Sharpening nature's tools for efficient tuberculosis control: A review of the potential role and development of host-directed therapies and strategies for targeted respiratory delivery

O'Connor, Gemma; Gleeson, Laura E.; Fagan-Murphy, Aidan; Cryan, Sally‐Ann; O’Sullivan, Mary P.; Keane, Joseph

doi:10.1016/j.addr.2016.04.024

Cited by 21 publications

(15 citation statements)

References 292 publications

(381 reference statements)

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“…Mixed effects on macrophages have been reported for vitamin A and vitamin D 85,86 . Mechanistically, vitamin D3 induces the AMP cathelicidine 87 , triggers ROS production and promotes autophagy in infected macrophages 88 . AMP induction is potentiated by the co-administration of histone deacetylase inhibitors, such as phenylbutyrate 89,90 (FIG.…”

Section: Activating Myeloid Cells With Vitamins In Tbmentioning

confidence: 99%

Host-directed therapies for bacterial and viral infections

Kaufmann

Dorhoi

Hotchkiss

et al. 2017

Nat Rev Drug Discov

508

431

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Despite the recent increase in the development of antivirals and antibiotics, antimicrobial resistance and the lack of broad-spectrum virus-targeting drugs are still important issues and additional alternative approaches to treat infectious diseases are urgently needed. Host-directed therapy (HDT) is an emerging approach in the field of anti-infectives. The strategy behind HDT is to interfere with host cell factors that are required by a pathogen for replication or persistence, to enhance protective immune responses against a pathogen, to reduce exacerbated inflammation and to balance immune reactivity at sites of pathology. Although HDTs encompassing interferons are well established for the treatment of chronic viral hepatitis, novel strategies aimed at the functional cure of persistent viral infections and the development of broad-spectrum antivirals against emerging viruses seem to be crucial. In chronic bacterial infections, such as tuberculosis, HDT strategies aim to enhance the antimicrobial activities of phagocytes and to curtail inflammation through interference with soluble factors (such as eicosanoids and cytokines) or cellular factors (such as co-stimulatory molecules). This Review describes current progress in the development of HDTs for viral and bacterial infections, including sepsis, and the challenges in bringing these new approaches to the clinic.

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Section: Activating Myeloid Cells With Vitamins In Tbmentioning

confidence: 99%

Host-directed therapies for bacterial and viral infections

Kaufmann

Dorhoi

Hotchkiss

et al. 2017

Nat Rev Drug Discov

508

431

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“…Tuberculosis (TB) continues to be the cause of the most deaths worldwide due to a single organism, with some sources pairing it to the Human Immunodeficiency Virus (HIV) 1 and others indicating that TB has surpassed HIV as a major killer 2 . The World Health Organization (WHO) estimated that in 2014 more than 9 million people developed TB, and 5% of those patients were infected with multidrug resistant (MDR; resistance against isoniazid and rifampicin) bacterial strains 3 .…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of Ethionamide Delivered in Spray-Dried Microparticles to the Lungs of Guinea Pigs

García-Contreras

Padilla-Carlin

Sung

et al. 2017

Journal of Pharmaceutical Sciences

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The use of ethionamide (ETH) in treating multi-drug resistant tuberculosis is limited by severe side effects. ETH disposition after pulmonary administration in spray dried particles might minimize systemic exposure and side effects. Methods Spray dried ETH particles were optimized for performance in a dry powder aerosol generator (DPAG) and exposure chamber. ETH particles were administered by the IV, oral, or pulmonary routes to guinea pigs. ETH appearance in plasma, bronchoalveolar lavage and lung tissues were measured and subjected to non-compartmental pharmacokinetic analysis. Results DPAG dispersion of 20% ETH particles gave the highest dose at the exposure chamber ports and fine particle fraction of 72.3%. Pulmonary ETH was absorbed more rapidly and to a greater extent than orally administered drug. At Tmax, ETH concentrations were significantly higher in plasma than lungs from IV dosing, whereas, following insufflation lung concentrations were 5-fold higher than in plasma. AUC(0-t), and CL were similar after IV administration and insufflation. AUC(0-t) after oral administration was 6–7-fold smaller and CL was 6-fold faster. Notably, ETH bioavailability after pulmonary administration was significantly higher (85%) than after oral administration (17%). Conclusion Pulmonary ETH delivery would potentially enhance efficacy for TB treatment given the high lung concentrations and bioavailability

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“…Advanced knowledge of the pulmonary elements described in this review is also necessary from the standpoint of effectively engineering inhaled immunotherapies and/or inhaled vaccines [95]. Impacting this is the realization that lungs are constantly exposed to high levels of cigarette and environmental smoke as well as other pollutants in many countries where TB is endemic.…”

Section: Discussionmentioning

confidence: 99%

Integrating Lung Physiology, Immunology, and Tuberculosis

Torrelles

Schlesinger

2017

Trends in Microbiology

105

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Lungs are directly exposed to the air, have enormous surface area and enable gas exchange in air-breathing animals. They are constantly “attacked” by microbes from both outside and inside and thus possess a unique, highly regulated local immune defense system which efficiently allows for microbial clearance while minimizing damaging inflammatory responses. As a prototypic host-adapted airborne pathogen, Mycobacterium tuberculosis traverses the lung and has several ‘interaction points (IPs)’ which it must overcome to cause infection. These interactions are critical, not only from a pathogenesis perspective but also in considering the effectiveness of therapies and vaccines in the lungs. Here we discuss emerging views on immunologic interactions occurring in the lungs for M. tuberculosis and their impact on infection and persistence.

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Sharpening nature's tools for efficient tuberculosis control: A review of the potential role and development of host-directed therapies and strategies for targeted respiratory delivery

Cited by 21 publications

References 292 publications

Host-directed therapies for bacterial and viral infections

Host-directed therapies for bacterial and viral infections

Pharmacokinetics of Ethionamide Delivered in Spray-Dried Microparticles to the Lungs of Guinea Pigs

Integrating Lung Physiology, Immunology, and Tuberculosis

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