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An Automated Culture System for Use in Preclinical Testing of Host-Directed Therapies for Tuberculosis

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), was the most significant infectious disease killer globally until the advent ...

The University of Dublin

Newer TNF blockers (etanercept, infliximab and adalimumab) have contributed greatly to the control of chronic inflammatory disease. Many of the damaging inflammatory mechanisms that they inhibit are, however, important in maintaining tuberculosis in the latent phase (latent tuberculosis infection or LTBI). There is considerable evidence that links reactivation of LTBI to the use of anti-TNF monoclonal antibody (mAb) treatments, which appear to result in disruption of the granuloma that normally compartmentalizes but does not kill Mycobacterium tuberculosis during LTBI. This effect can be explained, in part, by directly neutralizing TNF, which plays a key role in tuberculosis immunity. To the clinician, dealing with LTBI in patients on these medications is an important issue. Prescribers should seek local expert help in this regard, as global LTBI treatment regimens differ. Nonetheless, screening for and treating LTBI will prevent reactivation in most patients. LTBI screening should include a careful history, tuberculin skin test and chest radiograph. Prophylactic treatment (e.g. isoniazid for 9 months) should be offered to patients with LTBI, in accordance with local advice. False-negative tuberculin skin test results can be expected in these patient groups. False-negative skin tests also mean that clinicians cannot be complacent about patients on TNF blockers who lack evidence of LTBI. On the contrary, because tuberculosis disease can be lethal, all treated patients should be advised to seek medical attention if symptoms suggestive of tuberculosis emerge. The indications for these successful agents are expanding, and efficient management of the LTBI issue should improve their safety profile.

TNF-blocking agents and tuberculosis: new drugs illuminate an old topic.

Biological agents used to treat rheumatologic conditions have made a significant impact on these difficult to treat autoimmune diseases. The tradeoff has been an increase in infections, and particularly tuberculosis with tumor necrosis factor blocker use. Because reactivation of latent tuberculosis infection is preventable, new data have demonstrated that these agents can be made safer when the clinician addresses latent tuberculosis infection.

Tuberculosis reactivation during immunosuppressive therapy in rheumatic diseases: diagnostic and therapeutic strategies.

Untreated chronic tuberculous salpingitis followed by successful in vitro fertilization conception and congenital tuberculosis.

Centuries since it was first described, tuberculosis (TB) remains a significant global public health issue. Despite ongoing holistic measures implemented by health authorities and a number of new oral treatments reaching the market, there is still a need for an advanced, efficient TB treatment. An adjunctive, host-directed therapy designed to enhance endogenous pathways and hence compliment current regimens could be the answer. The integration of drug repurposing, including synthetic and naturally occurring compounds, with a targeted drug delivery platform is an attractive development option. In order for a new anti-tubercular treatment to be produced in a timely manner, a multidisciplinary approach should be taken from the outset including stakeholders from academia, the pharmaceutical industry, and regulatory bodies keeping the patient as the key focus. Pre-clinical considerations for the development of a targeted host-directed therapy are discussed here.

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.

Ending the tuberculosis (TB) epidemic by 2030 was recently listed in the United Nations (UN) Sustainable Development Goals alongside HIV/AIDS and malaria as it continues to be a major cause of death worldwide. With a significant proportion of TB cases caused by resistant strains of Mycobacterium tuberculosis (Mtb), there is an urgent need to develop new and innovative approaches to treatment. Since 1989, researchers have been assessing the anti-bacterial effects of the active metabolite of vitamin A, all trans-Retinoic acid (ATRA) solution, in Mtb models. More recently the antibacterial effect of ATRA has been shown to regulate the immune response to infection via critical gene expression, monocyte activation and the induction of autophagy leading to its application as a host-directed therapy (HDT). Inhalation is an attractive route for targeted treatment of TB, and therefore we have developed ATRA-loaded microparticles (ATRA-MP) within the inhalable size range (2.07 ± 0.5 µm) offering targeted delivery of the encapsulated cargo (70.5 ± 2.3%) to the site of action within the alveolar macrophage, which was confirmed by confocal microscopy. Efficient cellular delivery of ATRA was followed by a reduction in Mtb growth (H37Ra) in THP-1 derived macrophages evaluated by both the BACT/ALERT® system and enumeration of colony forming units (CFU). The antibacterial effect of ATRA-MP treatment was further assessed in BALB/c mice infected with the virulent strain of Mtb (H37Rv). ATRA-MP treatments significantly decreased the bacterial burden in the lungs alongside a reduction in pulmonary pathology following just three doses administered intratracheally. The immunomodulatory effects of targeted ATRA treatment in the lungs indicate a distinct yet effective mechanism of action amongst the formulations. This is the first study to-date of a controlled release ATRA treatment for TB suitable for inhalation that offers improved targeting of a HDT, retains antibacterial efficacy and improves pulmonary pathology compared to ATRA solution.

Inhalable poly(lactic-co-glycolic acid) (PLGA) microparticles encapsulating all-trans-Retinoic acid (ATRA) as a host-directed, adjunctive treatment for Mycobacterium tuberculosis infection.

Joseph M. Keane

Department of Clinical Medicine,
Trinity Translational Medicine Institute,
St. James's Hospital,
Trinity College Dublin,
Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin

The University of Dublin

An Automated Culture System for Use in Preclinical Testing of Host-Directed Therapies for Tuberculosis