Outcome Of Mycobacterium Tuberculosis Infection Research Articles

Differential expression of CD64 in patients with Mycobacterium tuberculosis infection: A potential biomarker for clinical diagnosis and prognosis.

To evaluate the clinical utility of neutrophil (n)CD64 index to diagnose pulmonary tuberculosis (PTB) and extrapulmonary TB (ePTB) and to predict the outcome of Mycobacterium tuberculosis infection. We recruited 189 patients with active TB and 140 controls and measured the differential expression of nCD64 index using flow cytometry. The receiver operating characteristics (ROC) curve analysis was performed to estimate the diagnostic performance of the nCD64 index and T‐SPOT.TB assay for the diagnosis of TB. Furthermore, we analysed whether the nCD64 index in patients with TB was correlated with inflammatory indicators. Finally, we assessed the prognosis of patients by following the dynamic changes of the nCD64 index once a week. The nCD64 index was significantly higher in active TB group (PTB and ePTB), than in the anti‐TB and healthy controls (HC) groups. The sensitivity and specificity of nCD64 index for the differential diagnosis of PTB and pneumonia (PN) patients were 68.33% and 77.55%, respectively. The sensitivity and specificity of nCD64 index for the diagnosis of tuberculous meningitis (TBM) were 53.85% and 100%, respectively. Furthermore, there was a weak correlation between the nCD64 index and inflammatory indicators. More importantly, with the improvement in patient condition, the nCD64 index started to decline in the first week of anti‐TB therapy and significantly decreased at 4 weeks after treatment. Our study demonstrated that the CD64 assay is a rapid, non‐invasive and stable method for clinical application, and the nCD64 index can serve as a potential biomarker for the diagnosis and prognosis of TB.

Cutting Edge: Bacillus Calmette-Guérin-Induced T Cells Shape Mycobacterium tuberculosis Infection before Reducing the Bacterial Burden.

Growing evidence suggests the outcome of Mycobacterium tuberculosis infection is established rapidly after exposure, but how the current tuberculosis vaccine, bacillus Calmette-Guérin (BCG), impacts early immunity is poorly understood. In this study, we found that murine BCG immunization promotes a dramatic shift in infected cell types. Although alveolar macrophages are the major infected cell for the first 2 weeks in unimmunized animals, BCG promotes the accelerated recruitment and infection of lung-infiltrating phagocytes. Interestingly, this shift is dependent on CD4 T cells, yet does not require intrinsic recognition of Ag presented by infected alveolar macrophages. M. tuberculosis-specific T cells are first activated in lung regions devoid of infected cells, and these events precede vaccine-induced reduction of the bacterial burden, which occurs only after the colocalization of T cells and infected cells. Understanding how BCG alters early immune responses to M. tuberculosis provides new avenues to improve upon the immunity it confers.

The Patterns of Interferon-Gamma and Interleukin-10 Production as a Potential Immunological Biomarker for the Outcome of Mycobacterium Tuberculosis Infection

Deficiencies in current tuberculosis (TB) immunodiagnostics pipeline demand new approaches to control TB. Because the balance in key pro- and anti-inflammatory cytokines production could determine Mycobacterium Tuberculosis (MTb) infection outcome, this study aimed to determine the patterns of MTb-specific antigen-stimulated Interferon-gamma (IFN-y) and Interleukin-10 (IL-10) production in different clinical forms of MTb infection and to evaluate their concomitant changes during anti-TB treatment (ATT). Overall, 84 BCG-vaccinated HIV-negative adults, consisting of 25 Healthy Community Controls (HCC), 27 Latent Tuberculosis Infection (LTBI) cases, and a cohort of 32 Acute Pulmonary Tuberculosis (APTB) patients were investigated for IFN-y and IL-10 responses at enrollment (base-line) and during ATT at 2-month (ATT1) and 6-month (ATT2). At enrollment, groups didn’t differ significantly in age, gender, or CD4+ T counts but differed in the other socio-demographics, and hematological parameters, p<0.05. Base-line Sandwich ELISA – measured IFN-y responses were significantly higher in HCC (223.50±58.11pg/ml) compared with LTBI (128.82±41.81pg/ml) and APTB (47.82±22.05pg/ml), p<0.0001 in each case. During treatment, IFN-y levels increased significantly at ATT1 (125.37±16.09pg/ml) and ATT2 (203.35±23.24pg/ml), p<0.0001. Conversely, base-line IL-10 responses increased significantly in APTB (17.53±6.30pg/ml), compared with LTBI (10.71±2.39pg/ml) and HCC (7.49±2.02pg/ml), P<0.0001, but declined significantly at ATT1 (10.54±2.25pg/ml) and ATT2 (5.25±1.45pg/ml), P=<0.0001. Cytokines response combination ratio showed: ‘High’ HCC, ‘Intermediate’ LTBI, or ‘Low’ APTB ratio that increased during successful ATT; the two identified MDR-TB patients recorded fluctuating but constantly low ratio during ATT. These results demonstrate the immunocompetence of MTb-exposed adults, and that IFN-y and IL-10 cytokines cross-regulate, and strongly suggest a shift toward IFN-y-mediated pro-inflammatory host immune phenotype during effective control of MTb infection. The IFN-y/IL-10 response ratio is a novel potential immunological biomarker to assess if MTb infection is going to resolve, result in latency, progress to TB; or become drug-resistant.

Tuberculosis Susceptibility and Vaccine Protection Are Independently Controlled by Host Genotype.

ABSTRACTThe outcome of Mycobacterium tuberculosis infection and the immunological response to the bacillus Calmette-Guerin (BCG) vaccine are highly variable in humans. Deciphering the relative importance of host genetics, environment, and vaccine preparation for the efficacy of BCG has proven difficult in natural populations. We developed a model system that captures the breadth of immunological responses observed in outbred individual mice, which can be used to understand the contribution of host genetics to vaccine efficacy. This system employs a panel of highly diverse inbred mouse strains, consisting of the founders and recombinant progeny of the “Collaborative Cross” project. Unlike natural populations, the structure of this panel allows the serial evaluation of genetically identical individuals and the quantification of genotype-specific effects of interventions such as vaccination. When analyzed in the aggregate, our panel resembled natural populations in several important respects: the animals displayed a broad range of susceptibility to M. tuberculosis, differed in their immunological responses to infection, and were not durably protected by BCG vaccination. However, when analyzed at the genotype level, we found that these phenotypic differences were heritable. M. tuberculosis susceptibility varied between lines, from extreme sensitivity to progressive M. tuberculosis clearance. Similarly, only a minority of the genotypes was protected by vaccination. The efficacy of BCG was genetically separable from susceptibility to M. tuberculosis, and the lack of efficacy in the aggregate analysis was driven by nonresponsive lines that mounted a qualitatively distinct response to infection. These observations support an important role for host genetic diversity in determining BCG efficacy and provide a new resource to rationally develop more broadly efficacious vaccines.

Route of delivery to the airway influences the distribution of pulmonary disease but not the outcome of Mycobacterium tuberculosis infection in rhesus macaques

Non-human primates (NHP) provide a key component in the preclinical assessment pathway for new TB vaccines. In the established models, Mycobacterium tuberculosis challenge is typically delivered to airways of macaques either by aerosol or bronchoscopic instillation and therefore, an understanding of these delivery routes would facilitate the comparison of data generated from models using different challenge methods. This study compared the clinical effects, antigen-specific IFNγ response profiles and disease burden following delivery of comparable doses of M. tuberculosis to the lungs of rhesus macaques by either aerosol or bronchoscopic instillation. The outcome of infection in terms of clinical effects and overall disease burden was comparable between both routes of challenge. However, the pathology in the lungs differed as disease was localised to the site of inoculation following bronchoscopic instillation while aerosol exposure resulted in lesions being evenly distributed through the lung. Whilst the IFNγ response to PPD was similar, responses to CFP10 and ESAT6 peptide pools measured with an ex vivo ELISPOT differed with regards to responses to the N-terminal regions depending on the route of infection. Both challenge routes therefore provide valid and comparable models for evaluation of new TB vaccines, although subtle differences in host responses may occur.

Proteome-Scale Antibody Responses and Outcome of Mycobacterium tuberculosis Infection in Nonhuman Primates and in Tuberculosis Patients

Biomarkers of progression from latent Mycobacterium tuberculosis infection to active tuberculosis are needed. We assessed correlations between infection outcome and antibody responses in macaques and humans by high-throughput, proteome-scale serological studies. Mycobacterium tuberculosis proteome microarrays were probed with serial sera from macaques representing various infection outcomes and with single-point human sera from tuberculosis suspects. Fluorescence intensity data were analyzed by calculating Z scores and associated P values. Temporal changes in macaque antibody responses were analyzed by polynomial regression. Correlations between human responses and sputum bacillary burden were assessed by quantile and hurdle regression. Macaque outcome groups exhibited distinct antibody profiles: early, transient responses in latent infection and stable antibody increase in active and reactivation disease. In humans, antibody levels and reactive protein numbers increased with bacillary burden. Responses to a subset of 10 proteins were more tightly associated with disease state than reactivity to the broader reactive proteome. Integration of macaque and human data reveals dynamic properties of antibody responses in relation to outcome and leads to actionable findings for translational research. These include the potential of antibody responses to detect acute infection and preclinical tuberculosis and to identify serodiagnostic proteins for the spectrum of bacillary burden in tuberculosis.

Intranasal Poly-IC treatment exacerbates tuberculosis in mice through the pulmonary recruitment of a pathogen-permissive monocyte/macrophage population

Type I IFN has been demonstrated to have major regulatory effects on the outcome of bacterial infections. To assess the effects of exogenously induced type I IFN on the outcome of Mycobacterium tuberculosis infection, we treated pathogen-exposed mice intranasally with polyinosinic-polycytidylic acid condensed with poly-l-lysine and carboxymethylcellulose (Poly-ICLC), an agent designed to stimulate prolonged, high-level production of type I IFN. Drug-treated, M. tuberculosis-infected WT mice, but not mice lacking IFN-alphabeta receptor 1 (IFNalphabetaR; also known as IFNAR1), displayed marked elevations in lung bacillary loads, accompanied by widespread pulmonary necrosis without detectable impairment of Th1 effector function. Importantly, lungs from Poly-ICLC-treated M. tuberculosis-infected mice exhibited a striking increase in CD11b+F4/80+Gr1int cells that displayed decreased MHC II expression and enhanced bacterial levels relative to the same subset of cells purified from infected, untreated controls. Moreover, both the Poly-ICLC-triggered pulmonary recruitment of the CD11b+F4/80+Gr1int population and the accompanying exacerbation of infection correlated with type I IFN-induced upregulation of the chemokine-encoding gene Ccl2 and were dependent on host expression of the chemokine receptor CCR2. The above findings suggest that Poly-ICLC treatment can detrimentally affect the outcome of M. tuberculosis infection, by promoting the accumulation of a permissive myeloid population in the lung. In addition, these data suggest that agents that stimulate type I IFN should be used with caution in patients exposed to this pathogen.

Suppressive Th17 responses in patients with active tuberculosis is associated with reduced IL-6R expression on CD4+ T cells (37.51)

Abstract The frequencies of IFN-γ-, IL-4-, IL-17-, FoxP3- and IL-6R- expressing CD4+ T cells in blood and/or pleural effusion sample of healthy donors, subjects with latent tuberculosis infection and patients with active tuberculosis, were analyzed by flow cytometry. The frequency of Th17 cells in patients with active tuberculosis is significantly lower than those in healthy donors and individuals with latent tuberculosis infection. The reduction of Th17 response was significantly more profound in patients with severe tuberculosis disease compared to those with pulmonary tuberculosis only. The frequency of Th17 cells was significantly lower in pleural effusion samples than in cohort peripheral blood from patients with tuberculous pleurisy. Correlation analysis showed that suppressive Th17 response observed in patients with active tuberculosis was significantly correlated with the reduced expression of interleukin-6 receptor on CD4+ T cells, but not the concentration of cytokine TGF-βand IL-6. consistently, in vitro study showed that Mycobacterium tuberculosis products inhibit the expression of interleukin-6 receptor on CD4+ T cells. Our results demonstrated that decreased Th17 responses were associated with the clinical outcome of Mycobacterium tuberculosis infection. Suppression of Th17 response through down-regulation of interleukin-6 receptor expression may be an important mechanism in the development of active tuberculosis.

Progression to Active Tuberculosis, but Not Transmission, Varies byMycobacterium tuberculosisLineage in The Gambia

There is considerable variability in the outcome of Mycobacterium tuberculosis infection. We hypothesized that Mycobacterium africanum was less likely than M. tuberculosis to transmit and progress to tuberculosis disease. In a cohort study of patients with tuberculosis and their household contacts in The Gambia, we categorized 1808 HIV-negative tuberculosis contacts according to exposure to M. tuberculosis or M. africanum. Positive skin test results indicated transmission, and development of tuberculosis during 2 years of follow-up indicated progression to disease. Transmission rates were similar, but rates of progression to disease were significantly lower in contacts exposed to M. africanum than in those exposed to M. tuberculosis (1.0% vs. 2.9%; hazard ratio [HR], 3.1 [95% confidence interval {CI}, 1.1-8.7]). Within M. tuberculosis sensu stricto, contacts exposed to a Beijing family strain were most likely to progress to disease (5.6%; HR relative to M. africanum, 6.7 [95% CI, 2.0-22]). M. africanum and M. tuberculosis transmit equally well to household contacts, but contacts exposed to M. africanum are less likely to progress to tuberculosis disease than those exposed to M. tuberculosis. The variable rate of progression by lineage suggests that tuberculosis variability matters in clinical settings and should be accounted for in studies evaluating tuberculosis vaccines and treatment regimens for latent tuberculosis infection.