Diabetes screen during tuberculosis contact investigations highlights opportunity for new diabetes diagnosis and reveals metabolic differences between ethnic groups

Type 2 diabetes (T2D) is a prevalent risk factor for tuberculosis (TB), but most studies on TB-T2D have focused on TB patients, been limited to one community, and shown a variable impact of T2D on TB risk or treatment outcomes. We conducted a cross-sectional assessment of sociodemographic and metabolic factors in adult TB contacts with T2D (versus no T2D), from the Texas-Mexico border to study Hispanics, and in Cape Town to study South African Coloured ethnicities. The prevalence of T2D was 30.2% in Texas-Mexico and 17.4% in South Africa, with new diagnosis in 34.4% and 43.9%, respectively. Contacts with T2D differed between ethnicities, with higher smoking, hormonal contraceptive use and cholesterol levels in South Africa, and higher obesity in Texas-Mexico (p \u3c 0.05). PCA analysis revealed striking differences between ethnicities in the relationships between factors defining T2D and dyslipidemias. Our findings suggest that screening for new T2D in adult TB contacts is effective to identify new T2D patients at risk for TB. Furthermore, studies aimed at predicting individual TB risk in T2D patients, should take into account the heterogeneity in dyslipidemias that are likely to modify the estimates of TB risk or adverse treatment outcomes that are generally attributed to T2D alone

Diabetes screen during tuberculosis contact investigations highlights opportunity for new diabetes diagnosis and reveals metabolic differences between ethnic groups

Type 2 diabetes (T2D) is a prevalent risk factor for tuberculosis (TB), but most studies on TB-T2D have focused on TB patients, been limited to one community, and shown a variable impact of T2D on TB risk or treatment outcomes. We conducted a cross-sectional assessment of sociodemographic and metabolic factors in adult TB contacts with T2D (versus no T2D), from the Texas-Mexico border to study Hispanics, and in Cape Town to study South African Coloured ethnicities. The prevalence of T2D was 30.2% in Texas-Mexico and 17.4% in South Africa, with new diagnosis in 34.4% and 43.9%, respectively. Contacts with T2D differed between ethnicities, with higher smoking, hormonal contraceptive use and cholesterol levels in South Africa, and higher obesity in Texas-Mexico (p < 0.05). PCA analysis revealed striking differences between ethnicities in the relationships between factors defining T2D and dyslipidemias. Our findings suggest that screening for new T2D in adult TB contacts is effective to identify new T2D patients at risk for TB. Furthermore, studies aimed at predicting individual TB risk in T2D patients, should take into account the heterogeneity in dyslipidemias that are likely to modify the estimates of TB risk or adverse treatment outcomes that are generally attributed to T2D alone

Medroxyprogesterone Acetate Alters Mycobacterium Bovis BCG-Induced Cytokine Production in Peripheral Blood Mononuclear Cells of Contraceptive Users

Most individuals latently infected with Mycobacterium tuberculosis (M.tb) contain the infection by a balance of effector and regulatory immune responses. This balance can be influenced by steroid hormones such as glucocorticoids. The widely used contraceptive medroxyprogesterone acetate (MPA) possesses glucocorticoid activity. We investigated the effect of this hormone on immune responses to BCG in household contacts of active TB patients. Multiplex bead array analysis revealed that MPA demonstrated both glucocorticoid and progestogenic properties at saturating and pharmacological concentrations in peripheral blood mononuclear cells (PBMCs) and suppressed antigen specific cytokine production. Furthermore we showed that PBMCs from women using MPA produced significantly lower levels of IL-1α, IL-12p40, IL-10, IL-13 and G-CSF in response to BCG which corresponded with lower numbers of circulating monocytes observed in these women. Our research study is the first to show that MPA impacts on infections outside the genital tract due to a systemic effect on immune function. Therefore MPA use could alter susceptibility to TB, TB disease severity as well as change the efficacy of new BCG-based vaccines, especially prime-boost vaccine strategies which may be administered to adult or adolescent women in the future

Distinct serum biosignatures are associated with different tuberculosis treatment outcomes.

Biomarkers for TB treatment response and outcome are needed. This study characterize changes in immune profiles during TB treatment, define biosignatures associated with treatment outcomes, and explore the feasibility of predictive models for relapse. Seventy-two markers were measured by multiplex cytokine array in serum samples from 78 cured, 12 relapsed and 15 failed treatment patients from South Africa before and during therapy for pulmonary TB. Promising biosignatures were evaluated in a second cohort from Uganda/Brazil consisting of 17 relapse and 23 cured patients. Thirty markers changed significantly with different response patterns during TB treatment in cured patients. The serum biosignature distinguished cured from relapse patients and a combination of two clinical (time to positivity in liquid culture and BMI) and four immunological parameters (TNF-?, sIL-6R, IL-12p40 and IP-10) at diagnosis predicted relapse with a 75% sensitivity (95%CI 0.38-1) and 85% specificity (95%CI 0.75-0.93). This biosignature was validated in an independent Uganda/Brazil cohort correctly classifying relapse patients with 83% (95%CI 0.58-1) sensitivity and 61% (95%CI 0.39-0.83) specificity. A characteristic biosignature with value as predictor of TB relapse was identified. The repeatability and robustness of these biomarkers require further validation in well-characterized cohorts

Culture-Independent PCR Detection and Differentiation of <i>Mycobacteria</i> spp. in Antemortem Respiratory Samples from African Elephants (<i>Loxodonta Africana</i>) and Rhinoceros (<i>Ceratotherium Simum</i>, <i>Diceros Bicornis</i>) in South Africa

Since certain Mycobacterium tuberculosis complex (MTBC) members, such as M. bovis, are endemic in specific South African wildlife reserves and zoos, cases of clinically important nontuberculous mycobacteria (NTM) in wildlife may be neglected. Additionally, due to the inability of tests to differentiate between the host responses to MTBC and NTM, the diagnosis of MTBC may be confounded by the presence of NTMs. This may hinder control efforts. These constraints highlight the need for enhanced rapid detection and differentiation methods for MTBC and NTM, especially in high MTBC burden areas. We evaluated the use of the GeneXpert MTB/RIF Ultra, the Hain CMdirect V1.0 line probe assay, and novel amplicon sequencing PCRs targeting the mycobacterial rpoB and ku gene targets, directly on antemortem African elephant (n = 26) bronchoalveolar lavage fluid (BALF) (n = 22) and trunk washes (n = 21) and rhinoceros (n = 23) BALF (n = 23), with known MTBC culture-positive and NTM culture-positive results. Our findings suggest that the Ultra is the most sensitive diagnostic test for MTBC DNA detection directly in raw antemortem respiratory specimens and that the rpoB PCR is ideal for Mycobacterium genus DNA detection and species identification through amplicon sequencing

Identification and Characterisation of Nontuberculous Mycobacteria in African Buffaloes (<i>Syncerus caffer</i>), South Africa

Diagnosis of bovine tuberculosis (bTB) may be confounded by immunological cross-reactivity to Mycobacterium bovis antigens when animals are sensitised by certain nontuberculous mycobacteria (NTMs). Therefore, this study aimed to investigate NTM species diversity in African buffalo (Syncerus caffer) respiratory secretions and tissue samples, using a combination of novel molecular tools. Oronasal swabs were collected opportunistically from 120 immobilised buffaloes in historically bTB-free herds. In addition, bronchoalveolar lavage fluid (BALF; n = 10) and tissue samples (n = 19) were obtained during post-mortem examination. Mycobacterial species were identified directly from oronasal swab samples using the Xpert MTB/RIF Ultra qPCR (14/120 positive) and GenoType CMdirect (104/120 positive). In addition, all samples underwent mycobacterial culture, and PCRs targeting hsp65 and rpoB were performed. Overall, 55 NTM species were identified in 36 mycobacterial culture-positive swab samples with presence of esat-6 or cfp-10 detected in 20 of 36 isolates. The predominant species were M. avium complex and M. komanii. Nontuberculous mycobacteria were also isolated from 6 of 10 culture-positive BALF and 4 of 19 culture-positive tissue samples. Our findings demonstrate that there is a high diversity of NTMs present in buffaloes, and further investigation should determine their role in confounding bTB diagnosis in this species

Clinical immunology and multiplex biomarkers of human tuberculosis

The discovery of tuberculosis (TB) biomarkers is an important goal in current TB research, because the availability of such markers would have significant impact on TB prevention and treatment. Correlates of protection would greatly facilitate vaccine development and evaluation, whereas correlates of TB disease risk would facilitate early diagnosis and help installing early or preventive treatment. Currently, no such markers are available. This review describes several strategies that are currently being pursued to identify TB biomarkers and places these in a clinical context. The approaches discussed include both targeted and untargeted hypothesis-free strategies. Among the first are the measurements of specific biomarkers in antigen-stimulated peripheral blood, in serum or plasma, and detailed immune cell phenotyping. Among the latter are proteomic, genomic, and transcriptomic (mRNA, miRNA) approaches. Recent and promising developments are described

Patients with Concurrent Tuberculosis and Diabetes Have a Pro-Atherogenic Plasma Lipid Profile

Background: Type 2 diabetes mellitus (DM) is a major risk factor for development of tuberculosis (TB), however the underlying molecular foundations are unclear. Since lipids play a central role in the development of both DM and TB, lipid metabolism may be important for TB-DM pathophysiology. Methods: A 1 H NMR spectroscopy-based platform was used to determine 225 lipid and other metabolic intermediates in plasma samples of healthy controls (n = 50) and patients with TB (n = 50), DM (n = 50) or TB-DM (n = 27). Results: TB patients presented with wasting disease, represented by decreased amino acid levels including histidine and alanine. Conversely, DM patients were dyslipidemic as evidenced by high levels of very low-density lipoprotein triglycerides and low high-density lipoprotein cholesterol. TB-DM patients displayed metabolic characteristics of both wasting and dyslipidemia combined with disease interaction-specific increases in phospholipid metabolites (e.g. sphingomyelins) and atherogenic remnant-like lipoprotein particles. Biomarker analysis identified the ratios of phenylalanine/histidine and esterified cholesterol/sphingomyelin as markers for TB classification regardless of DM-status. Conclusions: TB-DM patients possess a distinctive plasma lipid profile with pro-atherogenic properties. These findings support further research on the benefits of improved blood lipid control in the treatment of TB-DM. Pattern Recognition and Bioinformatic

The functional response of B cells to antigenic stimulation: a preliminary report of latent tuberculosis

Mycobacterium tuberculosis (M.tb) remains a successful pathogen, causing tuberculosis disease numbers to constantly increase. Although great progress has been made in delineating the disease, the host-pathogen interaction is incompletely described. B cells have shown to function as both effectors and regulators of immunity via non-humoral methods in both innate and adaptive immune settings. Here we assessed specific B cell functional interaction following stimulation with a broad range of antigens within the LTBI milieu. Our results indicate that B cells readily produce pro- and anti-inflammatory cytokines (including IL-1β, IL-10, IL-17, IL-21 and TNF-α) in response to stimulation. TLR4 and TLR9 based stimulations achieved the greatest secreted cytokine-production response and BCG stimulation displayed a clear preference for inducing IL-1β production. We also show that the cytokines produced by B cells are implicated strongly in cell-mediated communication and that plasma (memory) B cells (CD19CD27CD138) is the subset with the greatest contribution to cytokine production. Collectively our data provides insight into B cell responses, where they are implicated in and quantifies responses from specific B cell phenotypes. These findings warrant further functional B cell research with a focus on specific B cell phenotypes under conditions of active TB disease to further our knowledge about the contribution of various cell subsets which could have implications for future vaccine development or refined B cell orientated treatment in the health setting