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1.
MedComm (2020) ; 4(2): e250, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37009413

RESUMO

Tuberculosis (TB) remains a serious global public health threat. Accumulated evidence has demonstrated that human susceptibility to TB has a strong genetic basis. And different susceptibility single nucleotide polymorphisms (SNP) have been reported in different studies. To gain greater insight into the host susceptibility to TB, we perform a two-stage genome-wide association study to identify the susceptible loci of TB. In the discovery stage, 3116 (1532 TB patients and 1584 healthy controls) and 439 (211 TB patients and 228 healthy controls) individuals were genome-wide genotyped from a western Chinese Han and Tibetan population, respectively. Based on the additive genetic model, we discovered 14 and three independent loci that had potential associations with TB susceptibility in the Chinese Han and Tibetan populations, respectively (p < 1 × 10-5). Furthermore, we conducted an imputation-based meta-analysis on another two East Asia cohorts to replicate our findings. We identified one independent locus harbored by the human leukocyte antigen (HLA) class II genes that was genome-wide significantly associated with TB (lead SNP rs111875628 with a p-value of 2.20 × 10-9). Our findings suggest a novel mechanism of the interaction with the HLA class II genes and reinforce the importance of the HLA class II alleles in response to TB.

2.
Medicine (Baltimore) ; 101(42): e31065, 2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36281118

RESUMO

We aimed to identify long non-coding RNAs (lncRNAs) aberrantly expressed in peripheral blood mononuclear cells (PBMCs) triggered by active tuberculosis (ATB), latent tuberculosis infection (LTBI), and healthy controls (HC). We examined lncRNAs expression in PBMCs isolated from children with ATB and LTBI, and from HC using RNA sequencing. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were used to explore the biological processes and signaling pathways of aberrantly expressed mRNAs. A total of 348 and 205 lncRNAs were differentially expressed in the ATB and LTBI groups, respectively, compared to the HC group. Compared to the LTBI group, 125 lncRNAs were differentially expressed in the ATB group. Compared to the HC group, 2317 mRNAs were differentially expressed in the ATB group, and 1093 mRNAs were differentially expressed in the LTBI group. Compared to the LTBI group, 2328 mRNAs were differentially expressed in the ATB group. The upregulated mRNAs were mainly enriched in neutrophil activation, neutrophil-mediated biological processes, and positive regulation of immune response in tuberculosis (TB), whereas the downregulated mRNAs were enriched in signaling pathways and structural processes, such as the Wnt signaling pathway and rDNA heterochromatin assembly. This is the first study on the differential expression of lncRNAs in PBMCs of children with TB. We identified significant differences in the expression profiles of lncRNAs and mRNAs in the PBMCs of children with ATB, LTBI, and HC, which has important implications for exploring lncRNAs as novel biomarkers for the diagnosis of TB. In addition, further experimental identification and validation of lncRNA roles could help elucidate the underlying mechanisms of Mycobacterium tuberculosis infection in children.


Assuntos
Tuberculose Latente , RNA Longo não Codificante , Tuberculose , Criança , Humanos , RNA Longo não Codificante/metabolismo , Leucócitos Mononucleares/metabolismo , Heterocromatina/metabolismo , Perfilação da Expressão Gênica , Tuberculose/genética , Tuberculose Latente/genética , Tuberculose Latente/diagnóstico , RNA Mensageiro/metabolismo , Biomarcadores/metabolismo , DNA Ribossômico
3.
Front Cell Infect Microbiol ; 11: 726740, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34796125

RESUMO

Background: Streptococcus pneumoniae is an important pathogen causing high morbidity and high mortality in children and undergoes frequent recombination for capsule switching to neutralize the 13-valent pneumococcal conjugate vaccine (PCV13). This study aimed to investigate the prevalence, and molecular characteristics including serotypes and antibiotic susceptibility of S. pneumoniae isolated from children living in Southwest China from 2017 to 2019 to facilitate the selection of effective vaccine formulations and appropriate antibiotic treatment regimens. Methods: This study was conducted at West China Second University Hospital (Chengdu, Sichuan Province, China), Zunyi Medical University Third Affiliated Hospital/First People's Hospital of Zunyi (Zunyi, Guizhou Province, China) and Chengdu Jinjiang District Maternal and Child Healthcare Hospital (Chengdu, Sichuan Province, China). Demographic and clinical characteristics of children infected with S. pneumoniae were collected and analysed. Next-generation sequencing and sequence analysis were used to determine the serotypes, sequence types, antibiotic resistance and potential protein vaccine target genes of the pneumococcal isolates. The coverage rate provided by PCV13 was estimated by calculating the percentage of the specific serotypes that were specifically the PCV13-included serotypes. Antimicrobial susceptibility was determined by the microdilution broth method. Results: The most prevalent pneumococcal serotypes were 19F (25.8%), 19A (14.1%), 6B (12.5%), 6A (9.4%) and 14 (7.8%). The predominant STs were ST271 (23.3%), ST320 (15.5%) and ST90 (8.6%), dominated by the clonal complex Taiwan19F-14 (39.1%). The coverage rate of PCV13 was 77.3% in all the isolates, with relatively higher values in invasive isolates (86.4%). Over the decade, the rates of resistance to penicillin, amoxicillin and cefotaxime were 5.6%, 5.3% and 5.1%, respectively, with significantly higher values in invasive isolates (22.4%, 14.9% and 11.9%). Almost all the isolates were resistant to erythromycin (99.1%) and clindamycin (95.9%). All isolates carried virulence-related genes, including ply, psaA, piaA, piuA, phtE, nanA, pepO, danJ, pvaA, clpP, pcsB, stkP, potD, and strH. The carriage of virulence and resistance genes varied among serotypes and clades, with serotype 19F/ST271 showing higher resistance to antibiotics and being more likely to carry pilus genes and other virulence genes. Conclusion: These data provide valuable information for the understanding of pneumococcal pathogenesis, antimicrobial resistance and the development of protein-based vaccines against pneumococcal infection.


Assuntos
Infecções Pneumocócicas , Streptococcus pneumoniae , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Criança , China/epidemiologia , Humanos , Lactente , Testes de Sensibilidade Microbiana , Tipagem de Sequências Multilocus , Infecções Pneumocócicas/tratamento farmacológico , Infecções Pneumocócicas/epidemiologia , Vacinas Pneumocócicas , Sorogrupo , Streptococcus pneumoniae/genética
4.
Cell Host Microbe ; 29(3): 489-502.e8, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33548198

RESUMO

The SARS-CoV-2 virus, the causative agent of COVID-19, is undergoing constant mutation. Here, we utilized an integrative approach combining epidemiology, virus genome sequencing, clinical phenotyping, and experimental validation to locate mutations of clinical importance. We identified 35 recurrent variants, some of which are associated with clinical phenotypes related to severity. One variant, containing a deletion in the Nsp1-coding region (Δ500-532), was found in more than 20% of our sequenced samples and associates with higher RT-PCR cycle thresholds and lower serum IFN-ß levels of infected patients. Deletion variants in this locus were found in 37 countries worldwide, and viruses isolated from clinical samples or engineered by reverse genetics with related deletions in Nsp1 also induce lower IFN-ß responses in infected Calu-3 cells. Taken together, our virologic surveillance characterizes recurrent genetic diversity and identified mutations in Nsp1 of biological and clinical importance, which collectively may aid molecular diagnostics and drug design.


Assuntos
COVID-19/imunologia , COVID-19/virologia , Interferon Tipo I/imunologia , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Proteínas não Estruturais Virais/genética , Células A549 , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Sequência de Bases , COVID-19/sangue , Linhagem Celular , Criança , Pré-Escolar , Chlorocebus aethiops , Feminino , Deleção de Genes , Genômica , Células HEK293 , Humanos , Lactente , Interferon Tipo I/sangue , Interferon beta/sangue , Interferon beta/metabolismo , Masculino , Pessoa de Meia-Idade , Epidemiologia Molecular , Genética Reversa , Células Vero , Proteínas não Estruturais Virais/imunologia , Adulto Jovem
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