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1.
J Immunol ; 207(5): 1239-1249, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34389623

RESUMO

HIV-1 infection substantially increases the risk of developing tuberculosis (TB). Mechanisms such as defects in the Th1 response to Mycobacterium tuberculosis in HIV-infected persons have been widely reported. However, Th1-independent mechanisms also contribute to protection against TB. To identify a broader spectrum of defects in TB immunity during HIV infection, we examined IL-17A and IL-22 production in response to mycobacterial Ags in peripheral blood of persons with latent TB infection and HIV coinfection. Upon stimulating with mycobacterial Ags, we observed a distinct CD4+ Th lineage producing IL-22 in the absence of IL-17A and IFN-γ. Mycobacteria-specific Th22 cells were present at high frequencies in blood and contributed up to 50% to the CD4+ T cell response to mycobacteria, comparable in magnitude to the IFN-γ Th1 response (median 0.91% and 0.55%, respectively). Phenotypic characterization of Th22 cells revealed that their memory differentiation was similar to M. tuberculosis-specific Th1 cells (i.e., predominantly early differentiated CD45RO+CD27+ phenotype). Moreover, CCR6 and CXCR3 expression profiles of Th22 cells were similar to Th17 cells, whereas their CCR4 and CCR10 expression patterns displayed an intermediate phenotype between Th1 and Th17 cells. Strikingly, mycobacterial IL-22 responses were 3-fold lower in HIV-infected persons compared with uninfected persons, and the magnitude of responses correlated inversely with HIV viral load. These data provide important insights into mycobacteria-specific Th subsets in humans and suggest a potential role for IL-22 in protection against TB during HIV infection. Further studies are needed to fully elucidate the role of IL-22 in protective TB immunity.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Interleucinas/metabolismo , Tuberculose Latente/imunologia , Mycobacterium tuberculosis/fisiologia , Subpopulações de Linfócitos T/imunologia , Adulto , Células Cultivadas , Coinfecção , Feminino , Soropositividade para HIV , Humanos , Interleucina-17/metabolismo , Masculino , África do Sul , Carga Viral , Adulto Jovem
2.
BMC Infect Dis ; 21(1): 651, 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34225667

RESUMO

BACKGROUND: The differential diagnosis of active tuberculosis (ATB) and latent tuberculosis infection (LTBI) remains challenging in clinical practice. We aimed to evaluate the diagnostic accuracy of the IFN-γ/TNF-α FluoroSpot assay for differentiating ATB from LTBI. METHODS: We conducted a pilot study of case-control design, using the FluoroSpot assay to simultaneously detect IFN-γ and TNF-α secretion at the single-cell level. The frequencies of antigen-specific single TNF-α-, total TNF-α-, single IFN-γ-, total IFN-γ- and dual IFN-γ/TNF-α-secreting T cells were detected. The optimal cutoffs value of frequencies for differentiating ATB from LTBI were determined according to receiver operating characteristic curve analysis. The sensitivity, specificity, predictive values (PV) and likelihood ratios (LR) of the FluoroSpot assay were calculated. RESULTS: Thirty patients diagnosed microbiologically with ATB, 36 healthcare workers with LTBI and 36 healthy controls were enrolled. After stimulated by ESAT-6 or CFP-10 peptides, the median frequencies of single TNF-α-, total TNF-α-, single IFN-γ-, total IFN-γ- and dual IFN-γ/TNF-α-secreting T cells in ATB patients were all significantly higher than those in LTBI and HC groups (P < 0.01). The frequencies of total IFN-γ-secreting T cells detected by FluoroSpot assay correlated significantly with those of T-SPOT.TB (r = 0.910 for ESAT-6, P < 0.001, r = 0.845 for CFP-10, P < 0.001). After stimulated by ESAT-6 peptides, with total TNF-α-secreting T cells frequencies at a cut off value of 21 iSFCs/250,000 PBMCs, the sensitivity, specificity, PLR, NLR, PPV, NPV of IFN-γ/TNF-α FluoroSpot assay in differentiating ATB from LTBI were 96.7% (95%CI, 82.8-99.9%), 94.3% (95%CI, 80.8-99.3%), 16.92 (95%CI, 4.40-65.08), 0.04 (95%CI, 0.01-0.24), 93.6% (95%CI,78.6-99.2%) and 97.1% (95%CI, 84.7-99.9%), respectively. With the frequencies of total TNF-α- and total IFN-γ-secreting T cells stimulated by ESAT-6 peptides combined, the specificity was increased to 97.1%, and the positive likelihood ratio to 31.5. The combination with CFP-10 might not improve the diagnostic accuracy of the ESAT-6 for differentiating ATB from LTBI. CONCLUSIONS: IFN-γ/TNF-α FluoroSpot assay might have potential to help differentiate ATB from LTBI, but the findings need to be further verified by cross-sectional or prospective cohort studies.


Assuntos
Testes de Liberação de Interferon-gama , Tuberculose Latente/diagnóstico , Tuberculose/diagnóstico , Fator de Necrose Tumoral alfa/sangue , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Diagnóstico Diferencial , Humanos , Interferon gama/sangue , Tuberculose Latente/imunologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Tuberculose/imunologia , Adulto Jovem
3.
Front Immunol ; 12: 641378, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33953714

RESUMO

Background: Inadequate tuberculosis (TB) diagnostics, especially for discrimination between active TB (ATB) and latent TB infection (LTBI), are major hurdle in the reduction of the disease burden. The present study aims to investigate the role of lymphocyte non-specific function detection for TB diagnosis in clinical practice. Methods: A total of 208 participants including 49 ATB patients, 64 LTBI individuals, and 95 healthy controls were recruited at Tongji hospital from January 2019 to October 2020. All subjects were tested with lymphocyte non-specific function detection and T-SPOT assay. Results: Significantly positive correlation existed between lymphocyte non-specific function and phytohemagglutinin (PHA) spot number. CD4+ T cell non-specific function showed the potential for differentiating patients with negative T-SPOT results from those with positive T-SPOT results with an area under the curve (AUC) of 0.732 (95% CI, 0.572-0.893). The non-specific function of CD4+ T cells, CD8+ T cells, and NK cells was found significantly lower in ATB patients than in LTBI individuals. The AUCs presented by CD4+ T cell non-specific function, CD8+ T cell non-specific function, and NK cell non-specific function for discriminating ATB patients from LTBI individuals were 0.845 (95% CI, 0.767-0.925), 0.770 (95% CI, 0.683-0.857), and 0.691 (95% CI, 0.593-0.789), respectively. Application of multivariable logistic regression resulted in the combination of CD4+ T cell non-specific function, NK cell non-specific function, and culture filtrate protein-10 (CFP-10) spot number as the optimally diagnostic model for differentiating ATB from LTBI. The AUC of the model in distinguishing between ATB and LTBI was 0.939 (95% CI, 0.898-0.981). The sensitivity and specificity were 83.67% (95% CI, 70.96%-91.49%) and 90.63% (95% CI, 81.02%-95.63%) with the threshold as 0.57. Our established model showed superior performance to TB-specific antigen (TBAg)/PHA ratio in stratifying TB infection status. Conclusions: Lymphocyte non-specific function detection offers an attractive alternative to facilitate TB diagnosis. The three-index diagnostic model was proved to be a potent tool for the identification of different events involved in TB infection, which is helpful for the treatment and management of patients.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Técnicas Imunológicas , Células Matadoras Naturais/imunologia , Tuberculose Latente/diagnóstico , Adulto , Antígenos de Bactérias/análise , Feminino , Humanos , Tuberculose Latente/imunologia , Masculino , Pessoa de Meia-Idade , Tuberculose/diagnóstico , Tuberculose/imunologia
4.
Sci Transl Med ; 13(592)2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33952677

RESUMO

Host immune responses at the site of Mycobacterium tuberculosis infection can mediate pathogenesis of tuberculosis (TB) and onward transmission of infection. We hypothesized that pathological immune responses would be enriched at the site of host-pathogen interactions modeled by a standardized tuberculin skin test (TST) challenge in patients with active TB compared to those without disease, and interrogated immune responses by genome-wide transcriptional profiling. We show exaggerated interleukin-17A (IL-17A) and T helper 17 (TH17) responses among 48 individuals with active TB compared to 191 with latent TB infection, associated with increased neutrophil recruitment and matrix metalloproteinase-1 expression, both involved in TB pathogenesis. Curative antimicrobial treatment reversed these observed changes. Increased IL-1ß and IL-6 responses to mycobacterial stimulation were evident both in circulating monocytes and in molecular changes at the site of TST in individuals with active TB, supporting a model in which monocyte-derived IL-1ß and IL-6 promote TH17 differentiation within tissues. Modulation of these cytokine pathways may provide a rational strategy for host-directed therapy in active TB.


Assuntos
Interleucina-17/imunologia , Tuberculose Latente , Tuberculose , Humanos , Tuberculose Latente/diagnóstico , Tuberculose Latente/imunologia , Mycobacterium tuberculosis , Tuberculose/tratamento farmacológico , Tuberculose/imunologia
5.
Front Immunol ; 12: 631410, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33897687

RESUMO

Mucosal associated invariant T (MAIT) cells are a class of innate-like T cells that utilize a semi-invariant αß T cell receptor to recognize small molecule ligands produced by bacteria and fungi. Despite growing evidence that immune cells at mucosal surfaces are often phenotypically and functionally distinct from those in the peripheral circulation, knowledge about the characteristics of MAIT cells at the lung mucosal surface, the site of exposure to respiratory pathogens, is limited. HIV infection has been shown to have a profound effect on the number and function of MAIT cells in the peripheral blood, but its effect on lung mucosal MAIT cells is unknown. We examined the phenotypic, functional, and transcriptomic features of major histocompatibility complex (MHC) class I-related (MR1)-restricted MAIT cells from the peripheral blood and bronchoalveolar compartments of otherwise healthy individuals with latent Mycobacterium tuberculosis (Mtb) infection who were either HIV uninfected or HIV infected. Peripheral blood MAIT cells consistently co-expressed typical MAIT cell surface markers CD161 and CD26 in HIV-negative individuals, while paired bronchoalveolar MAIT cells displayed heterogenous expression of these markers. Bronchoalveolar MAIT cells produced lower levels of pro-inflammatory cytokine IFN-γ and expressed higher levels of co-inhibitory markers PD-1 and TIM-3 than peripheral MAIT cells. HIV infection resulted in decreased frequencies and pro-inflammatory function of peripheral blood MAIT cells, while in the bronchoalveolar compartment MAIT cell frequency was decreased but phenotype and function were not significantly altered. Single-cell transcriptomic analysis demonstrated greater heterogeneity among bronchoalveolar compared to peripheral blood MAIT cells and suggested a distinct subset in the bronchoalveolar compartment. The transcriptional features of this bronchoalveolar subset were associated with MAIT cell tissue repair functions. In summary, we found previously undescribed phenotypic and transcriptional heterogeneity of bronchoalveolar MAIT cells in HIV-negative people. In HIV infection, we found numeric depletion of MAIT cells in both anatomical compartments but preservation of the novel phenotypic and transcriptional features of bronchoalveolar MAIT cells.


Assuntos
Perfilação da Expressão Gênica , Infecções por HIV/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Pulmão/citologia , Antígenos de Histocompatibilidade Menor/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Mucosa Respiratória/citologia , Mucosa Respiratória/imunologia , Adulto , Feminino , Infecções por HIV/microbiologia , Humanos , Imunidade nas Mucosas , Tuberculose Latente/imunologia , Pulmão/imunologia , Pulmão/virologia , Masculino , Pessoa de Meia-Idade , Células T Invariantes Associadas à Mucosa/classificação , Membrana Mucosa/citologia , Membrana Mucosa/imunologia , Fenótipo , Transcriptoma , Adulto Jovem
6.
Front Immunol ; 12: 637114, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815390

RESUMO

Introduction: The immunogenicity of BCG vaccination in infants differs between populations. We hypothesized that prenatal exposure to mycobacterial antigens might explain the differences in immune responses to BCG seen in other studies of infants in Africa and the United Kingdom (UK) and we explored this in birth cohorts in Uganda and the UK. Materials and Methods: Blood samples were obtained from BCG-immunized infants of mothers with (n = 110) and without (n = 121) latent Mycobacterium tuberculosis infection (LTBI) in Uganda and BCG-immunized infants of mothers without LTBI (n = 25) in the UK at 10 and 52 weeks after birth. Cytokine and chemokine responses to PPD were measured to assess responses to BCG immunization, and to ESAT6/CFP10 to assess exposure to or infection with M. tuberculosis or non-tuberculous mycobacteria (NTM) in 6-day whole blood culture supernatants by a 17-plex Luminex assay. Median responses were compared between Ugandan infants (together, and separated by maternal LTBI status) and UK infants. Results: The IFN-γ response to BCG vaccination was similar between Ugandan and UK infants at 10 and 52 weeks. At week 52, TNF production was marginally higher in Ugandan infants, but after adjusting for multiple comparisons this difference was not significant. At weeks 10 and 52, stimulation of blood with ESAT6/CFP10 produced significantly higher IFN-γ, TNF, IL-12p40, IL-1α, IL-1ß, IL-1Ra, IP-10, MIP-1α, MIP-1ß, and GM-CSF in Ugandan compared to UK infants. Stimulation of blood with ESAT6/CFP10 produced significantly higher amounts of IL-8 (p = 0.0001), IL-10 (p = 0.0022), and IL-13 (p = 0.0020) in the UK than in Ugandan infants of mothers without LTBI at week 10, but not at week 52. Conclusions: Immune responses to mycobacterial antigens following BCG immunization are similar for PPD, but differ for ESAT6/CFP10, between infants in Uganda and the UK. Neither maternal LTBI nor infant exposure to or infection with mycobacteria impacts the response to BCG. The observed global differences in immune response to BCG immunization are likely to be due to other causes.


Assuntos
Anticorpos Antibacterianos/sangue , Antígenos de Bactérias/imunologia , Vacina BCG/imunologia , Proteínas de Bactérias/imunologia , Mycobacterium tuberculosis/imunologia , Fragmentos de Peptídeos/imunologia , Tuberculina/imunologia , Feminino , Humanos , Lactente , Interferon gama/sangue , Tuberculose Latente/imunologia , Mycobacterium tuberculosis/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/imunologia , Fator de Necrose Tumoral alfa/sangue , Uganda , Reino Unido
7.
PLoS One ; 16(4): e0249477, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33836031

RESUMO

BACKGROUND: The search for immune correlates of protection against Mycobacterium tuberculosis (MTB) infection in humans is limited by the focus on peripheral blood measures. Bronchoalveolar lavage (BAL) can safely be done and provides insight into cellular function in the lung where infection is first established. In this study, blood and lung samples were assayed to determine if heavily MTB exposed persons who resist development of latent MTB infection (RSTR) vs those who develop latent MTB infection (LTBI), differ in the make-up of resident BAL innate and adaptive immune cells. METHODS: Bronchoscopy was performed on 21 healthy long-term Ugandan RSTR and 25 LTBI participants. Immune cell distributions in BAL and peripheral blood were compared by differential cell counting and flow cytometry. RESULTS: The bronchoscopy procedure was well tolerated with few adverse reactions. Differential macrophage and lymphocyte frequencies in BAL differed between RSTR and LTBI. When corrected for age, this difference lost statistical significance. BAL CD4+ and CD8+ T cells were almost entirely composed of effector memory T cells in contrast to PBMC, and did not differ between RSTR and LTBI. BAL NKT, γδ T cells and NK cells also did not differ between RTSR and LTBI participants. There was a marginally significant increase (p = 0.034) in CD8 T effector memory cells re-expressing CD45RA (TEMRA) in PBMC of LTBI vs RSTR participants. CONCLUSION: This observational case-control study comparing unstimulated BAL from RSTR vs LTBI, did not find evidence of large differences in the distribution of baseline BAL immune cells. PBMC TEMRA cell percentage was higher in LTBI relative to RSTR suggesting a role in the maintenance of latent MTB infection. Functional immune studies are required to determine if and how RSTR and LTBI BAL immune cells differ in response to MTB.


Assuntos
Líquido da Lavagem Broncoalveolar/imunologia , Resistência à Doença/imunologia , Tuberculose Latente/imunologia , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Leucócitos Mononucleares/imunologia , Masculino , Uganda
8.
Nat Commun ; 12(1): 2299, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863908

RESUMO

Mycobacterial cell-wall glycolipids elicit an anti-mycobacterial immune response via FcRγ-associated C-type lectin receptors, including Mincle, and caspase-recruitment domain family member 9 (CARD9). Additionally, mycobacteria harbor immuno-evasive cell-wall lipids associated with virulence and latency; however, a mechanism of action is unclear. Here, we show that the DAP12-associated triggering receptor expressed on myeloid cells 2 (TREM2) recognizes mycobacterial cell-wall mycolic acid (MA)-containing lipids and suggest a mechanism by which mycobacteria control host immunity via TREM2. Macrophages respond to glycosylated MA-containing lipids in a Mincle/FcRγ/CARD9-dependent manner to produce inflammatory cytokines and recruit inducible nitric oxide synthase (iNOS)-positive mycobactericidal macrophages. Conversely, macrophages respond to non-glycosylated MAs in a TREM2/DAP12-dependent but CARD9-independent manner to recruit iNOS-negative mycobacterium-permissive macrophages. Furthermore, TREM2 deletion enhances Mincle-induced macrophage activation in vitro and inflammation in vivo and accelerates the elimination of mycobacterial infection, suggesting that TREM2-DAP12 signaling counteracts Mincle-FcRγ-CARD9-mediated anti-mycobacterial immunity. Mycobacteria, therefore, harness TREM2 for immune evasion.


Assuntos
Evasão da Resposta Imune , Tuberculose Latente/imunologia , Glicoproteínas de Membrana/metabolismo , Mycobacterium tuberculosis/imunologia , Ácidos Micólicos/metabolismo , Receptores Imunológicos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Parede Celular/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Feminino , Glicolipídeos/metabolismo , Humanos , Tuberculose Latente/microbiologia , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Masculino , Glicoproteínas de Membrana/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Mycobacterium tuberculosis/metabolismo , Mycobacterium tuberculosis/patogenicidade , Cultura Primária de Células , Receptores de IgG/metabolismo , Receptores Imunológicos/genética , Fatores de Virulência/metabolismo
9.
Front Immunol ; 12: 575519, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33790886

RESUMO

Diagnosis of tuberculosis (TB) in children remains challenging due to unspecific clinical presentation and low bacillary load. In low TB incidence countries, most cases are diagnosed by a contact screening strategy after exposure to an index TB case. Due to the severity of TB in young children, the priority is to determine whether a child is infected or not, whereas differential diagnosis between active TB (aTB) and latent TB constitutes a second step. In Belgium, a low TB incidence country, we prospectively included 47 children with a defined M. tuberculosis infection status (12 children with aTB, 18 with latent TB, and 17 uninfected) (exploratory cohort), and determined the optimal combinations of cytokines secreted by their peripheral blood mononuclear cells in response to a 5-days in vitro stimulation with four different mycobacterial antigens, in an attempt to classify the children according to their infectious status. Correct identification of all infected children was obtained by several combinations of two purified protein derivative (PPD)-induced cytokines (IFN-γ and either GM-CSF, MIP-1α, sCD40L or TNF-α), or by combining PPD-induced IFN-γ with culture-filtrate protein-10 (CFP-10)-induced TNF-α. Alternatively, combining CFP-10-induced TNF-α and IP-10 with heparin-binding haemagglutinin (HBHA)-induced-IFN-γ was more effective in testing recently BCG-vaccinated children or those suspected to be infected with non-tuberculous mycobacteria, providing a correct classification of 97% of the M. tuberculosis-infected children. This combination also correctly classified 98% of the children from a validation cohort comprising 40 M. tuberculosis infected children and 20 non-infected children. Further differentiation between aTB and children with latent TB was more difficult. Combining ESAT-6-induced MIP1-α and IP-10, CFP-10-induced MIG, and HBHA-induced MIG provided a correct classification of 77% of the children from the exploratory cohort but only of 57.5% of those from the validation cohort. We conclude that combining the measurement of 2-4 cytokines induced by three different mycobacterial antigens allows an excellent identification of M. tuberculosis-infected children, whereas differentiating children with aTB from those with latent TB remains far from perfect.


Assuntos
Tuberculose Latente/imunologia , Mycobacterium tuberculosis/imunologia , Linfócitos T/imunologia , Tuberculose/imunologia , Adolescente , Bélgica/epidemiologia , Células Cultivadas , Criança , Pré-Escolar , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Interações Hospedeiro-Patógeno/imunologia , Humanos , Incidência , Lactente , Recém-Nascido , Tuberculose Latente/diagnóstico , Tuberculose Latente/microbiologia , Masculino , Mycobacterium tuberculosis/fisiologia , Linfócitos T/metabolismo , Linfócitos T/microbiologia , Tuberculose/diagnóstico , Tuberculose/epidemiologia
10.
Front Immunol ; 12: 595746, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33897680

RESUMO

Latent tuberculosis infection (LTBI) poses a major roadblock in the global effort to eradicate tuberculosis (TB). A deep understanding of the host responses involved in establishment and maintenance of TB latency is required to propel the development of sensitive methods to detect and treat LTBI. Given that LTBI individuals are typically asymptomatic, it is challenging to differentiate latently infected from uninfected individuals. A major contributor to this problem is that no clear pattern of host response is linked with LTBI, as molecular correlates of latent infection have been hard to identify. In this study, we have analyzed the global perturbations in host response in LTBI individuals as compared to uninfected individuals and particularly the heterogeneity in such response, across LTBI cohorts. For this, we constructed individualized genome-wide host response networks informed by blood transcriptomes for 136 LTBI cases and have used a sensitive network mining algorithm to identify top-ranked host response subnetworks in each case. Our analysis indicates that despite the high heterogeneity in the gene expression profiles among LTBI samples, clear patterns of perturbation are found in the immune response pathways, leading to grouping LTBI samples into 4 different immune-subtypes. Our results suggest that different subnetworks of molecular perturbations are associated with latent tuberculosis.


Assuntos
Tuberculose Latente/imunologia , Tuberculose Latente/microbiologia , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Tuberculose/microbiologia , Biologia Computacional , Bases de Dados Genéticas , Suscetibilidade a Doenças/imunologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Tuberculose Latente/diagnóstico , Tuberculose Latente/genética , Transcriptoma , Tuberculose/diagnóstico , Tuberculose/genética
12.
Front Immunol ; 12: 645446, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33746987

RESUMO

Antiretroviral treatment (ART) reduces the risk of developing active tuberculosis (TB) in HIV-1 co-infected persons. In order to understand host immune responses during ART in the context of Mycobacterium tuberculosis (Mtb) sensitization, we performed RNAseq analysis of whole blood-derived RNA from individuals with latent TB infection coinfected with HIV-1, during the first 6 months of ART. A significant fall in RNA sequence abundance of the Hallmark IFN-alpha, IFN-gamma, IL-6/JAK/STAT3 signaling, and inflammatory response pathway genes indicated reduced immune activation and inflammation at 6 months of ART compared to day 0. Further exploratory evaluation of 65 soluble analytes in plasma confirmed the significant decrease of inflammatory markers after 6 months of ART. Next, we evaluated 30 soluble analytes in QuantiFERON Gold in-tube (QFT) samples from the Ag stimulated and Nil tubes, during the first 6 months of ART in 30 patients. There was a significant decrease in IL-1alpha and IL-1beta (Ag-Nil) concentrations as well as MCP-1 (Nil), supporting decreased immune activation and inflammation. At the same time, IP-10 (Ag-nil) concentrations significantly increased, together with chemokine receptor-expressing CD4 T cell numbers. Our data indicate that ART-induced decrease in immune activation combined with improved antigen responsiveness may contribute to reduced susceptibility to tuberculosis in HIV-1/Mtb co-infected persons.


Assuntos
Antirretrovirais/administração & dosagem , Coinfecção/imunologia , Infecções por HIV , HIV-1/imunologia , Tuberculose Latente/imunologia , Mycobacterium tuberculosis/imunologia , RNA-Seq , Adulto , Citocinas/imunologia , Suscetibilidade a Doenças , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade
13.
Front Immunol ; 12: 620622, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33777000

RESUMO

Background: In individuals living with HIV infection the development of tuberculosis (TB) is associated with rapid progression from asymptomatic TB infection to active TB disease. Sputum-based diagnostic tests for TB have low sensitivity in minimal and subclinical TB precluding early diagnosis. The immune response to novel Mycobacterium tuberculosis in-vivo expressed and latency associated antigens may help to measure the early stages of infection and disease progression and thereby improve early diagnosis of active TB disease. Methods: Serial prospectively sampled cryopreserved lymphocytes from patients of the Swiss HIV Cohort Study developing TB disease ("cases") and matched patients with no TB disease ("controls") were stimulated with 10 novel Mycobacterium tuberculosis antigens. Cytokine concentrations were measured in cases and controls at four time points prior to diagnosis of TB: T1-T4 with T4 being the closest time point to diagnosis. Results: 50 samples from nine cases and nine controls were included. Median CD4 cell count at T4 was 289/ul for the TB-group and 456/ul for the control group. Viral loads were suppressed in both groups. At T4 Rv2431c-induced and Rv3614/15c-induced interferon gamma-induced protein (IP)-10 responses and Rv2031c-induced and Rv2346/Rv2347c-induced tumor necrosis factor (TNF)-α responses were significantly higher in cases compared to controls (p < 0.004). At T3 - being up to 2 years prior to TB diagnosis - Rv2031c-induced TNF-α was significantly higher in cases compared to controls (p < 0.004). Area under the receiver operating characteristics (AUROC) curves resulted in an AUC > 0.92 for all four antigen-cytokine pairs. Conclusion: The in vitro Mycobacterium tuberculosis-specific immune response in HIV-infected individuals that progress toward developing TB disease is different from those in HIV-infected individuals that do not progress to developing TB. These differences precede the clinical diagnosis of active TB up to 2 years, paving the way for the development of immune based diagnostics to predict TB disease at an early stage.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Tuberculose Latente/imunologia , Mycobacterium tuberculosis/fisiologia , Tuberculose/imunologia , Adulto , Antígenos de Bactérias/imunologia , Estudos de Casos e Controles , Células Cultivadas , Estudos de Coortes , Citocinas/metabolismo , Feminino , Infecções por HIV/diagnóstico , Humanos , Imunidade , Testes Imunológicos , Tuberculose Latente/diagnóstico , Masculino , Pessoa de Meia-Idade , Tuberculose/diagnóstico
14.
J Clin Invest ; 131(3)2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33529162

RESUMO

Humans have been infected with Mycobacterium tuberculosis (Mtb) for thousands of years. While tuberculosis (TB), one of the deadliest infectious diseases, is caused by uncontrolled Mtb infection, over 90% of presumed infected individuals remain asymptomatic and contain Mtb in a latent TB infection (LTBI) without ever developing disease, and some may clear the infection. A small number of heavily Mtb-exposed individuals appear to resist developing traditional LTBI. Because Mtb has mechanisms for intracellular survival and immune evasion, successful control involves all of the arms of the immune system. Here, we focus on immune responses to Mtb in humans and nonhuman primates and discuss new concepts and outline major knowledge gaps in our understanding of LTBI, ranging from the earliest events of exposure and infection to success or failure of Mtb control.


Assuntos
Evasão da Resposta Imune , Tuberculose Latente/imunologia , Mycobacterium tuberculosis/imunologia , Animais , Humanos , Tuberculose Latente/patologia , Tuberculose Latente/terapia
15.
Am J Respir Crit Care Med ; 203(12): 1556-1565, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33406011

RESUMO

Rationale: Current diagnostic tests fail to identify individuals at higher risk of progression to tuberculosis disease, such as those with recent Mycobacterium tuberculosis infection, who should be prioritized for targeted preventive treatment. Objectives: To define a blood-based biomarker, measured with a simple flow cytometry assay, that can stratify different stages of tuberculosis infection to infer risk of disease. Methods: South African adolescents were serially tested with QuantiFERON-TB Gold to define recent (QuantiFERON-TB conversion <6 mo) and persistent (QuantiFERON-TB+ for >1 yr) infection. We defined the ΔHLA-DR median fluorescence intensity biomarker as the difference in HLA-DR expression between IFN-γ+ TNF+ Mycobacterium tuberculosis-specific T cells and total CD3+ T cells. Biomarker performance was assessed by blinded prediction in untouched test cohorts with recent versus persistent infection or tuberculosis disease and by unblinded analysis of asymptomatic adolescents with tuberculosis infection who remained healthy (nonprogressors) or who progressed to microbiologically confirmed disease (progressors). Measurements and Main Results: In the test cohorts, frequencies of Mycobacterium tuberculosis-specific T cells differentiated between QuantiFERON-TB- (n = 25) and QuantiFERON-TB+ (n = 47) individuals (area under the receiver operating characteristic curve, 0.94; 95% confidence interval, 0.87-1.00). ΔHLA-DR significantly discriminated between recent (n = 20) and persistent (n = 22) QuantiFERON-TB+ (0.91; 0.83-1.00); persistent QuantiFERON-TB+ and newly diagnosed tuberculosis (n = 19; 0.99; 0.96-1.00); and tuberculosis progressors (n = 22) and nonprogressors (n = 34; 0.75; 0.63-0.87). However, ΔHLA-DR median fluorescent intensity could not discriminate between recent QuantiFERON-TB+ and tuberculosis (0.67; 0.50-0.84). Conclusions: The ΔHLA-DR biomarker can identify individuals with recent QuantiFERON-TB conversion and those with disease progression, allowing targeted provision of preventive treatment to those at highest risk of tuberculosis. Further validation studies of this novel immune biomarker in various settings and populations at risk are warranted.


Assuntos
Biomarcadores/sangue , Tuberculose Latente/diagnóstico , Tuberculose Latente/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/diagnóstico , Tuberculose/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco/métodos , África do Sul , Teste Tuberculínico/métodos , Adulto Jovem
16.
JAMA Dermatol ; 157(1): 43-51, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33001147

RESUMO

Importance: Approximately one-quarter of the global population have latent tuberculosis infection (LTBI), and tuberculosis (TB) is accountable for more than 1.5 million deaths annually. Methotrexate, cyclosporine, and tumor necrosis factor inhibitors may be associated with increased risk of TB and LTBI reactivation, although data are limited on the risks of TB with use of newer biologics. Objective: To assess the association of secukinumab with reporting of active TB development, TB reactivation, and LTBI activation as an adverse event (AE) in patients with psoriasis, psoriatic arthritis, or ankylosing spondylitis. Design, Setting, and Participants: This pooled cohort study pooled data from 28 clinical trials of secukinumab used in psoriasis (17 phase 3 or 3b and 2 phase 4 trials), psoriatic arthritis (5 phase 3 trials), and ankylosing spondylitis (4 phase 3 trials). A search of the Novartis Secukinumab Compound Pool Database was conducted for the 28 trials. All trial participants who had received at least 1 approved subcutaneous dose of secukinumab (150 mg or 300 mg) were included. Before randomization in these trials, patients underwent screening for TB. Patients with active TB were excluded, and patients with LTBI were treated according to local guidelines. Data were analyzed from the start of treatment in the individual studies through December 25, 2018. Main Outcomes and Measures: Reporting of active TB or LTBI as an AE over a 5-year period using exposure-adjusted incidence rates (EAIR; incidence rates per 100 patient-years). Results: A total of 12 319 patients were included, of whom 8819 patients had psoriasis (71.6%; 5930 men [67.2%]; mean [SD] age, of 44.9 [13.5] years), 2523 had psoriatic arthritis (20.5%; 1323 women [52.4%]; mean [SD] age, 48.8 [12.1] years), and 977 had ankylosing spondylitis (7.3%; 658 men [67.3%]; mean [SD] age, 42.3 [11.9] years). In the total population, 684 patients (5.6%) had tested positive for LTBI at screening. Over 5 years, LTBI as an AE during secukinumab treatment was reported in 13 patients (0.1% of 12 319). Of these 13 patients, 6 had a prior positive LTBI test result, and 7 were newly diagnosed as having LTBI. Four of the 7 patients had psoriasis (EAIR, 0.03; 95% CI, 0.01-0.07), 1 had psoriatic arthritis (EAIR, 0.02; 95% CI, 0.00-0.11), and 2 had ankylosing spondylitis (EAIR, 0.08; 95% CI, 0.01-0.28). No cases of active TB were reported. Conclusions and Relevance: This study found that LTBI reported as an AE after secukinumab treatment was uncommon and appeared to support the use of secukinumab in chronic systemic inflammatory conditions.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Artrite Psoriásica/tratamento farmacológico , Tuberculose Latente/epidemiologia , Psoríase/tratamento farmacológico , Espondilite Anquilosante/tratamento farmacológico , Adulto , Artrite Psoriásica/imunologia , Conjuntos de Dados como Assunto , Feminino , Humanos , Incidência , Interleucina-17/antagonistas & inibidores , Interleucina-17/imunologia , Tuberculose Latente/diagnóstico , Tuberculose Latente/imunologia , Masculino , Pessoa de Meia-Idade , Psoríase/imunologia , Pesquisa Qualitativa , Ensaios Clínicos Controlados Aleatórios como Assunto , Espondilite Anquilosante/imunologia
17.
Cell Host Microbe ; 29(2): 165-178.e8, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33340449

RESUMO

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) latently infects approximately one-fourth of the world's population. The immune mechanisms that govern progression from latent (LTBI) to active pulmonary TB (PTB) remain poorly defined. Experimentally Mtb-infected non-human primates (NHP) mirror the disease observed in humans and recapitulate both PTB and LTBI. We characterized the lung immune landscape in NHPs with LTBI and PTB using high-throughput technologies. Three defining features of PTB in macaque lungs include the influx of plasmacytoid dendritic cells (pDCs), an Interferon (IFN)-responsive macrophage population, and activated T cell responses. In contrast, a CD27+ Natural killer (NK) cell subset accumulated in the lungs of LTBI macaques. This NK cell population was also detected in the circulation of LTBI individuals. This comprehensive analysis of the lung immune landscape will improve the understanding of TB immunopathogenesis, providing potential targets for therapies and vaccines for TB control.


Assuntos
Células Dendríticas/imunologia , Células Matadoras Naturais/imunologia , Tuberculose Latente/imunologia , Macrófagos/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/imunologia , Animais , Humanos , Pulmão/citologia , Pulmão/imunologia , Macaca mulatta , Tuberculose Pulmonar/patologia
19.
Sci Rep ; 10(1): 21367, 2020 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-33288814

RESUMO

A significantly negative reversion in the QuantiFERON-TB Gold In-tube (QFT-GIT) test is reported in patients on dialysis, which makes the results unreliable. The CD4 and CD8 responses of the QFT-Gold plus (QFT-Plus) may have better positive consistency, but this needs to be investigated. We enrolled dialysis patients with baseline positive QFT-GIT0 results and conducted two rounds of follow-up paired QFT-GIT1&2 and QFT-Plus1&2 tests at an interval of 6 months. The positive consistency, concordance, and discordance of the QFT results were analyzed. A total of 236 patients on dialysis were screened, and 73 participants with positive QFT-GIT0 results were enrolled. The baseline QFT-GIT0 response was higher in the 1st QFT-Plus1(+) group than in the QFT-Plus1(-) group, but insignificantly different between the 1st QFT-GIT1(+) and QFT-GIT1(-) groups. The two assays had good correlation when concurrently tested. Fifty-three subjects completed a second round of the QFT-GIT2 and QFT-Plus2. Persistent positivity was higher with the QFT-Plus2 (81.8%) than with the QFT-GIT2 (58.8%, p = 0.040). The QFT-GIT1 and QFT-Plus1 CD4 responses were higher in patients with persistent positivity than in those with negative reversion, whereas the difference of the QFT-Plus TB1 and TB2 data, representative of the CD8 response, were similar between positive persistence and negative reversion. In conclusion, the QFT-Plus provides more reliable positive consistency than does the QFT-GIT. The CD4 interferon-γ response might play a role in maintaining positivity of LTBI.


Assuntos
Tuberculose Latente/diagnóstico , Adulto , Idoso , Biomarcadores/sangue , Linfócitos T CD8-Positivos/metabolismo , Atenção à Saúde , Feminino , Humanos , Testes de Liberação de Interferon-gama , Tuberculose Latente/imunologia , Tuberculose Latente/terapia , Masculino , Pessoa de Meia-Idade , Diálise Renal , Fatores de Risco
20.
Med Hypotheses ; 144: 110214, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33254521

RESUMO

Since the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, there has been significant interest in the potential protective effect of the Bacillus Calmette-Guerin (BCG) vaccine against COVID-19 mortality. This effect has been attributed to innate immune responses induced by BCG vaccination. However, these studies ignore an important fact: according to World Health Organization estimates, about a quarter of the world's population may have latent tuberculosis infection (LTBI), a condition in which there is no evidence of clinically active tuberculosis but persistent immune responses are stimulated by Mycobacterium tuberculosis antigens. Thus, both LTBI and BCG induce lifelong immunity and may provide immunological protection against COVID-19. In this study, the relationship between LTBI and reduced COVID-19 mortality was analyzed using the instrumental variable method. The results showed with robust statistical support that LTBI was also associated with reduced COVID-19 mortality.


Assuntos
COVID-19/complicações , COVID-19/mortalidade , Tuberculose Latente/complicações , Pandemias , Vacina BCG/imunologia , COVID-19/imunologia , Humanos , Imunidade Inata , Japão/epidemiologia , Tuberculose Latente/epidemiologia , Tuberculose Latente/imunologia , Modelos Estatísticos , Pandemias/prevenção & controle , Prevalência , SARS-CoV-2/imunologia
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