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1.
MBio ; 10(3)2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088926

RESUMO

In this study, we examined the relationships between anti-influenza virus serum antibody titers, clinical disease, and peripheral blood leukocyte (PBL) global gene expression during presymptomatic, acute, and convalescent illness in 83 participants infected with 2009 pandemic H1N1 virus in a human influenza challenge model. Using traditional statistical and logistic regression modeling approaches, profiles of differentially expressed genes that correlated with active viral shedding, predicted length of viral shedding, and predicted illness severity were identified. These analyses further demonstrated that challenge participants fell into three peripheral blood leukocyte gene expression phenotypes that significantly correlated with different clinical outcomes and prechallenge serum titers of antibodies specific for the viral neuraminidase, hemagglutinin head, and hemagglutinin stalk. Higher prechallenge serum antibody titers were inversely correlated with leukocyte responsiveness in participants with active disease and could mask expression of peripheral blood markers of clinical disease in some participants, including viral shedding and symptom severity. Consequently, preexisting anti-influenza antibodies may modulate PBL gene expression, and this must be taken into consideration in the development and interpretation of peripheral blood diagnostic and prognostic assays of influenza infection.IMPORTANCE Influenza A viruses are significant human pathogens that caused 83,000 deaths in the United States during 2017 to 2018, and there is need to understand the molecular correlates of illness and to identify prognostic markers of viral infection, symptom severity, and disease course. Preexisting antibodies against viral neuraminidase (NA) and hemagglutinin (HA) proteins play a critical role in lessening disease severity. We performed global gene expression profiling of peripheral blood leukocytes collected during acute and convalescent phases from a large cohort of people infected with A/H1N1pdm virus. Using statistical and machine-learning approaches, populations of genes were identified early in infection that correlated with active viral shedding, predicted length of shedding, or disease severity. Finally, these gene expression responses were differentially affected by increased levels of preexisting influenza antibodies, which could mask detection of these markers of contagiousness and disease severity in people with active clinical disease.


Assuntos
Anticorpos Antivirais/sangue , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Influenza Humana/imunologia , Leucócitos/imunologia , Neuraminidase/imunologia , Doença Aguda , Adolescente , Adulto , Convalescença , Proteção Cruzada , Feminino , Perfilação da Expressão Gênica , Voluntários Saudáveis , Testes de Inibição da Hemaglutinação , Experimentação Humana , Humanos , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/sangue , Masculino , Pessoa de Meia-Idade , Eliminação de Partículas Virais , Adulto Jovem
2.
J Cell Mol Med ; 22(5): 2760-2773, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29516617

RESUMO

Preterm birth (PTB) can lead to lifelong complications and challenges. Identifying and monitoring molecular signals in easily accessible biological samples that can diagnose or predict the risk of preterm labour (PTL) in pregnant women will reduce or prevent PTBs. A number of studies identified putative biomarkers for PTL including protein, miRNA and hormones from various body fluids. However, biomarkers identified from these studies usually lack consistency and reproducibility. Extracellular vesicles (EVs) in circulation have gained significant interest in recent years as these vesicles may be involved in cell-cell communication. We have used an improved small RNA library construction protocol and a newly developed size exclusion chromatography (SEC)-based EV purification method to gain a comprehensive view of circulating RNA in plasma and its distribution by analysing RNAs in whole plasma and EV-associated and EV-depleted plasma. We identified a number of miRNAs in EVs that can be used as biomarkers for PTL, and these miRNAs may reflect the pathological changes of the placenta during the development of PTL. To our knowledge, this is the first study to report a comprehensive picture of circulating RNA, including RNA in whole plasma, EV and EV-depleted plasma, in PTL and reveal the usefulness of EV-associated RNAs in disease diagnosis.

3.
Nucleic Acids Res ; 45(21): 12140-12151, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29069500

RESUMO

Although many tools have been developed to analyze small RNA sequencing (sRNA-Seq) data, it remains challenging to accurately analyze the small RNA population, mainly due to multiple sequence ID assignment caused by short read length. Additional issues in small RNA analysis include low consistency of microRNA (miRNA) measurement results across different platforms, miRNA mapping associated with miRNA sequence variation (isomiR) and RNA editing, and the origin of those unmapped reads after screening against all endogenous reference sequence databases. To address these issues, we built a comprehensive and customizable sRNA-Seq data analysis pipeline-sRNAnalyzer, which enables: (i) comprehensive miRNA profiling strategies to better handle isomiRs and summarization based on each nucleotide position to detect potential SNPs in miRNAs, (ii) different sequence mapping result assignment approaches to simulate results from microarray/qRT-PCR platforms and a local probabilistic model to assign mapping results to the most-likely IDs, (iii) comprehensive ribosomal RNA filtering for accurate mapping of exogenous RNAs and summarization based on taxonomy annotation. We evaluated our pipeline on both artificial samples (including synthetic miRNA and Escherichia coli cultures) and biological samples (human tissue and plasma). sRNAnalyzer is implemented in Perl and available at: http://srnanalyzer.systemsbiology.net/.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , MicroRNAs/química , Análise de Sequência de RNA/métodos , Escherichia coli/genética , Perfilação da Expressão Gênica , Humanos , MicroRNAs/sangue , MicroRNAs/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , RNA Bacteriano/química , RNA Bacteriano/metabolismo , Pequeno RNA não Traduzido/química , Pequeno RNA não Traduzido/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Software
4.
Sci Transl Med ; 9(385)2017 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-28404864

RESUMO

The 2013-2015 outbreak of Ebola virus disease in Guinea, Liberia, and Sierra Leone was unprecedented in the number of documented cases, but there have been few published reports on immune responses in clinical cases and their relationships with the course of illness and severity of Ebola virus disease. Symptoms of Ebola virus disease can include severe headache, myalgia, asthenia, fever, fatigue, diarrhea, vomiting, abdominal pain, and hemorrhage. Although experimental treatments are in development, there are no current U.S. Food and Drug Administration-approved vaccines or therapies. We report a detailed study of host gene expression as measured by microarray in daily peripheral blood samples collected from a patient with severe Ebola virus disease. This individual was provided with supportive care without experimental therapies at the National Institutes of Health Clinical Center from before onset of critical illness to recovery. Pearson analysis of daily gene expression signatures revealed marked gene expression changes in peripheral blood leukocytes that correlated with changes in serum and peripheral blood leukocytes, viral load, antibody responses, coagulopathy, multiple organ dysfunction, and then recovery. This study revealed marked shifts in immune and antiviral responses that preceded changes in medical condition, indicating that clearance of replicating Ebola virus from peripheral blood leukocytes is likely important for systemic viral clearance.


Assuntos
Ebolavirus/patogenicidade , Doença pelo Vírus Ebola/virologia , Leucócitos/metabolismo , Surtos de Doenças , Doença pelo Vírus Ebola/sangue , Humanos , Estudos Longitudinais , RNA Viral/sangue , RNA Viral/genética , Replicação Viral/fisiologia
5.
Hum Mol Genet ; 26(5): 913-922, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28334820

RESUMO

Huntington's disease is a dominantly inherited neurodegenerative disease caused by the expansion of a CAG repeat in the HTT gene. In addition to the length of the CAG expansion, factors such as genetic background have been shown to contribute to the age at onset of neurological symptoms. A central challenge in understanding the disease progression that leads from the HD mutation to massive cell death in the striatum is the ability to characterize the subtle and early functional consequences of the CAG expansion longitudinally. We used dense time course sampling between 4 and 20 postnatal weeks to characterize early transcriptomic, molecular and cellular phenotypes in the striatum of six distinct knock-in mouse models of the HD mutation. We studied the effects of the HttQ111 allele on the C57BL/6J, CD-1, FVB/NCr1, and 129S2/SvPasCrl genetic backgrounds, and of two additional alleles, HttQ92 and HttQ50, on the C57BL/6J background. We describe the emergence of a transcriptomic signature in HttQ111/+ mice involving hundreds of differentially expressed genes and changes in diverse molecular pathways. We also show that this time course spanned the onset of mutant huntingtin nuclear localization phenotypes and somatic CAG-length instability in the striatum. Genetic background strongly influenced the magnitude and age at onset of these effects. This work provides a foundation for understanding the earliest transcriptional and molecular changes contributing to HD pathogenesis.


Assuntos
Corpo Estriado/metabolismo , Proteína Huntingtina/genética , Doença de Huntington/genética , Expansão das Repetições de Trinucleotídeos/genética , Animais , Corpo Estriado/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Introdução de Genes , Patrimônio Genético , Instabilidade Genômica/genética , Humanos , Proteína Huntingtina/biossíntese , Doença de Huntington/patologia , Camundongos , Mutação/genética , Neurônios/metabolismo , Neurônios/patologia , Fenótipo , Transcriptoma/genética
6.
Mol Diagn Ther ; 21(3): 259-268, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28039578

RESUMO

Circulating RNAs, especially microRNAs (miRNAs), have recently emerged as non-invasive disease biomarkers. Despite enthusiasm and numerous reports on disease-associated circulating miRNAs, currently there is no circulating miRNA-based diagnostic in use. In addition, there are many contradictory reports on the concentration changes of specific miRNA in circulation. Here we review the impact of various technical and non-technical factors related to circulating miRNA measurement and elucidate the importance of having a general guideline for sample preparation and concentration measurement in studying circulating RNA.


Assuntos
Ácidos Nucleicos Livres/análise , Marcadores Genéticos , Sequenciamento de Nucleotídeos em Larga Escala/normas , Biomarcadores Tumorais/genética , Plaquetas , Ácidos Nucleicos Livres/isolamento & purificação , Dieta , Exercício , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , MicroRNAs/genética , Reação em Cadeia da Polimerase/métodos , Reação em Cadeia da Polimerase/normas , Manejo de Espécimes/normas , Fatores de Tempo
7.
Ann Hum Genet ; 80(5): 247-56, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27402348

RESUMO

Human life expectancy is influenced not only by longevity assurance mechanisms and disease susceptibility loci but also by the environment, gene-environment interactions, and chance. MicroRNAs (miRNAs) are a class of small noncoding RNAs closely related to genes. Circulating miRNAs have been shown as promising noninvasive biomarkers in the development of many pathophysiological conditions. However, the concentration of miRNA in the circulation may also be affected by environmental factors. We used a next-generation sequencing platform to assess the association of circulating miRNA with life expectancy, for which deaths are due to all causes independent of genes. In addition, we showed that miRNAs are present in 41-year archived plasma samples, which may be useful for both life expectancy and all-cause mortality risk assessment. Plasma miRNAs from nine identical male twins were profiled using next-generation sequencing. The average absolute difference in the minimum life expectancy was 9.68 years. Intraclass correlation coefficients were above 0.4 for 50% of miRNAs. Comparing deceased twins with their alive co-twin brothers, the concentrations were increased for 34 but decreased for 30 miRNAs. Identical twins discordant in life expectancy were dissimilar in the majority of miRNAs, suggesting that environmental factors are pivotal in miRNAs related to life expectancy.


Assuntos
Expectativa de Vida , MicroRNAs/sangue , Gêmeos Monozigóticos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Mortalidade
8.
MBio ; 5(6): e02116, 2014 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-25406382

RESUMO

UNLABELLED: Zoonotic avian influenza virus infections may lead to epidemics or pandemics. The 1918 pandemic influenza virus has an avian influenza virus-like genome, and its H1 hemagglutinin was identified as a key mammalian virulence factor. A chimeric 1918 virus expressing a contemporary avian H1 hemagglutinin, however, displayed murine pathogenicity indistinguishable from that of the 1918 virus. Here, isogenic chimeric avian influenza viruses were constructed on an avian influenza virus backbone, differing only by hemagglutinin subtype expressed. Viruses expressing the avian H1, H6, H7, H10, and H15 subtypes were pathogenic in mice and cytopathic in normal human bronchial epithelial cells, in contrast to H2-, H3-, H5-, H9-, H11-, H13-, H14-, and H16-expressing viruses. Mouse pathogenicity was associated with pulmonary macrophage and neutrophil recruitment. These data suggest that avian influenza virus hemagglutinins H1, H6, H7, H10, and H15 contain inherent mammalian virulence factors and likely share a key virulence property of the 1918 virus. Consequently, zoonotic infections with avian influenza viruses bearing one of these hemagglutinins may cause enhanced disease in mammals. IMPORTANCE: Influenza viruses from birds can cause outbreaks in humans and may contribute to the development of pandemics. The 1918 pandemic influenza virus has an avian influenza virus-like genome, and its main surface protein, an H1 subtype hemagglutinin, was identified as a key mammalian virulence factor. In a previous study, a 1918 virus expressing an avian H1 gene was as virulent in mice as the reconstructed 1918 virus. Here, a set of avian influenza viruses was constructed, differing only by hemagglutinin subtype. Viruses with the avian H1, H6, H7, H10, and H15 subtypes caused severe disease in mice and damaged human lung cells. Consequently, infections with avian influenza viruses bearing one of these hemagglutinins may cause enhanced disease in mammals, and therefore surveillance for human infections with these subtypes may be important in controlling future outbreaks.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Vírus da Influenza A/crescimento & desenvolvimento , Influenza Aviária/virologia , Fatores de Virulência/metabolismo , Animais , Aves , Efeito Citopatogênico Viral , Modelos Animais de Doenças , Células Epiteliais/virologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Humanos , Vírus da Influenza A/genética , Vírus da Influenza A/patogenicidade , Pulmão/imunologia , Pulmão/patologia , Macrófagos/imunologia , Mamíferos , Camundongos , Neutrófilos/imunologia , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Vírus Reordenados/genética , Vírus Reordenados/crescimento & desenvolvimento , Vírus Reordenados/patogenicidade , Genética Reversa , Fatores de Virulência/genética
9.
Proc Natl Acad Sci U S A ; 111(8): 3188-93, 2014 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-24516145

RESUMO

Posttraumatic stress disorder (PTSD) is a common condition induced by life-threatening stress, such as that experienced by soldiers under battlefield conditions. Other than the commonly recognized behavioral and psychological dysfunction, epidemiological studies have also revealed that PTSD patients have a higher risk of other diseases, such as cardiovascular disorders. Using a PTSD mouse model, we investigated the longitudinal transcriptomic changes in heart tissues after the exposure to stress through intimidation. Our results revealed acute heart injury associated with the traumatic experience, reflecting the underlying biological injury processes of the immune response, extracellular matrix remodeling, epithelial-to-mesenchymal cell transitions, and cell proliferation. Whether this type of injury has any long-term effects on heart function is yet to be determined. The differing responses to stress leading to acute heart injury in different inbred strains of mice also suggest that this response has a genetic as well as an environmental component. Accordingly, the results from this study suggest a molecular basis for the observed higher risk of cardiovascular disorders in PTSD patients, which raises the likelihood of cardiac dysfunction induced by long-term stress exposures.


Assuntos
Regulação da Expressão Gênica/fisiologia , Miocardite/etiologia , Miocardite/metabolismo , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Estresse Psicológico/complicações , Transcriptoma/fisiologia , Animais , Linhagem Celular , Proliferação de Células , Transição Epitelial-Mesenquimal/fisiologia , Matriz Extracelular/fisiologia , Perfilação da Expressão Gênica , Humanos , Estudos Longitudinais , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Análise em Microsséries , Transtornos de Estresse Pós-Traumáticos/etiologia , Estresse Psicológico/imunologia , Biologia de Sistemas
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