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1.
Genes Immun ; 16(5): 347-55, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26043170

RESUMO

The epidemiology of Mycobacterium tuberculosis (Mtb) and M. africanum (Maf) suggests differences in their virulence, but the host immune profile to better understand the pathogenesis of tuberculosis (TB) have not been studied. We compared the transcriptomic and metabolic profiles between Mtb- and Maf-infected TB cases to identify host biomarkers associated with lineages-specific pathogenesis and response to anti-TB chemotherapy. Venous blood samples from Mtb- and Maf-infected patients obtained before and after anti-TB treatment were analyzed for cell composition, gene expression and metabolic profiles. Prior to treatment, similar transcriptomic profiles were seen in Maf- and Mtb-infected patients. In contrast, post treatment, over 1600 genes related to immune responses and metabolic diseases were differentially expressed between the groups. Notably, the upstream regulator hepatocyte nuclear factor 4-alpha (HNF4α), which regulated 15% of these genes, was markedly enriched. Serum metabolic profiles were similar in both group pre-treatment, but the decline in pro-inflammatory metabolites post treatment were most pronounced in Mtb-infected patients. Together, the differences in both peripheral blood transcriptomic and serum metabolic profiles between Maf- and Mtb-infected patients observed over the treatment period, might be indicative of intrinsic host factors related to susceptibility to TB and/or differential efficacy of the standard anti-TB treatment on the two lineages.


Assuntos
Antituberculosos/farmacologia , Metaboloma/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Tuberculose/genética , Adolescente , Adulto , Antituberculosos/uso terapêutico , Feminino , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/patogenicidade , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia
2.
Vaccine ; 33(40): 5256-61, 2015 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-25858856

RESUMO

The immune system has evolved complex and specialized mechanisms to mount specific defense responses against the various types of pathogens it encounters. For the development of new vaccines, it is crucial to gain a better understanding of what these mechanisms are and how they work. The field of vaccinology has adopted high-throughput profiling techniques to gain more detailed insights into the various immune responses elicited by different vaccines and natural infections. From all detailed transcriptional profiles generated today, a general picture of immunological responses emerges. First, almost every type of vaccine induces an early interferon-dominated signature. Second, different vaccine formulations induce distinct transcriptional signatures, representing the highly specialized defense mechanisms that must cope with the different pathogens and insults they cause. Transcriptional profiling has shifted its attention toward early molecular signatures, with a growing awareness that early innate responses are likely critical instructors for the development of adaptive immunity at later time points.


Assuntos
Imunidade Adaptativa , Imunidade Inata , Transcriptoma , Vacinas/imunologia , Imunidade Adaptativa/genética , Pesquisa Biomédica , Ensaios Clínicos como Assunto , Perfilação da Expressão Gênica/métodos , Humanos , Imunidade Inata/genética , Interferons/genética , Interferons/imunologia
3.
Clin Microbiol Infect ; 20(4): O230-8, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24205913

RESUMO

New diagnostics and vaccines for tuberculosis (TB) are urgently needed, but require an understanding of the requirements for protection from/susceptibility to TB. Previous studies have used unbiased approaches to determine gene signatures in single-site populations. The present study utilized a targeted approach, reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA), to validate these genes in a multisite study. We analysed ex vivo whole blood RNA from a total of 523 participants across four sub-Saharan countries (Ethiopia, Malawi, South Africa, and The Gambia) with differences in TB and human immunodeficiency virus (HIV) status. We found a number of genes that were expressed at significantly lower levels in participants with active disease than in those with latent TB infection (LTBI), with restoration following successful TB treatment. The most consistent classifier of active disease was FCGR1A (high-affinity IgG Fc receptor 1 (CD64)), which was the only marker expressed at significantly higher levels in participants with active TB than in those with LTBI before treatment regardless of HIV status or genetic background. This is the first study to identify a biomarker for TB that is not affected by HIV status or geo-genetic differences. These data provide valuable clues for understanding TB pathogenesis, and also provide a proof-of-concept for the use of RT-MLPA in rapid and inexpensive validation of unbiased gene expression findings.


Assuntos
Biomarcadores/sangue , Expressão Gênica , Receptores de IgG/sangue , Tuberculose/diagnóstico , Adolescente , Adulto , África Subsaariana , Sangue , Etnicidade , Feminino , Perfilação da Expressão Gênica , Infecções por HIV/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
4.
Int J Tuberc Lung Dis ; 16(9): 1140-8, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22871324

RESUMO

Accelerated control of tuberculosis (TB) requires better control measures. Biomarkers, which reliably diagnose active TB or even predict risk of disease progression in individuals, could facilitate rapid diagnosis and treatment of TB patients and allow preventive measures for latently infected individuals with a high risk of TB. Moreover, biomarkers could speed up clinical trials with novel drug and vaccine candidates. Three platforms of global biomarker profiling will be described, with an emphasis on the most recent achievements: transcriptomics, proteomics and metabolomics. Moreover, we will discuss the need for computational analyses to make the best use of the plethora of data generated by biomarker research. Aside from their potential prognostic and diagnostic value, biomarkers could provide deeper insight into pathological processes underlying disease, and hence form the basis for novel intervention measures that target host molecules and pathways. We propose that biosignatures, which discriminate active TB from both latent infection and uninfected status, as well as from other diseases, will become available within the next decade. However, simple, low-cost biomarker-based point-of-care diagnosis will probably not be achieved in the next few years.


Assuntos
Biologia Computacional , Tuberculose/diagnóstico , Algoritmos , Animais , Antituberculosos/uso terapêutico , Biomarcadores/metabolismo , Biologia Computacional/métodos , Diagnóstico Precoce , Marcadores Genéticos , Genômica , Humanos , Metabolômica , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/isolamento & purificação , Sistemas Automatizados de Assistência Junto ao Leito , Valor Preditivo dos Testes , Prognóstico , Proteômica , Tuberculose/tratamento farmacológico , Tuberculose/genética , Tuberculose/metabolismo , Tuberculose/microbiologia , Vacinas contra a Tuberculose/uso terapêutico
5.
Genes Immun ; 12(1): 15-22, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20861863

RESUMO

Tuberculosis (TB) still poses a profound burden on global health, owing to significant morbidity and mortality worldwide. Although a fully functional immune system is essential for the control of Mycobacterium tuberculosis infection, the underlying mechanisms and reasons for failure in part of the infected population remain enigmatic. Here, whole-blood microarray gene expression analyses were performed in TB patients and in latently as well as uninfected healthy controls to define biomarkers predictive of susceptibility and resistance. Fc gamma receptor 1B (FCGRIB)was identified as the most differentially expressed gene, and, in combination with four other markers, produced a high degree of accuracy in discriminating TB patients and latently infected donors. We determined differentially expressed genes unique for active disease and identified profiles that correlated with susceptibility and resistance to TB. Elevated expression of innate immune-related genes in active TB and higher expression of particular gene clusters involved in apoptosis and natural killer cell activity in latently infected donors are likely to be the major distinctive factors determining failure or success in controlling M. tuberculosis infection. The gene expression profiles defined in this study provide valuable clues for better understanding of progression from latent infection to active disease and pave the way for defining predictive correlates of protection in TB.


Assuntos
Perfilação da Expressão Gênica , Predisposição Genética para Doença , Tuberculose/genética , Tuberculose/imunologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tuberculose/fisiopatologia , Adulto Jovem
6.
J Med Virol ; 73(4): 601-4, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15221906

RESUMO

Clinical recurrences of Herpes simplex virus type 1 (HSV-1)-associated genital herpes are thought to be caused by reactivation of latent endogenous HSV-1. However, the possibility of reinfection with exogenous HSV-1 cannot be excluded. This study aimed to determine the incidence of genital HSV-1 superinfection in patients by investigating the genotype of sequential HSV-1 isolates obtained from the same anatomical site of patients with clinical recurrences of genital HSV-1 recurrent genital herpes. Sequential genital HSV-1 isolates were genotyped by PCR amplification of the hypervariable regions located within the HSV-1 genes US1 and US12. Whereas the sequential HSV-1 isolates in 11 of the 13 patients studied had the same genotypes, the sequential isolates of 2 patients showed a different genotype. The data suggest that HSV-1-induced recurrent genital herpes can be associated with genital reinfection with an exogenous HSV-1 strain.


Assuntos
Herpes Genital/virologia , Herpesvirus Humano 1/classificação , Herpesvirus Humano 1/genética , Adulto , Feminino , Genótipo , Herpesvirus Humano 1/isolamento & purificação , Humanos , Proteínas Imediatamente Precoces/genética , Masculino , Reação em Cadeia da Polimerase/métodos , Recidiva , Análise de Sequência de DNA , Proteínas Virais/genética
7.
Lancet ; 357(9254): 442, 2001 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-11273067

RESUMO

Genetic characterisation of herpes simplex virus type 1 (HSV-1) DNA isolated from a donor cornea before and after corneal transplantation demonstrated the transmission of HSV-1 through transplantation. This study is the first to provide conclusive evidence for the transmission of HSV-1 by penetrating keratoplasty with subsequent reactivation of donor-derived HSV-1 in the transplanted cornea.


Assuntos
Glaucoma/congênito , Herpesvirus Humano 1 , Ceratite Herpética/transmissão , Ceratoplastia Penetrante , Adulto , Anticorpos Antivirais/sangue , Impressões Digitais de DNA , Glaucoma/cirurgia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/imunologia , Humanos , Ceratite Herpética/imunologia , Ceratite Herpética/virologia , Masculino , Reação em Cadeia da Polimerase , Reoperação , Doadores de Tecidos , Ativação Viral
8.
Ann Neurol ; 49(1): 104-6, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11198277

RESUMO

Herpes simplex encephalitis is a severe neurological disease with high mortality and morbidity rates. Reactivated herpes simplex virus type 1 (HSV-1) can cause relapses and might even spread to the retina, where it can induce a potentially blinding eye disease, known as acute retinal necrosis. In the present study, the HSV-1 strains in the brain and eye of 2 patients with acute retinal necrosis following an episode of herpes simplex encephalitis were genotyped. The HSV-1 strains in both the brain and eye were identical in each patient, but they differed interindividually. The data suggest brain-to-eye transmission of HSV-1 in these patients.


Assuntos
Encefalite por Herpes Simples/genética , Encefalite por Herpes Simples/transmissão , Herpesvirus Humano 1/genética , Retinite/genética , Idoso , Sequência de Bases , DNA Viral/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular
9.
Ann Neurol ; 48(6): 936-9, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11117552

RESUMO

Herpes simplex encephalitis is a severe neurological disease with high mortality and morbidity rates. Reactivated herpes simplex virus type 1 (HSV-1) can cause relapses and might even spread to the retina, where it can induce a potentially blinding eye disease, known as acute retinal necrosis. In the present study, the HSV-1 strains in the brain and eye of 2 patients with acute retinal necrosis following an episode of herpes simplex encephalitis were genotyped. The HSV-1 strains in both the brain and eye were identical in each patient, but they differed interindividually. The data suggest brain-to-eye transmission of HSV-1 in these patients.


Assuntos
Encefalite por Herpes Simples/genética , Encefalite por Herpes Simples/transmissão , Herpesvirus Humano 1/genética , Retinite/etiologia , Idoso , Sequência de Bases , Encefalite por Herpes Simples/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Reação em Cadeia da Polimerase
10.
J Clin Microbiol ; 37(11): 3518-23, 1999 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-10523545

RESUMO

Herpes simplex virus type 1 (HSV-1)-related disease ranges from a localized, self-limiting illness to fatal disease in immunocompromised individuals. The corneal disease herpetic keratitis may develop after reactivation of a latent virus or reinfection with an exogenous herpesvirus. Molecular analysis of the virus involved may allow distinction between these two options. The HSV-1 genome contains several hypervariable regions that vary in numbers of reiterating regions (reiterations I to VIII [ReI to ReVIII]) between individual strains. Twenty-four HSV-1 clones, derived by subcloning of HSV-1 (strain F) twice in limiting dilutions, were tested in a PCR-based assay to analyze the stabilities of ReI, ReIII, ReIV, and ReVII. ReI and ReIII proved to vary in size upon subcloning, whereas ReIV and ReVII were stable. Subsequently, 37 unrelated isolates and 10 sequential isolates from five patients, all with HSV-1-induced keratitis, were genotyped for ReIV and ReVII. Of the 37 unrelated samples, 34 (92%) could be discriminated, while the genotypes of the viruses in sequential samples were identical for each individual. Conclusively, the data show that the approach presented allows the rapid and accurate discrimination of HSV-1 strains in studies that address the transmission and pathogenesis of HSV-1 infections.


Assuntos
DNA Viral/genética , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/isolamento & purificação , Ceratite Herpética/virologia , Sequências Repetitivas de Ácido Nucleico , Sequência de Bases , Primers do DNA/genética , Amplificação de Genes , Genoma Viral , Herpesvirus Humano 1/classificação , Humanos , Reação em Cadeia da Polimerase , Recidiva
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