Abstract
A long duration of treatment and emerging drug resistance pose significant challenges for global tuberculosis (TB) eradication efforts. Therefore, there is an urgent need to develop novel strategies to shorten TB treatment regimens and to treat drug-resistant TB. Using an albumin-fusion strategy, we created a novel albumin-fused granulocyte-macrophage colony-stimulating factor (albGM-CSF) molecule that harnesses albumin’s long half-life and targeting abilities to enhance the biostability of GM-CSF and direct it to the lymph nodes, where the effects of GM-CSF can increase dendritic cell populations crucial for eliciting a potent immune response. In this study, we demonstrate that albGM-CSF serves as a novel immunotherapy for chronic Mycobacterium tuberculosis (Mtb) infections by enhancing GM-CSF biostability in serum. Specifically, albumin is very safe, stable, and has a long half-life, thereby enhancing the biostability of GM-CSF. In the lungs and draining lymph nodes, albGM-CSF is able to increase the numbers of dendritic cells, which are crucial for the activation of naive T cells and for eliciting potent immune responses. Subcutaneous administration of albGM-CSF alone reduced the mean lung bacillary burden in mice with chronic tuberculosis infection. While GM-CSF administration was associated with IL-1β release from Mtb-infected dendritic cells and macrophages, higher IL-1β levels were observed in albGM-CSF-treated mice with chronic tuberculosis infection than in mice receiving GM-CSF. Albumin fusion with GM-CSF represents a promising strategy for the control of chronic lung tuberculosis infections and serves as a novel therapeutic vaccination platform for other infectious diseases and malignancies.
Highlights
Tuberculosis (TB) is currently the most common cause of death by a single infectious agent worldwide.[1]
The luciferase activity was at least fivefold higher in the inguinal and mediastinal LNs of mice injected with albumin-fused GLuc (albGLuc) than in mice injected with Gaussia luciferase (GLuc) alone after 72 h of injection (Fig. 1b)
Our findings demonstrate that Granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances IL-1β secretion from macrophages and Dendritic cells (DCs) and that administration of albGM-CSF to Mycobacterium tuberculosis (Mtb)-infected mice induces more IL-1β in the lungs
Summary
Tuberculosis (TB) is currently the most common cause of death by a single infectious agent worldwide.[1] Efforts have been made to implement a 6-month “short-course” combination regimen for the treatment of drug-susceptible TB. This regimen has been shown to be efficacious, it requires proper provision and direct supervision, which can be taxing for health care systems, especially in TB-endemic regions. In addition to novel antimicrobial agents, host-directed therapies represent attractive strategies to combat disease due to drug-susceptible and drugresistant Mycobacterium tuberculosis (Mtb).[3] In particular, hostdirected therapies may reverse TB-related lung inflammation and/ or augment innate and adaptive immune responses to accelerate mycobacterial clearance during anti-TB treatment.[4]
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