Nontuberculous mycobacteria (NTM) are emerging human pathogens, causing a wide range of clinical diseases affecting individuals who are immunocompromised and who have underlying health conditions. NTM are ubiquitous in the environment, with certain species causing opportunistic infection in humans, including Mycobacterium avium and Mycobacterium abscessus. The incidence and prevalence of NTM infections are rising globally, especially in developed countries with declining incidence rates of M. tuberculosis infection. Mycobacterium avium, a slow-growing mycobacterium, is associated with Mycobacterium avium complex (MAC) infections that can cause chronic pulmonary disease, disseminated disease, as well as lymphadenitis. M. abscessus infections are considered one of the most antibiotic-resistant mycobacteria and are associated with pulmonary disease, especially cystic fibrosis, as well as contaminated traumatic skin wounds, postsurgical soft tissue infections, and healthcare-associated infections (HAI). Clinical manifestations of diseases depend on the interaction of the host’s immune response and the specific mycobacterial species. This review will give a general overview of the general characteristics, vulnerable populations most at risk, pathogenesis, treatment, and prevention for infections caused by Mycobacterium avium, in the context of MAC, and M. abscessus.

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ObjectiveWe investigated the relationship between diabetes and telomere length by meta-analysis.MethodsWe searched five popular databases for articles published between 1990 and 2015 using “diabetes” and “telomere” as search terms. Data were processed with RevMan5, and random- or fixed-effects meta-analysis was applied. The effects of geographical region, diabetes type, body mass index (BMI), age and sex were examined. Funnel plots were applied to evaluate publication bias.ResultsSeventeen articles were obtained from 571 references. We identified a significant association between telomere length and diabetes mellitus (standardized mean difference [SMD]: −3.41; 95% confidence interval [CI]: −4.01, −2.80; heterogeneity, I2 = 99%) by comparing 5575 patients with diabetes and 6349 healthy individuals. The pooled SMD by geographic region indicated a significant association between shortened telomere length and diabetes mellitus (SMD: −3.41; 95% CI: −4.01, −2.80; heterogeneity, I2 = 99%). In addition, telomere length was significantly associated with age (SMD: −3.41; 95% CI: −4.01, −2.80), diabetes type (SMD: −3.41; 95% CI: −4.01, −2.80), BMI (SMD: −1.61; 95% CI: −1.98, −1.23) and sex (SMD: −4.94; 95% CI: −9.47, −0.40).ConclusionsThe study demonstrated a close relationship between diabetes mellitus and telomere length, which was influenced by region, age, diabetes type, BMI and sex.

Mycobacterium tuberculosis (M. tb), the causative bacterial agent responsible for tuberculosis (TB) continues to afflict millions of people worldwide. Although the human immune system plays a critical role in containing M. tb infection, elimination proves immensely more challenging. Consequently, there has been a worldwide effort to eradicate, and limit the spread of M. tb through the conventional use of first-line antibiotics. Unfortunately, with the emergence of drug resistant and multi-drug resistant strains of M. tb the archetypical antibiotics no longer provide the same ascendancy as they once did. Furthermore, when administered, these first-line antibiotics commonly present severe complications and side effects. The biological antioxidant glutathione (GSH) however, has been demonstrated to have a profound mycobactericidal effect with no reported adverse consequences. Therefore, we examined if N-Acetyl Cysteine (NAC), the molecular precursor to GSH, when supplemented in combination with suboptimal levels of standalone first-line antibiotics would be sufficient to completely clear M. tb infection within in vitro derived granulomas from healthy subjects and individuals with type 2 diabetes (T2DM). Our results revealed that by virtue of immune modulation, the addition of NAC to subprime levels of isoniazid (INH) and rifampicin (RIF) was indeed capable of inducing complete clearance of M. tb among healthy individuals.

Mycobacterium tuberculosis is the etiological agent that is responsible for causing tuberculosis (TB), which continues to affect millions of people worldwide, and the rate of resistance of M. tuberculosis to antibiotics is ever increasing. We tested the synergistic effects of N-acetyl cysteine (NAC; the precursor molecule for the synthesis of glutathione [GSH]) and individual first-line antibiotics typically given for the treatment of TB, such as isoniazid (INH), rifampin (RIF), ethambutol (EMB), and pyrazinamide (PZA), to improve the ability of macrophages to control intracellular M. tuberculosis infection.

Mycobacterium tuberculosis (M. tb) has been historically and is currently a threat to global public health. First-line antibiotics have been effective but proven to be burdensome as they have many potential adverse side effects. There has been a recent increase in the number of active tuberculosis (TB) cases due to a prevalence of multidrug and extensively drug-resistant strains of M. tb, and an increasing number of highly susceptible people such as those with Type 2 Diabetes (T2DM) and human immunodeficiency virus (HIV) infection. Multidrug-resistant M. tb infection (MDR-TB) is challenging to treat with existing therapeutics, so novel therapeutics and treatment strategies must be developed. Host-Directed Therapy (HDT) has been a potential target mechanism for effective clearance of infection. Host cell autophagy plays an essential role in antibacterial defense. The mammalian target of rapamycin (mTOR) has been negatively correlated with autophagy induction. Everolimus is an mTOR inhibitor that induces autophagy, but with higher water solubility. Therefore, targeting the mTOR pathway has the potential to develop novel and more effective combination drug therapy for TB. This study tested the effect of everolimus, alone and in combination with current first-line antibiotics (isoniazid and pyrazinamide), on the inhibition of M. tb inside in vitro human granulomas. We found that M. tb-infected in vitro granulomas treated with everolimus alone resulted in significantly decreased M. tb burden compared to similar granulomas in the control group. Cells treated with everolimus doses of either 1 nM or 2 nM in conjunction with pyrazinamide (PZA) produced a significant reduction in intracellular M. tb burden. Treatment groups that received everolimus alone in either 1 nM or 2 nM doses experienced a significant reduction in oxidative stress. Additionally, samples treated with 2 nM everolimus alone were observed to have significantly higher levels of autophagy and mTOR inhibition as well. Results from this study indicate that everolimus is efficacious in controlling M. tb infection in the granulomas and has additive effects when combined with the anti-TB drugs, isoniazid and pyrazinamide. This study has shown that everolimus is a promising host-directed therapeutic in the context of in vitro granuloma M. tb infection. Further study is warranted to better characterize these effects.

The World Health Organization (WHO) has identified type 2 diabetes (T2DM) as a neglected, important, and re-emerging risk factor for tuberculosis (TB), especially in low and middle-income countries where TB is endemic. In this clinical trial study, oral liposomal glutathione supplementation (L-GSH) or placebo was given to individuals with T2DM to investigate the therapeutic effects of L-GSH supplementation. We report that L-GSH supplementation for 3 months in people with T2DM was able to reduce the levels of oxidative stress in all blood components and prevent depletion of glutathione (GSH) in this population known to be GSH deficient. Additionally, L-GSH supplementation significantly reduced the burden of intracellular mycobacteria within in vitro granulomas generated from peripheral blood mononuclear cells (PBMCs) of T2DM subjects. L-GSH supplementation also increased the levels of Th1-associated cytokines, IFN-γ, TNF-α, and IL-2 and decreased levels of IL-6 and IL-10. In conclusion our studies indicate that oral L-GSH supplementation in individuals with T2DM for three months was able to maintain the levels of GSH, reduce oxidative stress, and diminish mycobacterial burden within in vitro generated granulomas of diabetics. L-GSH supplementation for 3 months in diabetics was also able to modulate the levels of various cytokines.

Mycobacterium tuberculosis (M. tb), a rod-shaped acid-fast bacterium, is the causative agent of tuberculosis (TB). TB remains one of the leading causes of morbidity and mortality worldwide. Additionally, approximately one-third of the world’s population has latent tuberculosis infection (LTBI) as a result of the body’s primary mechanism of defense against M. tb infection, the formation of a granuloma. A granuloma is the aggregation of immune cells that encapsulate the bacteria to keep them localized to prevent further infection and thus the bacteria become quiescent. However, if an individual becomes immunocompromised, they become more susceptible to M. tb, which may lead to bacterial reactivation and an active infection, because the host is no longer able to generate adequate immune responses. In this study, we examined liposomal glutathione’s (L-GSH) effectiveness in promoting the formation of solid, stable granulomas. We assessed this ability by generating in vitro human granulomas constructed from peripheral blood mononuclear cells (PBMCs) that were derived from healthy subjects and testing their granulomatous effector responses against both M. bovis bacille Calmette–Guérin (BCG) and the highly virulent Erdman strain of M. tb. Additionally, we measured the survival and immune characteristics of the Erdman strain of M. tb in THP-1 originated macrophages as well as in vitro granulomas generated from individuals from type 2 diabetes (T2DM). Our results demonstrate that L-GSH treatment can decrease the intracellular survival of both BCG and virulent M. tb, as well as downregulate the levels of overexpressed proinflammatory cytokines delegated from the granulomas derived from not only healthy subjects but also individuals with T2DM.