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Host-Directed Therapies for Tuberculosis
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Host-Directed Therapies for Tuberculosis

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Pulmonology".

Deadline for manuscript submissions: closed (30 June 2019) | Viewed by 38874

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Prof. Dr. Vishwanath Venketaraman

E-Mail Website
Guest Editor
Microbiology/Immunology Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766-1854, USA
Interests: mycobacterial diseases; tuberculosis; host immune responses; pathogenesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

TB is considered as one of the oldest documented infectious diseases in the world and is believed to be the leading cause of mortality due to a single infectious agent. Mtb, the causative agent responsible for TB, continues to afflict millions of people worldwide. Furthermore, one-third of the entire world's population has latent TB. Consequently, there has been a worldwide effort to eradicate and limit the spread of Mtb through the use of antibiotics. However, management of TB is becoming more challenging with the emergence of drug-resistant and multi-drug resistant strains of Mtb. Furthermore, when administered, many of the anti-TB drugs commonly present severe complications and side effects. Novel approaches to enhance the host immune responses to completely eradicate Mtb infection are urgently needed. This Special Issue will therefore cover most recent advances in the area of host-directed therapies for TB.

Prof. Dr. Vishwanath Venketaraman
Guest Editor

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Keywords

  • host-directed therapies for tuberculosis
  • immunoadjuvants
  • supplements
  • repurposing the drugs

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Published Papers (7 papers)

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Research

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25 pages, 6400 KiB  
Article
Elucidating the Efficacy of the Bacille Calmette–Guérin Vaccination in Conjunction with First Line Antibiotics and Liposomal Glutathione
by Rachel Abrahem, Ruoqiong Cao, Brittanie Robinson, Shalok Munjal, Thomas Cho, Kimberly To, David Ashley, Joshua Hernandez, Timothy Nguyen, Garrett Teskey and Vishwanath Venketaraman
J. Clin. Med. 2019, 8(10), 1556; https://doi.org/10.3390/jcm8101556 - 27 Sep 2019
Cited by 8 | Viewed by 2554
Abstract
Mycobacterium tuberculosis (M. tb) is the etiological agent that is responsible for causing tuberculosis (TB). Although every year M. tb infection affects millions of people worldwide, the only vaccine that is currently available is the Bacille Calmette–Guérin (BCG) vaccine. However, the [...] Read more.
Mycobacterium tuberculosis (M. tb) is the etiological agent that is responsible for causing tuberculosis (TB). Although every year M. tb infection affects millions of people worldwide, the only vaccine that is currently available is the Bacille Calmette–Guérin (BCG) vaccine. However, the BCG vaccine has varying efficacy. Additionally, the first line antibiotics administered to patients with active TB often cause severe complications and side effects. To improve upon the host response mechanism in containing M. tb infection, our lab has previously shown that the addition of the biological antioxidant glutathione (GSH) has profound antimycobacterial effects. The aim of this study is to understand the additive effects of BCG vaccination and ex-vivo GSH enhancement in improving the immune responses against M. tb in both groups; specifically, their ability to mount an effective immune response against M. tb infection, maintain CD4+ and CD8+ T cells in the granulomas, their response to liposomal glutathione (L-GSH), with varying suboptimal levels of the first line antibiotics isoniazid (INH) and pyrazinamide (PZA), the expressions of programmed death receptor 1 (PD-1), and their ability to induce autophagy. Our results revealed that BCG vaccination, along with GSH enhancement, can prevent the loss of CD4+ and CD8+ T cells in the granulomas and improve the control of M. tb infection by decreasing the expressions of PD-1 and increasing autophagy and production of the cytokines interferon gamma IFN-γ and tumor necrosis factor-α (TNF-α). Full article
(This article belongs to the Special Issue Host-Directed Therapies for Tuberculosis)
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19 pages, 4509 KiB  
Article
Effect of Iron Supplementation on the Outcome of Non-Progressive Pulmonary Mycobacterium tuberculosis Infection
by Afsal Kolloli, Pooja Singh, G. Marcela Rodriguez and Selvakumar Subbian
J. Clin. Med. 2019, 8(8), 1155; https://doi.org/10.3390/jcm8081155 - 2 Aug 2019
Cited by 8 | Viewed by 4071
Abstract
The human response to Mycobacterium tuberculosis (Mtb) infection is affected by the availability of iron (Fe), which is necessary for proper immune cell function and is essential for the growth and virulence of bacteria. Increase in host Fe levels promotes Mtb growth and [...] Read more.
The human response to Mycobacterium tuberculosis (Mtb) infection is affected by the availability of iron (Fe), which is necessary for proper immune cell function and is essential for the growth and virulence of bacteria. Increase in host Fe levels promotes Mtb growth and tuberculosis (TB) pathogenesis, while Fe-supplementation to latently infected, asymptomatic individuals is a significant risk factor for disease reactivation. However, the effect of Fe-supplementation on the host immunity during latent Mtb infection remains unclear, due partly to the paucity in availability of animal models that recapitulate key pathophysiological features seen in humans. We have demonstrated that rabbits can develop non-progressive latency similar to infected humans. In this study, using this model we have evaluated the effect of Fe-supplementation on the bacterial growth, disease pathology, and immune response. Systemic and lung Fe parameters, gene expression profile, lung bacterial burden, and disease pathology were determined in the Mtb-infected/Fe- or placebo-supplemented rabbits. Results show that Fe-supplementation to Mtb-infected rabbits did not significantly change the hematocrit and Hb levels, although it elevated total Fe in the lungs. Expression of selected host iron- and immune-response genes in the blood and lungs was perturbed in Mtb-infected/Fe-supplemented rabbits. Iron-supplementation during acute or chronic stages of Mtb infection did not significantly affect the bacterial burden or disease pathology in the lungs. Data presented in this study is of significant relevance for current public health policies on Fe-supplementation therapy given to anemic patients with latent Mtb infection. Full article
(This article belongs to the Special Issue Host-Directed Therapies for Tuberculosis)
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13 pages, 809 KiB  
Article
Use of Antiplatelet Agents and Survival of Tuberculosis Patients: A Population-Based Cohort Study
by Meng-Rui Lee, Ming-Chia Lee, Chia-Hao Chang, Chia-Jung Liu, Lih-Yu Chang, Jun-Fu Zhang, Jann-Yuan Wang and Chih-Hsin Lee
J. Clin. Med. 2019, 8(7), 923; https://doi.org/10.3390/jcm8070923 - 27 Jun 2019
Cited by 15 | Viewed by 3867
Abstract
While evidence is accumulating that platelets contribute to tissue destruction in tuberculosis (TB) disease, it is still not known whether antiplatelet agents are beneficial to TB patients. We performed this retrospective cohort study and identified incident TB cases in the Taiwan National Tuberculosis [...] Read more.
While evidence is accumulating that platelets contribute to tissue destruction in tuberculosis (TB) disease, it is still not known whether antiplatelet agents are beneficial to TB patients. We performed this retrospective cohort study and identified incident TB cases in the Taiwan National Tuberculosis Registry from 2008 to 2014. These cases were further classified into antiplatelet users and non-users according to the use of antiplatelet agents prior to the TB diagnosis, and the cohorts were matched using propensity scores (PSs). The primary outcome was survival after a TB diagnosis. In total, 74,753 incident TB cases were recruited; 9497 (12.7%) were antiplatelet users, and 7764 (10.4%) were aspirin (ASA) users. A 1:1 PS-matched cohort with 8864 antiplatelet agent users and 8864 non-users was created. After PS matching, antiplatelet use remained associated with a longer survival (adjusted hazard ratio (HR): 0.91, 95% confidence interval (CI): 0.88–0.95, p < 0.0001). The risk of major bleeding was not elevated in antiplatelet users compared to non-users (p = 0.604). This study shows that use of antiplatelet agents has been associated with improved survival in TB patients. The immunomodulatory and anti-inflammatory effects of antiplatelet agents in TB disease warrant further investigation. Antiplatelets are promising as an adjunct anti-TB therapy. Full article
(This article belongs to the Special Issue Host-Directed Therapies for Tuberculosis)
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9 pages, 1812 KiB  
Article
Factors for the Early Revision of Misdiagnosed Tuberculosis to Lung Cancer: A Multicenter Study in A Tuberculosis-Prevalent Area
by Chin-Chung Shu, Shih-Chieh Chang, Yi-Chun Lai, Cheng-Yu Chang, Yu-Feng Wei and Chung-Yu Chen
J. Clin. Med. 2019, 8(5), 700; https://doi.org/10.3390/jcm8050700 - 17 May 2019
Cited by 12 | Viewed by 3830
Abstract
Background: Lung cancer misdiagnosed as tuberculosis (TB) is not rare, but the factors associated with early diagnosis revision remain unclear. Methods: We screened the cases with TB notification from 2007 to 2018 and reviewed those with misdiagnosis with a revised diagnosis to lung [...] Read more.
Background: Lung cancer misdiagnosed as tuberculosis (TB) is not rare, but the factors associated with early diagnosis revision remain unclear. Methods: We screened the cases with TB notification from 2007 to 2018 and reviewed those with misdiagnosis with a revised diagnosis to lung cancer. We analyzed the factors associated with early diagnosis revision (≤1 months) and early obtained pathology (≤1 months) using multivariable Cox regression. Results: During the study period, 45 (0.7%) of 6683 patients were initially notified as having TB, but later diagnosed with lung cancer. The reasons for the original impression of TB were mostly due to image suspicion (51%) and positive sputum acid-fast stain (AFS) (27%). Using multivariable Cox proportional regression, early diagnosis revision was associated with obtaining the pathology early, lack of anti-TB treatment, and negative sputum AFS. Furthermore, the predictors for early obtained pathology included large lesion size (>3 cm), presence of a miliary radiological pattern, no anti-TB treatment, and a culture-negative result when testing for nontuberculous mycobacteria (NTM) using multivariable Cox regression. Conclusion: In patients who are suspected to have TB but no mycobacterial evidence is present, lung cancer should be kept in mind and pathology needs to be obtained early, especially for those with small lesions, radiological findings other than the miliary pattern, and a culture positive for NTM. Full article
(This article belongs to the Special Issue Host-Directed Therapies for Tuberculosis)
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Review

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11 pages, 568 KiB  
Review
Type 2 Diabetes Mellitus and Altered Immune System Leading to Susceptibility to Pathogens, Especially Mycobacterium tuberculosis
by Steve Ferlita, Aram Yegiazaryan, Navid Noori, Gagandeep Lal, Timothy Nguyen, Kimberly To and Vishwanath Venketaraman
J. Clin. Med. 2019, 8(12), 2219; https://doi.org/10.3390/jcm8122219 - 16 Dec 2019
Cited by 102 | Viewed by 14181
Abstract
There has been an alarming increase in the incidence of Type 2 Diabetes Mellitus (T2DM) worldwide. Uncontrolled T2DM can lead to alterations in the immune system, increasing the risk of susceptibility to infections such as Mycobacterium tuberculosis (M. tb). Altered immune responses [...] Read more.
There has been an alarming increase in the incidence of Type 2 Diabetes Mellitus (T2DM) worldwide. Uncontrolled T2DM can lead to alterations in the immune system, increasing the risk of susceptibility to infections such as Mycobacterium tuberculosis (M. tb). Altered immune responses could be attributed to factors such as the elevated glucose concentration, leading to the production of Advanced Glycation End products (AGE) and the constant inflammation, associated with T2DM. This production of AGE leads to the generation of reactive oxygen species (ROS), the use of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) via the Polyol pathway, and overall diminished levels of glutathione (GSH) and GSH-producing enzymes in T2DM patients, which alters the cytokine profile and changes the immune responses within these patients. Thus, an understanding of the intricate pathways responsible for the pathogenesis and complications in T2DM, and the development of strategies to enhance the immune system, are both urgently needed to prevent co-infections and co-morbidities in individuals with T2DM. Full article
(This article belongs to the Special Issue Host-Directed Therapies for Tuberculosis)
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12 pages, 233 KiB  
Review
Potentials of Host-Directed Therapies in Tuberculosis Management
by Yash Dara, Doron Volcani, Kush Shah, Kevin Shin and Vishwanath Venketaraman
J. Clin. Med. 2019, 8(8), 1166; https://doi.org/10.3390/jcm8081166 - 3 Aug 2019
Cited by 17 | Viewed by 3768
Abstract
Tuberculosis (TB) remains as a leading cause of mortality in developing countries, persisting as a major threat to the global public health. Current treatment involving a long antibiotic regimen brings concern to the topic of patient compliance, contributing to the emergence of drug [...] Read more.
Tuberculosis (TB) remains as a leading cause of mortality in developing countries, persisting as a major threat to the global public health. Current treatment involving a long antibiotic regimen brings concern to the topic of patient compliance, contributing to the emergence of drug resistant TB. The current review will provide an updated outlook on novel anti-TB therapies that can be given as adjunctive agents to current anti-TB treatments, with a particular focus on modulating the host immune response to effectively target all forms of TB. Additional potential therapeutic pathway targets, including lipid metabolism alteration and vascular endothelial growth factor (VEGF)-directed therapies, are discussed. Full article
(This article belongs to the Special Issue Host-Directed Therapies for Tuberculosis)
14 pages, 2549 KiB  
Review
Investigating the Role of Everolimus in mTOR Inhibition and Autophagy Promotion as a Potential Host-Directed Therapeutic Target in Mycobacterium tuberculosis Infection
by Stephen Cerni, Dylan Shafer, Kimberly To and Vishwanath Venketaraman
J. Clin. Med. 2019, 8(2), 232; https://doi.org/10.3390/jcm8020232 - 11 Feb 2019
Cited by 44 | Viewed by 5485
Abstract
Tuberculosis (TB) is a serious infectious disease caused by the pathogen Mycobacterium tuberculosis (Mtb). The current therapy consists of a combination of antibiotics over the course of four months. Current treatment protocols run into problems due to the growing antibiotic resistance [...] Read more.
Tuberculosis (TB) is a serious infectious disease caused by the pathogen Mycobacterium tuberculosis (Mtb). The current therapy consists of a combination of antibiotics over the course of four months. Current treatment protocols run into problems due to the growing antibiotic resistance of Mtb and poor compliance to the multi-drug-resistant TB treatment protocol. New treatments are being investigated that target host intracellular processes that could be effective in fighting Mtb infections. Autophagy is an intracellular process that is involved in eliminating cellular debris, as well as intracellular pathogens. Mammalian target of rapamycin (mTOR) is an enzyme involved in inhibiting this pathway. Modulation of mTOR and the autophagy cellular machinery are being investigated as potential therapeutic targets for novel Mtb treatments. In this review, we discuss the background of Mtb pathogenesis, including its interaction with the innate and adaptive immune systems, the mTOR and autophagy pathways, the interaction of Mtb with these pathways, and finally, the drug everolimus, which targets these pathways and is a potential novel therapy for TB treatment. Full article
(This article belongs to the Special Issue Host-Directed Therapies for Tuberculosis)
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