoniae can enhance its pathogenicity by adopting two opposing infection programs through easily acquired gain- and loss-of-function mutations. Single-nucleotide polymorphisms in the capsule biosynthesis gene wzc lead to hypercapsule production, which confers phagocytosis resistance, enhanced dissemination and increased mortality in animal models. In contrast, mutations disrupting capsule biosynthesis genes impair capsule production, which enhances epithelial cell invasion, in vitro biofilm formation and persistence in urinary tract infections. These two types of capsule mutants have emerged repeatedly and independently in Europe and the United States, with hypercapsule mutants associated with bloodstream infections and capsule-deficient mutants associated with urinary tract infections. In the latter case, drug-tolerant K. pneumoniae can persist to yield potentially untreatable, persistent infection.


Assuntos
Adaptação Biológica/genética , Enterobacteriáceas Resistentes a Carbapenêmicos/genética , Evolução Molecular , Klebsiella pneumoniae/genética , Virulência/genética , Resistência beta-Lactâmica/genética , Adulto , Animais , Cápsulas Bacterianas/genética , Enterobacteriáceas Resistentes a Carbapenêmicos/classificação , Enterobacteriáceas Resistentes a Carbapenêmicos/isolamento & purificação , Enterobacteriáceas Resistentes a Carbapenêmicos/patogenicidade , Carbapenêmicos/uso terapêutico , Células Cultivadas , Feminino , Genoma Bacteriano , Humanos , Infecções por Klebsiella/microbiologia , Infecções por Klebsiella/urina , Klebsiella pneumoniae/classificação , Klebsiella pneumoniae/isolamento & purificação , Klebsiella pneumoniae/patogenicidade , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Transgênicos , Filogenia , Polimorfismo de Nucleotídeo Único , Infecções Urinárias/microbiologia , Infecções Urinárias/urina , Peixe-Zebra
7.
Nat Biomed Eng ; 3(12): 961-973, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31712645

RESUMO

Dysregulated leukocyte responses underlie the pathobiology of sepsis, which is a leading cause of death. However, measures of leukocyte function are not routinely available in clinical care. Here we report the development and testing of an inertial microfluidic system for the label-free isolation and downstream functional assessment of leukocytes from 50 µl of peripheral blood. We used the system to assess leukocyte phenotype and function in serial samples from 18 hospitalized patients with sepsis and 10 healthy subjects. The sepsis samples had significantly higher levels of CD16dim and CD16- neutrophils and CD16+ 'intermediate' monocytes, as well as significantly lower levels of neutrophil-elastase release, O2- production and phagolysosome formation. Repeated sampling of sepsis patients over 7 days showed that leukocyte activation (measured by isodielectric separation) and leukocyte phenotype and function were significantly more predictive of the clinical course than complete-blood-count parameters. We conclude that the serial assessment of leukocyte function in microlitre blood volumes is feasible and that it provides significantly more prognostic information than leukocyte counting.


Assuntos
Leucócitos , Técnicas Analíticas Microfluídicas/métodos , Sepse/sangue , Sepse/diagnóstico , Índice de Gravidade de Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Proteínas Ligadas por GPI , Humanos , Contagem de Leucócitos , Elastase de Leucócito/sangue , Masculino , Técnicas Analíticas Microfluídicas/instrumentação , Pessoa de Meia-Idade , Monócitos , Neutrófilos , Fenótipo , Receptores de IgG , Adulto Jovem
8.
Sci Rep ; 9(1): 4516, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30872641

RESUMO

Rapid bacterial identification remains a critical challenge in infectious disease diagnostics. We developed a novel molecular approach to detect and identify a wide diversity of bacterial pathogens in a single, simple assay, exploiting the conservation, abundance, and rich phylogenetic content of ribosomal RNA in a rapid fluorescent hybridization assay that requires no amplification or enzymology. Of 117 isolates from 64 species across 4 phyla, this assay identified bacteria with >89% accuracy at the species level and 100% accuracy at the family level, enabling all critical clinical distinctions. In pilot studies on primary clinical specimens, including sputum, blood cultures, and pus, bacteria from 5 different phyla were identified.


Assuntos
Bactérias/classificação , Hibridização de Ácido Nucleico/métodos , RNA Ribossômico 16S/genética , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/patogenicidade , Mycobacterium/classificação , Mycobacterium/genética , Mycobacterium/isolamento & purificação , Mycobacterium/patogenicidade , Filogenia , Staphylococcus aureus/classificação , Staphylococcus aureus/genética , Staphylococcus aureus/isolamento & purificação , Staphylococcus aureus/patogenicidade
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