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Stimulation through CD40 and TLR-4 Is an Effective Host Directed Therapy against Mycobacterium tuberculosis

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus

C40.T4 triggering enhances the potency of RIF and INH to kill intracellular Mtb. DCs infected with Mtb were stimulated through the indicated combinations of C40.T4, CD40, TLR-4 with (A) RIF (24 h) (B) INH (24 h); (C) RIF (0–72 h). Later, cells were lysed and CFUs were monitored on 21 days. Data represented as mean ± SD (A–C) are of three independent experiments. “*,” “**,” and “***” indicate p < 0.05, p < 0.01, and p < 0.001, respectively.
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Figure 5: C40.T4 triggering enhances the potency of RIF and INH to kill intracellular Mtb. DCs infected with Mtb were stimulated through the indicated combinations of C40.T4, CD40, TLR-4 with (A) RIF (24 h) (B) INH (24 h); (C) RIF (0–72 h). Later, cells were lysed and CFUs were monitored on 21 days. Data represented as mean ± SD (A–C) are of three independent experiments. “*,” “**,” and “***” indicate p < 0.05, p < 0.01, and p < 0.001, respectively.

Mentions: The lengthy drug-regime for treating TB patients not only inflicts side-effects but also other serious problems like emergence of drug-resistant strains of Mtb. Therefore, we hypothesized to explore adjunct therapy with drugs in combination with immunomodulators to minimize the dose and duration of anti-TB drugs and increase their bactericidal activity. Mtb-infected DCs activated through C40.T4 considerably bolstered the bactericidal potency of anti-TB drugs RIF (p < 0.001) and isoniazid (p < 0.05), in comparison to drugs alone (Figures 5A,B). It may be concluded from these results that adjunct therapy of boosting immunity via CD40 and TLR-4 may be an important strategy to enhance the killing efficacy of drugs.


Stimulation through CD40 and TLR-4 Is an Effective Host Directed Therapy against Mycobacterium tuberculosis
C40.T4 triggering enhances the potency of RIF and INH to kill intracellular Mtb. DCs infected with Mtb were stimulated through the indicated combinations of C40.T4, CD40, TLR-4 with (A) RIF (24 h) (B) INH (24 h); (C) RIF (0–72 h). Later, cells were lysed and CFUs were monitored on 21 days. Data represented as mean ± SD (A–C) are of three independent experiments. “*,” “**,” and “***” indicate p < 0.05, p < 0.01, and p < 0.001, respectively.
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Figure 5: C40.T4 triggering enhances the potency of RIF and INH to kill intracellular Mtb. DCs infected with Mtb were stimulated through the indicated combinations of C40.T4, CD40, TLR-4 with (A) RIF (24 h) (B) INH (24 h); (C) RIF (0–72 h). Later, cells were lysed and CFUs were monitored on 21 days. Data represented as mean ± SD (A–C) are of three independent experiments. “*,” “**,” and “***” indicate p < 0.05, p < 0.01, and p < 0.001, respectively.
Mentions: The lengthy drug-regime for treating TB patients not only inflicts side-effects but also other serious problems like emergence of drug-resistant strains of Mtb. Therefore, we hypothesized to explore adjunct therapy with drugs in combination with immunomodulators to minimize the dose and duration of anti-TB drugs and increase their bactericidal activity. Mtb-infected DCs activated through C40.T4 considerably bolstered the bactericidal potency of anti-TB drugs RIF (p < 0.001) and isoniazid (p < 0.05), in comparison to drugs alone (Figures 5A,B). It may be concluded from these results that adjunct therapy of boosting immunity via CD40 and TLR-4 may be an important strategy to enhance the killing efficacy of drugs.

View Article: PubMed Central - PubMed

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&ndash;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-&alpha;. 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.

No MeSH data available.


Related in: MedlinePlus