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A blood RNA signature for tuberculosis disease risk: a prospective cohort study

ABSTRACT: Identification of blood biomarkers that prospectively predict progression of Mycobacterium tuberculosis infection to tuberculosis disease might lead to interventions that combat the tuberculosis epidemic. We aimed to assess whether global gene expression measured in whole blood of healthy people allowed identification of prospective signatures of risk of active tuberculosis disease. RESULTS:Between July 6, 2005, and April 23, 2007, we enrolled 6363 from the ACS study and 4466 from independent South African and Gambian cohorts. 46 progressors and 107 matched controls were identified in the ACS cohort. A 16 gene signature of risk was identified. The signature predicted tuberculosis progression with a sensitivity of 66·1% (95% CI 63·2–68·9) and a specificity of 80·6% (79·2–82·0) in the 12 months preceding tuberculosis diagnosis. The risk signature was validated in an untouched group of adolescents (p=0·018 for RNA sequencing and p=0·0095 for qRT-PCR) and in the independent South African and Gambian cohorts (p values <0·0001 by qRT-PCR) with a sensitivity of 53·7% (42·6–64·3) and a specificity of 82·8% (76·7–86) in 12 months preceding tuberculosis. Interpretation: The whole blood tuberculosis risk signature prospectively identified people at risk of developing active tuberculosis, opening the possibility for targeted intervention to prevent the disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE79362 | GEO | 2016/03/22

SECONDARY ACCESSION(S): PRJNA315611

REPOSITORIES: GEO

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Project description:Identification of blood biomarkers that prospectively predict progression of Mycobacterium tuberculosis infection to tuberculosis disease might lead to interventions that combat the tuberculosis epidemic. We aimed to assess whether global gene expression measured in whole blood of healthy people allowed identification of prospective signatures of risk of active tuberculosis disease. RESULTS:Between July 6, 2005, and April 23, 2007, we enrolled 6363 from the ACS study and 4466 from independent South African and Gambian cohorts. 46 progressors and 107 matched controls were identified in the ACS cohort. A 16 gene signature of risk was identified. The signature predicted tuberculosis progression with a sensitivity of 66Â·1% (95% CI 63Â·2â68Â·9) and a specificity of 80Â·6% (79Â·2â82Â·0) in the 12 months preceding tuberculosis diagnosis. The risk signature was validated in an untouched group of adolescents (p=0Â·018 for RNA sequencing and p=0Â·0095 for qRT-PCR) and in the independent South African and Gambian cohorts (p values <0Â·0001 by qRT-PCR) with a sensitivity of 53Â·7% (42Â·6â64Â·3) and a specificity of 82Â·8% (76Â·7â86) in 12 months preceding tuberculosis. Interpretation: The whole blood tuberculosis risk signature prospectively identified people at risk of developing active tuberculosis, opening the possibility for targeted intervention to prevent the disease. In this prospective cohort study, we followed up healthy, South African adolescents aged 12â18 years from the adolescent cohort study (ACS) who were infected with M tuberculosis for 2 years. We collected blood samples from study participants every 6 months and monitored the adolescents for progression to tuberculosis disease. A prospective signature of risk was derived from whole blood RNA sequencing data by comparing participants who developed active tuberculosis disease (progressors) with those who remained healthy (matched controls). After adaptation to multiplex qRT-PCR, the signature was used to predict tuberculosis disease in untouched adolescent samples and in samples from independent cohorts of South African and Gambian adult progressors and controls. Participants of the independent cohorts were household contacts of adults with active pulmonary tuberculosis disease.

Project description:Background. The bacterial foodborne pathogen Campylobacter jejuni is a common cause of acute gastroenteritis and is also associated with the postinfectious neuropathies, Guillain-Barré and Miller Fisher syndromes. This study described the use of multilocus sequence typing and DNA microarrays to examine the genetic content of a collection of South African C. jejuni strains, recovered from patients with enteritis, Guillain-Barré or Miller Fisher syndromes. Methodology/Principal Findings. The comparative genomic analysis by using multilocus sequence typing and DNA microarrays demonstrated that the South African strains with Penner heat-stable (HS) serotype HS:41 were clearly distinct from the other South African strains. Further analysis of the DNA microarray data demonstrated that the serotype HS:41 strains from South African GBS and enteritis patients are highly similar in gene content. Interestingly, the South African HS:41 strains were distinct in gene content when compared to serotype HS:41 strains from other geographical locations due to the presence of genomic islands, referred to as Campylobacter jejuni integrated elements. Only the genomic integrated element CJIE1, a Campylobacter Mu-like prophage, was present in the South African HS:41 strains whereas absent in the closely-related HS:41 strains from Mexico. A more distantly-related HS:41 strain from Canada possessed both genomic integrated elements CJIE1 and CJIE2. Conclusion/Significance. These findings demonstrated that these C. jejuni integrated elements may contribute to the differentiation of closely-related C. jejuni strains. In addition, the presence of bacteriophage-related genes in CJIE1 may probably contribute to increasing the genomic diversity of these C. jejuni strains. This comparative genomic analysis of the foodborne pathogen C. jejuni provides fundamental information that potentially could lead to improved methods for analyzing the epidemiology of disease outbreaks and their sources. Keywords: comparative genomic indexing analysis

Project description:Background. The bacterial foodborne pathogen Campylobacter jejuni is a common cause of acute gastroenteritis and is also associated with the postinfectious neuropathies, Guillain-BarrÃ© and Miller Fisher syndromes. This study described the use of multilocus sequence typing and DNA microarrays to examine the genetic content of a collection of South African C. jejuni strains, recovered from patients with enteritis, Guillain-BarrÃ© or Miller Fisher syndromes. Methodology/Principal Findings. The comparative genomic analysis by using multilocus sequence typing and DNA microarrays demonstrated that the South African strains with Penner heat-stable (HS) serotype HS:41 were clearly distinct from the other South African strains. Further analysis of the DNA microarray data demonstrated that the serotype HS:41 strains from South African GBS and enteritis patients are highly similar in gene content. Interestingly, the South African HS:41 strains were distinct in gene content when compared to serotype HS:41 strains from other geographical locations due to the presence of genomic islands, referred to as Campylobacter jejuni integrated elements. Only the genomic integrated element CJIE1, a Campylobacter Mu-like prophage, was present in the South African HS:41 strains whereas absent in the closely-related HS:41 strains from Mexico. A more distantly-related HS:41 strain from Canada possessed both genomic integrated elements CJIE1 and CJIE2. Conclusion/Significance. These findings demonstrated that these C. jejuni integrated elements may contribute to the differentiation of closely-related C. jejuni strains. In addition, the presence of bacteriophage-related genes in CJIE1 may probably contribute to increasing the genomic diversity of these C. jejuni strains. This comparative genomic analysis of the foodborne pathogen C. jejuni provides fundamental information that potentially could lead to improved methods for analyzing the epidemiology of disease outbreaks and their sources. The genomic diversity of 33 South African, 2 Mexican and 1 Canadian Campylobacter jejuni strains from humans were examined by microarray-based comparative genomic indexing (CGI) analysis. The CGI analysis allowed the assessment of CDS content for each C. jejuni strain relative to the C. jejuni DNA microarray, which comprises ORFs from strains NCTC 11168, RM1221. ORFs were spotted in duplicate. Genomic DNA from strains NCTC 11168/RM1221 were used as a reference DNA and competitively hybridized with genomic DNA from each of the other C. jejuni strains. Two or three replicates for each strain were performed. Data normalization was performed as in Parker et al. J Clin Microbiol 2006, 44(11):4125-4135.

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A blood RNA signature for tuberculosis disease risk: a prospective cohort study

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