Abstract
Tuberculosis (TB) is the leading cause of morbidity and mortality among all infectious diseases. Failure of Bacillus Calmette Guerin as a vaccine and serious side-effects and toxicity due to long-term TB drug regime are the major hurdles associated with TB control. The problem is further compounded by the emergence of drug-resistance strains of Mycobacterium tuberculosis (Mtb). Consequently, it demands a serious attempt to explore safer and superior treatment approaches. Recently, an improved understanding of host–pathogen interaction has opened up new avenues for immunotherapy for treating TB. Although, dendritic cells (DCs) show a profound role in generating immunity against Mtb, their immunotherapeutic potential needs to be precisely investigated in controlling TB. Here, we have devised an approach of bolstering DCs efficacy against Mtb by delivering signals through CD40 and TLR-4 molecules. We found that DCs triggered through CD40 and TLR-4 showed increased secretion of IL-12, IL-6, and TNF-α. It also augmented autophagy. Interestingly, CD40 and TLR-4 stimulation along with the suboptimal dose of anti-TB drugs significantly fortified their efficacy to kill Mtb. Importantly, animals treated with the agonists of CD40 and TLR-4 boosted Th1 and Th17 immunity. Furthermore, it amplified the pool of memory CD4 T cells as well as CD8 T cells. Furthermore, substantial reduction in the bacterial burden in the lungs was observed. Notably, this adjunct therapy employing immunomodulators and chemotherapy can reinvigorate host immunity suppressed due to drugs and Mtb. Moreover, it would strengthen the potency of drugs in curing TB.
Highlights
Tuberculosis (TB) is one of the world’s most devastating disease killing 2 million people annually [1,2,3]
We demonstrate that triggering of Mycobacterium tuberculosis (Mtb)-infected dendritic cells (DCs) through C40.T4 elicited T cell response, augmented the release of IL-6, IL-12, and TNF-α and reduced the intracellular bacterial burden
IL-6 and IL-12 are the major cytokines produced by DCs in response to infection by intracellular pathogens
Summary
Tuberculosis (TB) is one of the world’s most devastating disease killing 2 million people annually [1,2,3]. Even though TB drugs are the backbone of current treatment that successfully eliminate Mycobacterium tuberculosis (Mtb); their efficacy is limited by a narrow therapeutic index and chronic toxicities. The situation has worsened due to emergence of drug-resistant strains of Mtb. it is considerably important to discover effective therapeutic stratagems to treat TB. The paradigm shift in the treatment of various diseases, preferably tumors and autoimmune diseases have evolved from chemotherapeutic agents to selective and mechanismbased approaches [4]. An improved understanding of host–pathogen interaction has given rise to new treatment options, which includes immunomodulatory approaches
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