title: Stimulation through CD40 and TLR-4 Is an Effective Host Directed Therapy againstMycobacterium tuberculosis.
abstract: Tuberculosis (TB) is the leading cause of morbidity and mortality among all infectious diseases. Failure ofBacillus Calmette Guerinas 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 ofMycobacterium 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 againstMtb, their immunotherapeutic potential needs to be precisely investigated in controlling TB. Here, we have devised an approach of bolstering DCs efficacy againstMtbby 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 killMtb. 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 andMtb. Moreover, it would strengthen the potency of drugs in curing TB.
authors.affiliation: CSIR-Institute of Microbial Technology , Chandigarh , India.
authors.forename: Nargis
authors.initials: N
authors.lastname: Khan
authors.affiliation: CSIR-Institute of Microbial Technology , Chandigarh , India.
authors.forename: Susanta
authors.initials: S
authors.lastname: Pahari
authors.affiliation: CSIR-Institute of Microbial Technology , Chandigarh , India.
authors.forename: Aurobind
authors.initials: A
authors.lastname: Vidyarthi
authors.affiliation: CSIR-Institute of Microbial Technology , Chandigarh , India.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Aqdas
authors.affiliation: CSIR-Institute of Microbial Technology , Chandigarh , India.
authors.forename: Javed N
authors.initials: JN
authors.lastname: Agrewala
keywords: CD40; T cell response; TLR-4; autophagy; dendritic cells; immunomodulation; innate immunity