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1.
Proc Natl Acad Sci U S A ; 115(48): E11264-E11273, 2018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-30420518

RESUMO

Chronically undernourished children become stunted during their first 2 years and thereafter bear burdens of ill health for the rest of their lives. Contributors to stunting include poor nutrition and exposure to pathogens, and parental history may also play a role. However, the epigenetic impact of a poor environment on young children is largely unknown. Here we show the unfolding pattern of histone H3 lysine 4 trimethylation (H3K4me3) in children and mothers living in an urban slum in Dhaka, Bangladesh. A pattern of chromatin modification in blood cells of stunted children emerges over time and involves a global decrease in methylation at canonical locations near gene start sites and increased methylation at ectopic sites throughout the genome. This redistribution occurs at metabolic and immune genes and was specific for H3K4me3, as it was not observed for histone H3 lysine 27 acetylation in the same samples. Methylation changes in stunting globally resemble changes that occur in vitro in response to altered methylation capacity, suggesting that reduced levels of one-carbon nutrients in the diet play a key role in stunting in this population. A network of differentially expressed genes in stunted children reveals effects on chromatin modification machinery, including turnover of H3K4me3, as well as posttranscriptional gene regulation affecting immune response pathways and lipid metabolism. Consistent with these changes, reduced expression of the endocytic receptor gene LDL receptor 1 (LRP1) is a driver of stunting in a mouse model, suggesting a target for intervention.


Assuntos
Histonas/genética , Desnutrição/genética , Animais , Epigênese Genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Desnutrição/metabolismo , Metilação , Camundongos
2.
J Infect Dis ; 210(2): 171-82, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24436449

RESUMO

BACKGROUND: Rotavirus causes 500 000 deaths and millions of physician visits and hospitalizations per year, with worse outcomes and reduced vaccine efficacy in developing countries. We hypothesized that the gut microbiota might modulate rotavirus infection and/or antibody response and thus potentially play a role in such regional differences. METHODS: The microbiota was ablated via germ-free or antibiotic approaches. Enhanced exposure to microbiota was achieved via low-dose dextran sodium sulfate (DSS) treatment. Rotavirus infection and replication was assessed by enzyme-linked immunosorbent assay (ELISA) and quantitative reverse-transcription polymerase chain reaction. Diarrhea was scored visually. Humoral responses to rotavirus were measured by ELISA and enzyme-linked immunosorbent spot assay. RESULTS: Microbiota elimination delayed infection and reduced infectivity by 42%. Antibiotics did not alter ratios of positive-sense to negative-sense strands, suggesting that entry rather than replication was influenced. Antibiotics reduced the diarrhea incidence and duration, indicating that the reduction in the level of rotavirus antigen was biologically significant. Despite lowered antigen level, antibiotics resulted in a more durable rotavirus mucosal/systemic humoral response. Increased rotavirus antibody response durability correlated with increased small intestinal rotavirus-specific, immunoglobulin A-producing antibody-secreting cell concentration in antibiotic-treated mice. Conversely, DSS treatment impaired generation of rotavirus-specific antibodies. CONCLUSIONS: Microbiota ablation resulted in reduced rotavirus infection/diarrhea and a more durable rotavirus antibody response, suggesting that antibiotic administration before rotavirus vaccination could raise low seroconversion rates that correlate with the vaccine's inefficacy in developing regions.


Assuntos
Antibacterianos/administração & dosagem , Anticorpos Antivirais/sangue , Diarreia/imunologia , Imunidade Humoral , Infecções por Rotavirus/imunologia , Animais , Diarreia/patologia , Diarreia/virologia , Ensaio de Imunoadsorção Enzimática , Feminino , Trato Gastrointestinal/virologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rotavirus/isolamento & purificação , Infecções por Rotavirus/patologia , Infecções por Rotavirus/virologia , Carga Viral
3.
J Clin Virol ; 133: 104681, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33160178

RESUMO

In 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic. Disease diagnosis, appropriate clinical management and infection control are all important factors in controlling the spread of SARS-CoV-2. The QIAreach™ Anti-SARS-CoV-2 Total Test (Anti-CoV2) is a rapid, qualitative serological test, using proprietary nanoparticle fluorescence technology to detect total antibody (IgA, IgM, and IgG) against SARS-CoV-2. Here we report the results of the US Food and Drug Administration (FDA) clinical agreement study. Thirty positive plasma or serum samples were taken from consenting individuals with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection ≥14 days from symptom onset. Seventy-five samples from before the believed circulation of SARS-CoV-2 (November 1, 2019) were used to assess specificity. Positive percent agreement (PPA) and negative percent agreement (NPA) were calculated along with the corresponding exact two-sided 95 % confidence intervals (CI) using an FDA Emergency Use Authorized PCR test as the reference method. Anti-CoV2 was shown to have 100 % sensitivity (PPA; 95 % CI 88.4-100 %) and 100 % specificity (NPA; 95 % CI 95.2-100 %). Against 157 pre-pandemic samples, no cross-reactivity was observed with seasonal coronaviruses or other respiratory pathogens tested. Additionally, no interference was observed when samples were spiked with: conjugated bilirubin 0.4 mg/ml; unconjugated bilirubin 0.4 mg/ml; hemoglobin 5 mg/ml; prednisolone 0.12 mg/ml; triglycerides 15 mg/ml. In conclusion, Anti-CoV2 provides accurate qualitative detection of total antibodies against SARS-CoV-2.


Assuntos
Anticorpos Antivirais/sangue , Teste Sorológico para COVID-19/métodos , COVID-19/diagnóstico , Fluorescência , Nanopartículas , Tecnologia Digital , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Sensibilidade e Especificidade , Estados Unidos , United States Food and Drug Administration/legislação & jurisprudência
4.
Innate Immun ; 21(4): 416-28, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25213347

RESUMO

Rotavirus (RV) infects small intestinal epithelial cells, inducing severe diarrhea in children, resulting in over 500,000 deaths annually. Relatively little is known about how innate immunity contains acute infection and drives adaptive immune responses that afford complete clearance of RV and protection against future infection. Hence, we examined the consequence of the absence of MyD88, known to be central to innate immunity, in a mouse model of RV infection. The absence of MyD88, but not combined blockade of IL-1ß and IL-18 signaling, resulted in greater infectivity, as reflected by levels of RV in feces, intestinal lysates and viremia. Such increased RV levels correlated with an increase in incidence and duration of diarrhea. Loss of MyD88 also impaired humoral immunity to RV. Specifically, MyD88 knockout generated less RV-specific IgA and exhibited profoundly reduced RV-specific IgG2c/IgG1 ratios suggesting that MyD88 signaling drives RV-induced Th1 responses. A study of MyD88 bone marrow chimeras indicated that MyD88-dependent control of acute RV infection was mediated by both hemopoietic and non-hemopoietic cells, while generation of RV-specific humoral immunity was driven by MyD88 signaling in hemopoietic cells, which reflected the loss of IL-1ß and IL-18 expression by these cells. Thus, TLR signaling and inflammasome cytokines drive innate and adaptive immunity to RV.


Assuntos
Inflamassomos/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Infecções por Rotavirus/imunologia , Rotavirus/imunologia , Doença Aguda , Animais , Formação de Anticorpos/genética , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Imunidade Inata/genética , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Transdução de Sinais/genética , Receptores Toll-Like/metabolismo , Quimeras de Transplante , Carga Viral/genética
5.
Science ; 346(6211): 861-5, 2014 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-25395539

RESUMO

Activators of innate immunity may have the potential to combat a broad range of infectious agents. We report that treatment with bacterial flagellin prevented rotavirus (RV) infection in mice and cured chronically RV-infected mice. Protection was independent of adaptive immunity and interferon (IFN, type I and II) and required flagellin receptors Toll-like receptor 5 (TLR5) and NOD-like receptor C4 (NLRC4). Flagellin-induced activation of TLR5 on dendritic cells elicited production of the cytokine interleukin-22 (IL-22), which induced a protective gene expression program in intestinal epithelial cells. Flagellin also induced NLRC4-dependent production of IL-18 and immediate elimination of RV-infected cells. Administration of IL-22 and IL-18 to mice fully recapitulated the capacity of flagellin to prevent or eliminate RV infection and thus holds promise as a broad-spectrum antiviral agent.


Assuntos
Flagelina/administração & dosagem , Imunidade Inata , Interleucina-18/imunologia , Interleucinas/imunologia , Infecções por Rotavirus/prevenção & controle , Receptor 5 Toll-Like/fisiologia , Animais , Diarreia/imunologia , Diarreia/terapia , Diarreia/virologia , Modelos Animais de Doenças , Fezes/virologia , Flagelina/imunologia , Proteínas de Homeodomínio/genética , Interleucina-18/administração & dosagem , Interleucina-18/genética , Interleucinas/administração & dosagem , Interleucinas/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Mutação , Infecções por Rotavirus/imunologia , Infecções por Rotavirus/terapia , Receptor 5 Toll-Like/genética , Eliminação de Partículas Virais , Interleucina 22
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