|
Project Topic
|
Tuberculosis (TB) has resulted in one billion human deaths the last two centuries, more than any other infectious disease in history. Despite availability of the Bacille-Calmette-Guerin vaccine, immunization does not protect against infection or pulmonary TB. Current TB therapeutics involve a lengthy 6-month regimen depending on antibiotic resistance of Mycobacterium tuberculosis (Mtb). This treatment strategy often leads to poor compliance or discontinued treatment, which may facilitate development of antibiotic resistance. Strategies aimed at reducing therapy duration would limit disease spread and mutations conferring drug-resistance. Innovative treatment focused on host processes, termed host-directed-therapy (HDT), is an effective novel approach for shortening treatment without inducing drug-resistance. Myeloid-derived-suppressor-cells (MDSC) accumulate during inflammatory conditions to suppress host immunity, with the intent to limit tissue pathology. We and others showed that MDSC represent critical elements in the pathogenesis of pulmonary TB. MDSC are increased during TB disease, contain Mtb bacilli, suppress protective host immunity and modulate lung inflammation. Considering their down-regulation of protective immunity, MDSC are intensively studied in tumour biology as a major tumour escape mechanism and thus favoured as targets of immune checkpoint inhibitors. Phosphodiesterase-5 (PDE-5) inhibitors have been used therapeutically to treat pulmonary hypertension, cardiac hypertrophy and erectile dysfunction by increasing intracellular concentrations of cyclic-guanosine-monophosphate (cGMP). Recently, PDE-5 inhibition was tested in mouse tumour models and shown to reverse tumour-induced immunosuppression and induce antitumor immunity that delayed tumour progression. Subsequently, PDE-5 inhibitors (sildenafil/Viagra, tadalafil/Cialis) are being repurposed, tested in human clinical trials for treatment of malignancies. In particular, sildenafil has shown to improve cancer therapy by up-regulating T-cell numbers in tumours, increase T-cell activation and T-cell IL-2 production. Importantly, sildenafil mediated this improved response by dampening MDSC recruitment and down-regulating MDSC-derived T-cell suppression. Reports show that therapeutic treatment of Mtb-infected mice with sildenafil, accelerated lung sterilization when added to the standard TB-treatment regimen, but the mechanism of action remains unknown. The role of Sildenafil on human MDSC in the context of TB, has not been evaluated and further groundwork is needed to better understand how PDE-5 inhibitors might be beneficial in combination with standard TB-treatment. We hypothesize that delivery of sildenafil to MDSC from TB patients, could alter MDSC phenotype and function. We will test this by 2 aims: 1) Evaluate the immune modulatory capacity of sildenafil on the function and phenotype of MDSC from lungs and blood of TB patients. 2) Determine the effect of sildenafil on Mtb survival in MDSC. Expected outputs I anticipate that this fellowship will impact my career development by facilitating increased scientific outputs in the form of peer reviewed publications, increased student training, broaden local and international collaborators through interaction with EDCTP fellows and networks and support to establish myself as leader in the field of MDSC research in TB. Also, this study will provide me with much needed experience in management of large scientific studies and further develop my student supervision skills.
|
