RESUMO
The RTS,S/AS01 vaccine provides partial protection against Plasmodium falciparum infection but determinants of protection and/or disease are unclear. Previously, anti-circumsporozoite protein (CSP) antibody titers and blood RNA signatures were associated with RTS,S/AS01 efficacy against controlled human malaria infection (CHMI). By analyzing host blood transcriptomes from five RTS,S vaccination CHMI studies, we demonstrate that the transcript ratio MX2/GPR183, measured 1 day after third immunization, discriminates protected from non-protected individuals. This ratiometric signature provides information that is complementary to anti-CSP titer levels for identifying RTS,S/AS01 immunized people who developed protective immunity and suggests a role for interferon and oxysterol signaling in the RTS,S mode of action.
Assuntos
Vacinas Antimaláricas/imunologia , Malária Falciparum/genética , Malária Falciparum/prevenção & controle , Proteínas de Resistência a Myxovirus/genética , Plasmodium falciparum/imunologia , Receptores Acoplados a Proteínas G/genética , Transcriptoma , Vacinação , Vacinas Sintéticas/imunologia , Anticorpos Antiprotozoários/imunologia , Estudos de Coortes , Humanos , Imunogenicidade da Vacina/genética , Controle de Infecções/métodos , Malária Falciparum/imunologia , Malária Falciparum/parasitologia , Proteínas de Protozoários/imunologia , RNA-Seq , Análise de Célula ÚnicaRESUMO
There remains a pressing need for biomarkers that can predict who will progress to active tuberculosis (TB) after exposure to Mycobacterium tuberculosis (MTB) bacterium. By analyzing cohorts of household contacts of TB index cases (HHCs) and a stringent non-human primate (NHP) challenge model, we evaluated whether integration of blood transcriptional profiling with serum metabolomic profiling can provide new understanding of disease processes and enable improved prediction of TB progression. Compared to either alone, the combined application of pre-existing transcriptome- and metabolome-based signatures more accurately predicted TB progression in the HHC cohorts and more accurately predicted disease severity in the NHPs. Pathway and data-driven correlation analyses of the integrated transcriptional and metabolomic datasets further identified novel immunometabolomic signatures significantly associated with TB progression in HHCs and NHPs, implicating cortisol, tryptophan, glutathione, and tRNA acylation networks. These results demonstrate the power of multi-omics analysis to provide new insights into complex disease processes.
Assuntos
Tuberculose , Adolescente , Adulto , África , Animais , Biomarcadores , Progressão da Doença , Feminino , Humanos , Macaca mulatta , Masculino , Metaboloma , Mycobacterium tuberculosis , Transcriptoma , Tuberculose/genética , Tuberculose/imunologia , Tuberculose/metabolismo , Vacinas contra a Tuberculose , Adulto JovemRESUMO
Biomarkers that predict who among recently Mycobacterium tuberculosis (MTB)-exposed individuals will progress to active tuberculosis are urgently needed. Intracellular microRNAs (miRNAs) regulate the host response to MTB and circulating miRNAs (c-miRNAs) have been developed as biomarkers for other diseases. We performed machine-learning analysis of c-miRNA measurements in the serum of adult household contacts (HHCs) of TB index cases from South Africa and Uganda and developed a c-miRNA-based signature of risk for progression to active TB. This c-miRNA-based signature significantly discriminated HHCs within 6 months of progression to active disease from HHCs that remained healthy in an independent test set [ROC area under the ROC curve (AUC) 0.74, progressors < 6 Mo to active TB and ROC AUC 0.66, up to 24 Mo to active TB], and complements the predictions of a previous cellular mRNA-based signature of TB risk.