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1.
EClinicalMedicine ; 40: 101099, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34490415

RESUMO

Background: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there has been increasing urgency to identify pathophysiological characteristics leading to severe clinical course in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human leukocyte antigen alleles (HLA) have been suggested as potential genetic host factors that affect individual immune response to SARS-CoV-2. We sought to evaluate this hypothesis by conducting a multicenter study using HLA sequencing. Methods: We analyzed the association between COVID-19 severity and HLAs in 435 individuals from Germany (n = 135), Spain (n = 133), Switzerland (n = 20) and the United States (n = 147), who had been enrolled from March 2020 to August 2020. This study included patients older than 18 years, diagnosed with COVID-19 and representing the full spectrum of the disease. Finally, we tested our results by meta-analysing data from prior genome-wide association studies (GWAS). Findings: We describe a potential association of HLA-C*04:01 with severe clinical course of COVID-19. Carriers of HLA-C*04:01 had twice the risk of intubation when infected with SARS-CoV-2 (risk ratio 1.5 [95% CI 1.1-2.1], odds ratio 3.5 [95% CI 1.9-6.6], adjusted p-value = 0.0074). These findings are based on data from four countries and corroborated by independent results from GWAS. Our findings are biologically plausible, as HLA-C*04:01 has fewer predicted bindings sites for relevant SARS-CoV-2 peptides compared to other HLA alleles. Interpretation: HLA-C*04:01 carrier state is associated with severe clinical course in SARS-CoV-2. Our findings suggest that HLA class I alleles have a relevant role in immune defense against SARS-CoV-2. Funding: Funded by Roche Sequencing Solutions, Inc.

2.
Front Immunol ; 12: 694680, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34421903

RESUMO

Group-aggregated responses to tuberculosis (TB) have been well characterized on a molecular level. However, human beings differ and individual responses to infection vary. We have combined a novel approach to individual gene set analysis (GSA) with the clustering of transcriptomic profiles of TB patients from seven datasets in order to identify individual molecular endotypes of transcriptomic responses to TB. We found that TB patients differ with respect to the intensity of their hallmark interferon (IFN) responses, but they also show variability in their complement system, metabolic responses and multiple other pathways. This variability cannot be sufficiently explained with covariates such as gender or age, and the molecular endotypes are found across studies and populations. Using datasets from a Cynomolgus macaque model of TB, we revealed that transcriptional signatures of different molecular TB endotypes did not depend on TB progression post-infection. Moreover, we provide evidence that patients with molecular endotypes characterized by high levels of IFN responses (IFN-rich), suffered from more severe lung pathology than those with lower levels of IFN responses (IFN-low). Harnessing machine learning (ML) models, we derived gene signatures classifying IFN-rich and IFN-low TB endotypes and revealed that the IFN-low signature allowed slightly more reliable overall classification of TB patients from non-TB patients than the IFN-rich one. Using the paradigm of molecular endotypes and the ML-based predictions allows more precisely tailored treatment regimens, predicting treatment-outcome with higher accuracy and therefore bridging the gap between conventional treatment and precision medicine.

3.
Am J Respir Crit Care Med ; 204(7): 826-841, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34256007

RESUMO

Rationale: Suboptimal vaccine immunogenicity and antigenic mismatch, compounded by poor uptake, means that influenza remains a major global disease. T cells recognizing peptides derived from conserved viral proteins could enhance vaccine-induced cross-strain protection. Objectives: To investigate the kinetics, phenotypes, and function of influenza virus-specific CD8+ resident memory T (Trm) cells in the lower airway and infer the molecular pathways associated with their response to infection in vivo. Methods: Healthy volunteers, aged 18-55, were inoculated intranasally with influenza A/California/4/09(H1N1). Blood, upper airway, and (in a subgroup) lower airway samples were obtained throughout infection. Symptoms were assessed by using self-reported diaries, and the nasal viral load was assessed by using quantitative PCR. T-cell responses were analyzed by using a three-color FluoroSpot assay, flow cytometry with MHC I-peptide tetramers, and RNA sequencing, with candidate markers being confirmed by using the immunohistochemistry results for endobronchial biopsy specimens. Measurements and Main Results: After challenge, 57% of participants became infected. Preexisting influenza-specific CD8+ T cells in blood correlated strongly with a reduced viral load, which peaked at Day 3. Influenza-specific CD8+ T cells in BAL fluid were highly enriched and predominantly expressed the Trm markers CD69 and CD103. Comparison between preinfection CD8+ T cells in BAL fluid and blood by using RNA sequencing revealed 3,928 differentially expressed genes, including all major Trm-cell markers. However, gene set enrichment analysis of BAL-fluid CD8+ T cells showed primarily innate cell-related pathways and, during infection, included upregulation of innate chemokines (Cxcl1, Cxcl10, and Cxcl16) that were also expressed by CD8+ cells in bronchial tissues. Conclusions: CD8+ Trm cells in the human lung display innate-like gene and protein expression that demonstrates blurred divisions between innate and adaptive immunity. Clinical study registered with www.clinicaltrials.gov (NCT02755948).


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunidade Inata/genética , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/imunologia , Imunidade Adaptativa/genética , Adolescente , Adulto , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/metabolismo , Biomarcadores/metabolismo , Líquido da Lavagem Broncoalveolar/imunologia , Líquido da Lavagem Broncoalveolar/virologia , Linfócitos T CD8-Positivos/metabolismo , Quimiocinas/metabolismo , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Voluntários Saudáveis , Humanos , Influenza Humana/genética , Influenza Humana/virologia , Cadeias alfa de Integrinas/genética , Cadeias alfa de Integrinas/metabolismo , Cinética , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Sistema Respiratório/imunologia , Sistema Respiratório/virologia , Carga Viral , Adulto Jovem
4.
EMBO J ; 40(13): e106272, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33942347

RESUMO

Cellular stress has been associated with inflammation, yet precise underlying mechanisms remain elusive. In this study, various unrelated stress inducers were employed to screen for sensors linking altered cellular homeostasis and inflammation. We identified the intracellular pattern recognition receptors NOD1/2, which sense bacterial peptidoglycans, as general stress sensors detecting perturbations of cellular homeostasis. NOD1/2 activation upon such perturbations required generation of the endogenous metabolite sphingosine-1-phosphate (S1P). Unlike peptidoglycan sensing via the leucine-rich repeats domain, cytosolic S1P directly bound to the nucleotide binding domains of NOD1/2, triggering NF-κB activation and inflammatory responses. In sum, we unveiled a hitherto unknown role of NOD1/2 in surveillance of cellular homeostasis through sensing of the cytosolic metabolite S1P. We propose S1P, an endogenous metabolite, as a novel NOD1/2 activator and NOD1/2 as molecular hubs integrating bacterial and metabolic cues.


Assuntos
Inflamação/metabolismo , Lisofosfolipídeos/metabolismo , Proteína Adaptadora de Sinalização NOD1/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Esfingosina/análogos & derivados , Animais , Linhagem Celular , Linhagem Celular Tumoral , Feminino , Células HEK293 , Células HeLa , Humanos , Camundongos , NF-kappa B/metabolismo , Peptidoglicano/metabolismo , Transdução de Sinais/fisiologia , Esfingosina/metabolismo , Células THP-1
5.
Eur Respir J ; 58(3)2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33574078

RESUMO

BACKGROUND: The World Health Organization recommends standardised treatment durations for patients with tuberculosis (TB). We identified and validated a host-RNA signature as a biomarker for individualised therapy durations for patients with drug-susceptible (DS)- and multidrug-resistant (MDR)-TB. METHODS: Adult patients with pulmonary TB were prospectively enrolled into five independent cohorts in Germany and Romania. Clinical and microbiological data and whole blood for RNA transcriptomic analysis were collected at pre-defined time points throughout therapy. Treatment outcomes were ascertained by TBnet criteria (6-month culture status/1-year follow-up). A whole-blood RNA therapy-end model was developed in a multistep process involving a machine-learning algorithm to identify hypothetical individual end-of-treatment time points. RESULTS: 50 patients with DS-TB and 30 patients with MDR-TB were recruited in the German identification cohorts (DS-GIC and MDR-GIC, respectively); 28 patients with DS-TB and 32 patients with MDR-TB in the German validation cohorts (DS-GVC and MDR-GVC, respectively); and 52 patients with MDR-TB in the Romanian validation cohort (MDR-RVC). A 22-gene RNA model (TB22) that defined cure-associated end-of-therapy time points was derived from the DS- and MDR-GIC data. The TB22 model was superior to other published signatures to accurately predict clinical outcomes for patients in the DS-GVC (area under the curve 0.94, 95% CI 0.9-0.98) and suggests that cure may be achieved with shorter treatment durations for TB patients in the MDR-GIC (mean reduction 218.0 days, 34.2%; p<0.001), the MDR-GVC (mean reduction 211.0 days, 32.9%; p<0.001) and the MDR-RVC (mean reduction of 161.0 days, 23.4%; p=0.001). CONCLUSION: Biomarker-guided management may substantially shorten the duration of therapy for many patients with MDR-TB.


Assuntos
Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose Pulmonar , Adulto , Antituberculosos/uso terapêutico , Duração da Terapia , Humanos , Transcriptoma , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico
6.
Clin Infect Dis ; 72(1): 69-78, 2021 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-32533832

RESUMO

BACKGROUND: People with diabetes have an increased risk of developing active tuberculosis (TB) and are more likely to have poor TB-treatment outcomes, which may impact on control of TB as the prevalence of diabetes is increasing worldwide. Blood transcriptomes are altered in patients with active TB relative to healthy individuals. The effects of diabetes and intermediate hyperglycemia (IH) on this transcriptomic signature were investigated to enhance understanding of immunological susceptibility in diabetes-TB comorbidity. METHODS: Whole blood samples were collected from active TB patients with diabetes (glycated hemoglobin [HbA1c] ≥6.5%) or IH (HbA1c = 5.7% to <6.5%), TB-only patients, and healthy controls in 4 countries: South Africa, Romania, Indonesia, and Peru. Differential blood gene expression was determined by RNA-seq (n = 249). RESULTS: Diabetes increased the magnitude of gene expression change in the host transcriptome in TB, notably showing an increase in genes associated with innate inflammatory and decrease in adaptive immune responses. Strikingly, patients with IH and TB exhibited blood transcriptomes much more similar to patients with diabetes-TB than to patients with only TB. Both diabetes-TB and IH-TB patients had a decreased type I interferon response relative to TB-only patients. CONCLUSIONS: Comorbidity in individuals with both TB and diabetes is associated with altered transcriptomes, with an expected enhanced inflammation in the presence of both conditions, but also reduced type I interferon responses in comorbid patients, suggesting an unexpected uncoupling of the TB transcriptome phenotype. These immunological dysfunctions are also present in individuals with IH, showing that altered immunity to TB may also be present in this group. The TB disease outcomes in individuals with IH diagnosed with TB should be investigated further.


Assuntos
Diabetes Mellitus , Hiperglicemia , Mycobacterium tuberculosis , Tuberculose Pulmonar , Tuberculose , Humanos , Hiperglicemia/complicações , Indonésia , Peru , África do Sul/epidemiologia , Tuberculose/complicações , Tuberculose/epidemiologia
8.
Circulation ; 141(23): 1885-1902, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32160764

RESUMO

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy is often accompanied by immune-related pathology, with an increasing occurrence of high-risk ICI-related myocarditis. Understanding the mechanisms involved in this side effect could enable the development of management strategies. In mouse models, immune checkpoints, such as PD-1 (programmed cell death protein 1), control the threshold of self-antigen responses directed against cardiac TnI (troponin I). We aimed to identify how the immunoproteasome, the main proteolytic machinery in immune cells harboring 3 distinct protease activities in the LMP2 (low-molecular-weight protein 2), LMP7 (low-molecular-weight protein 7), and MECL1 (multicatalytic endopeptidase complex subunit 1) subunit, affects TnI-directed autoimmune pathology of the heart. METHODS: TnI-directed autoimmune myocarditis (TnI-AM), a CD4+ T-cell-mediated disease, was induced in mice lacking all 3 immunoproteasome subunits (triple-ip-/-) or lacking either the gene encoding LMP2 and LMP7 by immunization with a cardiac TnI peptide. Alternatively, before induction of TnI-AM or after establishment of autoimmune myocarditis, mice were treated with the immunoproteasome inhibitor ONX 0914. Immune parameters defining heart-specific autoimmunity were investigated in experimental TnI-AM and in 2 cases of ICI-related myocarditis. RESULTS: All immunoproteasome-deficient strains showed mitigated autoimmune-related cardiac pathology with less inflammation, lower proinflammatory and chemotactic cytokines, less interleukin-17 production, and reduced fibrosis formation. Protection from TnI-directed autoimmune heart pathology with improved cardiac function in LMP7-/- mice involved a changed balance between effector and regulatory CD4+ T cells in the spleen, with CD4+ T cells from LMP7-/- mice showing a higher expression of inhibitory PD-1 molecules. Blocked immunoproteasome proteolysis, by treatment of TLR2 (Toll-like receptor 2)-engaged and TLR7 (Toll-like receptor 7)/TLR8 (Toll-like receptor 8)-engaged CD14+ monocytes with ONX 0914, diminished proinflammatory cytokine responses, thereby reducing the boost for the expansion of self-reactive CD4+ T cells. Correspondingly, in mice, ONX 0914 treatment reversed cardiac autoimmune pathology, preventing the induction and progression of TnI-AM when self-reactive CD4+ T cells were primed. The autoimmune signature during experimental TnI-AM, with high immunoproteasome expression, immunoglobulin G deposition, interleukin-17 production in heart tissue, and TnI-directed humoral autoimmune responses, was also present in 2 cases of ICI-related myocarditis, demonstrating the activation of heart-specific autoimmune reactions by ICI therapy. CONCLUSIONS: By reversing heart-specific autoimmune responses, immunoproteasome inhibitors applied to a mouse model demonstrate their potential to aid in the management of autoimmune myocarditis in humans, possibly including patients with ICI-related heart-specific autoimmunity.


Assuntos
Doenças Autoimunes/imunologia , Modelos Animais de Doenças , Deleção de Genes , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunidade/imunologia , Miocardite/imunologia , Complexo de Endopeptidases do Proteassoma/imunologia , Idoso , Sequência de Aminoácidos , Animais , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/genética , Cisteína Endopeptidases/deficiência , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/imunologia , Feminino , Humanos , Imunidade/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Miocardite/induzido quimicamente , Miocardite/genética , Complexo de Endopeptidases do Proteassoma/deficiência , Complexo de Endopeptidases do Proteassoma/genética
9.
NPJ Vaccines ; 5: 29, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32219001

RESUMO

Vaccination in pregnancy is an effective tool to protect both the mother and infant; vaccines against influenza, pertussis and tetanus are currently recommended. A number of vaccines with a specific indication for use in pregnancy are in development, with the specific aim of providing passive humoral immunity to the newborn child against pathogens responsible for morbidity and mortality in young infants. However, the current understanding about the immune response to vaccination in pregnancy is incomplete. We analysed the effect of pregnancy on early transcriptional responses to vaccination. This type of systems vaccinology approach identifies genes and pathways that are altered in response to vaccination and can be used to understand both the acute inflammation in response to the vaccine and to predict immunogenicity. Pregnant women and mice were immunised with Boostrix-IPV, a multivalent vaccine, which contains three pertussis antigens. Blood was collected from women before and after vaccination and RNA extracted for analysis by microarray. While there were baseline differences between pregnant and non-pregnant women, vaccination induced characteristic patterns of gene expression, with upregulation in interferon response and innate immunity gene modules, independent of pregnancy. We saw similar patterns of responses in both women and mice, supporting the use of mice for preclinical screening of novel maternal vaccines. Using a systems vaccinology approach in pregnancy demonstrated that pregnancy does not affect the initial response to vaccination and that studies in non-pregnant women can provide information about vaccine immunogenicity and potentially safety.

10.
Dis Model Mech ; 13(3)2020 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-32034005

RESUMO

Lactate dehydrogenase A (LDHA) mediates interconversion of pyruvate and lactate, and increased lactate turnover is exhibited by malignant and infected immune cells. Hypoxic lung granuloma in Mycobacterium tuberculosis-infected animals present elevated levels of Ldha and lactate. Such alterations in the metabolic milieu could influence the outcome of host-M. tuberculosis interactions. Given the central role of LDHA for tumorigenicity, targeting lactate metabolism is a promising approach for cancer therapy. Here, we sought to determine the importance of LDHA for tuberculosis (TB) disease progression and its potential as a target for host-directed therapy. To this end, we orally administered FX11, a known small-molecule NADH-competitive LDHA inhibitor, to M. tuberculosis-infected C57BL/6J mice and Nos2 -/- mice with hypoxic necrotizing lung TB lesions. FX11 did not inhibit M. tuberculosis growth in aerobic/hypoxic liquid culture, but modestly reduced the pulmonary bacterial burden in C57BL/6J mice. Intriguingly, FX11 administration limited M. tuberculosis replication and onset of necrotic lung lesions in Nos2 -/- mice. In this model, isoniazid (INH) monotherapy has been known to exhibit biphasic killing kinetics owing to the probable selection of an INH-tolerant bacterial subpopulation. However, adjunct FX11 treatment corrected this adverse effect and resulted in sustained bactericidal activity of INH against M. tuberculosis As a limitation, LDHA inhibition as an underlying cause of FX11-mediated effect could not be established as the on-target effect of FX11 in vivo was unconfirmed. Nevertheless, this proof-of-concept study encourages further investigation on the underlying mechanisms of LDHA inhibition and its significance in TB pathogenesis.


Assuntos
Interações Hospedeiro-Patógeno/efeitos dos fármacos , Isoniazida/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Naftalenos/farmacologia , Animais , Modelos Animais de Doenças , Feminino , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/metabolismo
11.
Clin Infect Dis ; 71(1): 30-40, 2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31412355

RESUMO

BACKGROUND: Strategies to prevent Mycobacterium tuberculosis (Mtb) infection are urgently required. In this study, we aimed to identify correlates of protection against Mtb infection. METHODS: Two groups of Mtb-exposed contacts of tuberculosis (TB) patients were recruited and classified according to their Mtb infection status using the tuberculin skin test (TST; cohort 1) or QuantiFERON (QFT; cohort 2). A negative reading at baseline with a positive reading at follow-up classified TST or QFT converters and a negative reading at both time points classified TST or QFT nonconverters. Ribonucleic acid sequencing, Mtb proteome arrays, and metabolic profiling were performed. RESULTS: Several genes were found to be differentially expressed at baseline between converters and nonconverters. Gene set enrichment analysis revealed a distinct B-cell gene signature in TST nonconverters compared to converters. When infection status was defined by QFT, enrichment of type I interferon was observed. A remarkable area under the curve (AUC) of 1.0 was observed for IgA reactivity to Rv0134 and an AUC of 0.98 for IgA reactivity to both Rv0629c and Rv2188c. IgG reactivity to Rv3223c resulted in an AUC of 0.96 and was markedly higher compared to TST nonconverters. We also identified several differences in metabolite profiles, including changes in biomarkers of inflammation, fatty acid metabolism, and bile acids. Pantothenate (vitamin B5) was significantly increased in TST nonconverters compared to converters at baseline (q = 0.0060). CONCLUSIONS: These data provide new insights into the early protective response to Mtb infection and possible avenues to interfere with Mtb infection, including vitamin B5 supplementation.Analysis of blood from highly exposed household contacts from The Gambia who never develop latent Mycobacterium tuberculosis infection shows distinct transcriptomic, antibody, and metabolomic profiles compared to those who develop latent tuberculosis infection but prior to any signs of infection.


Assuntos
Tuberculose Latente , Mycobacterium tuberculosis , Tuberculose , Gâmbia , Humanos , Imunidade , Tuberculose Latente/diagnóstico , Mycobacterium tuberculosis/genética , Teste Tuberculínico , Tuberculose/diagnóstico
12.
Science ; 366(6472)2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31857448

RESUMO

Pseudomonas aeruginosa rapidly adapts to altered conditions by quorum sensing (QS), a communication system that it uses to collectively modify its behavior through the production, release, and detection of signaling molecules. QS molecules can also be sensed by hosts, although the respective receptors and signaling pathways are poorly understood. We describe a pattern of regulation in the host by the aryl hydrocarbon receptor (AhR) that is critically dependent on qualitative and quantitative sensing of P. aeruginosa quorum. QS molecules bind to AhR and distinctly modulate its activity. This is mirrored upon infection with P. aeruginosa collected from diverse growth stages and with QS mutants. We propose that by spying on bacterial quorum, AhR acts as a major sensor of infection dynamics, capable of orchestrating host defense according to the status quo of infection.


Assuntos
Interações Hospedeiro-Patógeno , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/patogenicidade , Percepção de Quorum/fisiologia , Receptores de Hidrocarboneto Arílico/fisiologia , Células A549 , Animais , Humanos , Larva , Macrófagos/microbiologia , Camundongos , Camundongos Knockout , Pseudomonas aeruginosa/genética , Percepção de Quorum/genética , Receptores de Hidrocarboneto Arílico/genética , Peixe-Zebra
13.
Sci Rep ; 9(1): 10878, 2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31350436

RESUMO

As a first host barrier, the skin is constantly exposed to environmental insults that perturb its integrity. Tight regulation of skin homeostasis is largely controlled by the aryl hydrocarbon receptor (AhR). Here, we demonstrate that Henna and its major pigment, the naphthoquinone Lawsone activate AhR, both in vitro and in vivo. In human keratinocytes and epidermis equivalents, Lawsone exposure enhances the production of late epidermal proteins, impacts keratinocyte differentiation and proliferation, and regulates skin inflammation. To determine the potential use of Lawsone for therapeutic application, we harnessed human, murine and zebrafish models. In skin regeneration models, Lawsone interferes with physiological tissue regeneration and inhibits wound healing. Conversely, in a human acute dermatitis model, topical application of a Lawsone-containing cream ameliorates skin irritation. Altogether, our study reveals how a widely used natural plant pigment is sensed by the host receptor AhR, and how the physiopathological context determines beneficial and detrimental outcomes.


Assuntos
Dermatite/tratamento farmacológico , Queratinócitos/metabolismo , Naftoquinonas/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Pele/metabolismo , Animais , Células Cultivadas , Regeneração Tecidual Guiada , Homeostase , Humanos , Lawsonia (Planta) , Camundongos , Modelos Animais , Naftoquinonas/uso terapêutico , Pele/efeitos dos fármacos , Pele/patologia , Cicatrização , Peixe-Zebra
14.
Bioinformatics ; 35(24): 5146-5154, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31165139

RESUMO

MOTIVATION: Analysis of gene set (GS) enrichment is an essential part of functional omics studies. Here, we complement the established evaluation metrics of GS enrichment algorithms with a novel approach to assess the practical reproducibility of scientific results obtained from GS enrichment tests when applied to related data from different studies. RESULTS: We evaluated eight established and one novel algorithm for reproducibility, sensitivity, prioritization, false positive rate and computational time. In addition to eight established algorithms, we also included Coincident Extreme Ranks in Numerical Observations (CERNO), a flexible and fast algorithm based on modified Fisher P-value integration. Using real-world datasets, we demonstrate that CERNO is robust to ranking metrics, as well as sample and GS size. CERNO had the highest reproducibility while remaining sensitive, specific and fast. In the overall ranking Pathway Analysis with Down-weighting of Overlapping Genes, CERNO and over-representation analysis performed best, while CERNO and GeneSetTest scored high in terms of reproducibility. AVAILABILITY AND IMPLEMENTATION: tmod package implementing the CERNO algorithm is available from CRAN (cran.r-project.org/web/packages/tmod/index.html) and an online implementation can be found at http://tmod.online/. The datasets analyzed in this study are widely available in the KEGGdzPathwaysGEO, KEGGandMetacoreDzPathwaysGEO R package and GEO repository. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Algoritmos , Software , Reprodutibilidade dos Testes
15.
Elife ; 82019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31084714

RESUMO

Systems vaccinology approaches have been used successfully to define early signatures of the vaccine-induced immune response. However, the possibility that transcriptomics can also identify a correlate or surrogate for vaccine inflammation has not been fully explored. We have compared four licensed vaccines with known safety profiles, as well as three agonists of Toll-like receptors (TLRs) with known inflammatory potential, to elucidate the transcriptomic profile of an acceptable response to vaccination versus that of an inflammatory reaction. In mice, we looked at the transcriptomic changes in muscle at the injection site, the lymph node that drained the muscle, and the peripheral blood mononuclear cells (PBMCs)isolated from the circulating blood from 4 hr after injection and over the next week. A detailed examination and comparative analysis of these transcriptomes revealed a set of novel biomarkers that are reflective of inflammation after vaccination. These biomarkers are readily measurable in the peripheral blood, providing useful surrogates of inflammation, and provide a way to select candidates with acceptable safety profiles.


Assuntos
Biomarcadores/análise , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Inflamação/patologia , Vacinas/efeitos adversos , Animais , Perfilação da Expressão Gênica , Injeções Intramusculares , Leucócitos Mononucleares/imunologia , Linfonodos/patologia , Camundongos , Músculos/patologia , Vacinas/administração & dosagem
16.
Front Immunol ; 10: 527, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30967866

RESUMO

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 Jovem
17.
Sci Rep ; 9(1): 20362, 2019 12 30.
Artigo em Inglês | MEDLINE | ID: mdl-31889148

RESUMO

Biomarkers predictive of inflammatory events post-vaccination could accelerate vaccine development. Within the BIOVACSAFE framework, we conducted three identically designed, placebo-controlled inpatient/outpatient clinical studies (NCT01765413/NCT01771354/NCT01771367). Six antiviral vaccination strategies were evaluated to generate training data-sets of pre-/post-vaccination vital signs, blood changes and whole-blood gene transcripts, and to identify putative biomarkers of early inflammation/reactogenicity that could guide the design of subsequent focused confirmatory studies. Healthy adults (N = 123; 20-21/group) received one immunization at Day (D)0. Alum-adjuvanted hepatitis B vaccine elicited vital signs and inflammatory (CRP/innate cells) responses that were similar between primed/naive vaccinees, and low-level gene responses. MF59-adjuvanted trivalent influenza vaccine (ATIV) induced distinct physiological (temperature/heart rate/reactogenicity) response-patterns not seen with non-adjuvanted TIV or with the other vaccines. ATIV also elicited robust early (D1) activation of IFN-related genes (associated with serum IP-10 levels) and innate-cell-related genes, and changes in monocyte/neutrophil/lymphocyte counts, while TIV elicited similar but lower responses. Due to viral replication kinetics, innate gene activation by live yellow-fever or varicella-zoster virus (YFV/VZV) vaccines was more suspended, with early IFN-associated responses in naïve YFV-vaccine recipients but not in primed VZV-vaccine recipients. Inflammatory responses (physiological/serum markers, innate-signaling transcripts) are therefore a function of the vaccine type/composition and presence/absence of immune memory. The data reported here have guided the design of confirmatory Phase IV trials using ATIV to provide tools to identify inflammatory or reactogenicity biomarkers.


Assuntos
Biomarcadores , Vacinas Virais/efeitos adversos , Proteínas de Fase Aguda , Adulto , Citocinas/sangue , Feminino , Testes Hematológicos , Humanos , Masculino , Avaliação de Sintomas , Transcrição Genética , Vacinação/efeitos adversos , Vacinação/métodos , Vacinas Virais/imunologia , Sinais Vitais , Adulto Jovem
18.
Nat Commun ; 9(1): 5208, 2018 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-30523338

RESUMO

New biomarkers of tuberculosis (TB) risk and disease are critical for the urgently needed control of the ongoing TB pandemic. In a prospective multisite study across Subsaharan Africa, we analyzed metabolic profiles in serum and plasma from HIV-negative, TB-exposed individuals who either progressed to TB 3-24 months post-exposure (progressors) or remained healthy (controls). We generated a trans-African metabolic biosignature for TB, which identifies future progressors both on blinded test samples and in external data sets and shows a performance of 69% sensitivity at 75% specificity in samples within 5 months of diagnosis. These prognostic metabolic signatures are consistent with development of subclinical disease prior to manifestation of active TB. Metabolic changes associated with pre-symptomatic disease are observed as early as 12 months prior to TB diagnosis, thus enabling timely interventions to prevent disease progression and transmission.


Assuntos
Biomarcadores/sangue , Metaboloma , Metabolômica/métodos , Tuberculose/sangue , Adolescente , Adulto , África ao Sul do Saara , Progressão da Doença , Feminino , Humanos , Masculino , Estudos Prospectivos , Sensibilidade e Especificidade , Tuberculose/diagnóstico , Adulto Jovem
19.
Front Immunol ; 9: 2417, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30405617

RESUMO

Tuberculosis (TB) has tremendous public health relevance. It most frequently affects the lung and is characterized by the development of unique tissue lesions, termed granulomas. These lesions encompass various immune populations, with macrophages being most extensively investigated. Myeloid derived suppressor cells (MDSCs) have been recently identified in TB patients, both in the circulation and at the site of infection, however their interactions with Mycobacterium tuberculosis (Mtb) and their impact on granulomas remain undefined. We generated human monocytic MDSCs and observed that their suppressive capacities are retained upon Mtb infection. We employed an in vitro granuloma model, which mimics human TB lesions to some extent, with the aim of analyzing the roles of MDSCs within granulomas. MDSCs altered the structure of and affected bacterial containment within granuloma-like structures. These effects were partly controlled through highly abundant secreted IL-10. Compared to macrophages, MDSCs activated primarily the NF-κB and MAPK pathways and the latter largely contributed to the release of IL-10 and replication of bacteria within in vitro generated granulomas. Moreover, MDSCs upregulated PD-L1 and suppressed proliferation of lymphocytes, albeit with negligible effects on Mtb replication. Further comprehensive characterization of MDSCs in TB will contribute to a better understanding of disease pathogenesis and facilitate the design of novel immune-based interventions for this deadly infection.


Assuntos
Granuloma do Sistema Respiratório/patologia , Linfócitos/imunologia , Mycobacterium tuberculosis/fisiologia , Células Supressoras Mieloides/imunologia , Tuberculose Pulmonar/imunologia , Antígeno B7-H1/metabolismo , Carga Bacteriana , Proliferação de Células , Células Cultivadas , Replicação do DNA , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Granuloma do Sistema Respiratório/microbiologia , Humanos , Tolerância Imunológica , Interleucina-10/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Regulação para Cima
20.
Semin Immunol ; 39: 44-51, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30033150

RESUMO

Recent technological advances have provided deeper insights into the role of small molecules in biological processes. Metabolic profiling has thus entered the arena of -omics studies and rapidly proven its value both as stand-alone and as complement to other more advanced approaches, notably transcriptomics. Here we describe the potential of metabolic profiling for vaccinology embedded in the context of infection and immunity. This discussion is preceded by a description of the relevant technical and analytical tools for biological interpretation of metabolic data. Although not as widely applied as other -omics technologies, we believe that metabolic profiling can make important contributions to the better understanding of mechanisms underlying vaccine-induced responses and their effects on the prevention of infection or disease.


Assuntos
Dengue/metabolismo , Oncocercose/metabolismo , Pneumonia/metabolismo , Raiva/metabolismo , Sepse/metabolismo , Tuberculose/metabolismo , Vacinas/metabolismo , Dengue/imunologia , Dengue/prevenção & controle , Humanos , Metaboloma , Metabolômica/métodos , Oncocercose/imunologia , Oncocercose/prevenção & controle , Pneumonia/imunologia , Pneumonia/prevenção & controle , Análise de Componente Principal , Raiva/imunologia , Raiva/prevenção & controle , Sepse/imunologia , Sepse/prevenção & controle , Biologia de Sistemas/métodos , Tuberculose/imunologia , Tuberculose/prevenção & controle , Vacinação , Vacinas/administração & dosagem , Vacinas/síntese química
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