Targeting dendritic cells with TLR-2 ligand-coated nanoparticles loaded with Mycobacterium tuberculosis epitope induce antituberculosis immunity.

Novel vaccination strategies are crucial to efficiently control tuberculosis, as proposed by the World Health Organization under its flagship program "End TB Strategy." However, the emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb), particularly in those coinfected with HIV-AIDS, constitutes a major impediment to achieving this goal. We report here a novel vaccination strategy that involves synthesizing a formulation of an immunodominant peptide derived from the Acr1 protein of Mtb. This nanoformulation in addition displayed on the surface a toll-like receptor-2 ligand to offer to target dendritic cells (DCs). Our results showed an efficient uptake of such a concoction by DCs in a predominantly toll-like receptor-2-dependent pathway. These DCs produced elevated levels of nitric oxide, proinflammatory cytokines interleukin-6, interleukin-12, and tumor necrosis factor-α, and upregulated the surface expression of major histocompatibility complex class II molecules as well as costimulatory molecules such as CD80 and CD86. Animals injected with such a vaccine mounted a significantly higher response of effector and memory Th1 cells and Th17 cells. Furthermore, we noticed a reduction in the bacterial load in the lungs of animals challenged with aerosolized live Mtb. Therefore, our findings indicated that the described vaccine triggered protective anti-Mtb immunity to control the tuberculosis infection.

Mycobacterium tuberculosis exploits MPT64 to generate myeloid-derived suppressor cells to evade the immune system.

Mycobacterium tuberculosis (Mtb) is a smart and successful pathogen since it can persist in the intimidating environment of the host by taming and tuning the immune system. Mtb releases MPT64 (Rv1980c) protein in high amounts in patients with active tuberculosis (TB). Consequently, we were curious to decipher the role of MPT64 on the differentiating dendritic cells (DCs) and its relation to evading the immune system. We observed that pre-exposure of differentiating DCs to MPT64 (DCMPT64) transformed them into a phenotype of myeloid-derived suppressor cells (MDSCs). DCMPT64 expressed a high level of immunosuppressive molecules PD-L1, TIM-3, nitric oxide (NO), arginase 1, IDO-1, IL-10 and TGF-ß, but inhibited the production of pro-inflammatory cytokines TNF-α, IL-6 and IL-12. DCMPT64 chemotaxis function was diminished due to the reduced expression of CCR7. DCMPT64 promoted the generation of regulatory T cells (Tregs) but inhibited the differentiation of Th1 cells and Th17 cells. Further, high lipid and methylglyoxal content, and reduced glucose consumption by DCMPT64, rendered them metabolically quiescent and consequently, reduced DCMPT64 ability to phagocytose Mtb and provided a safer shelter for the intracellular survival of the mycobacterium. The mechanism identified in impairing the function of DCMPT64 was through the increased production and accumulation of methylglyoxal. Hence, for the first time, we demonstrate the novel role of MPT64 in promoting the generation of MDSCs to favor Mtb survival and escape its destruction by the immune system.

Emerging role of microbiota in immunomodulation and cancer immunotherapy.

Gut microbiota is emerging as a key modulator of the immune system. Alteration of gut microbiota impacts functioning of the immune system and pathophysiology of several diseases, including cancer. Growing evidence indicates that gut microbiota is not only involved in carcinogenesis but also has an impact on the efficacy and toxicity of cancer therapy. Recently, several pre-clinical and clinical studies across diverse cancer types reported the influence of gut microbiota on the host immune response to immunotherapy. Advancement in our understanding of the mechanism behind microbiota-mediated modulation of immune response is paramount for their utilization as cancer therapeutics. These microbial therapies in combination with conventional immunotherapeutic methods have the potential to transform the pre-existing treatment strategies to personalized cancer therapy. In this review, we have summarized the current status of research in the field and discussed the role of microbiota as an immune system modulator in context of cancer and their impact on immunotherapy.

Gut Microbiota Regulates Mincle Mediated Activation of Lung Dendritic Cells to Protect Against Mycobacterium tuberculosis.

Gut microbial components serve as ligand for various pattern recognition receptors (PRRs) present on immune cells and thereby regulates host immunity. Dendritic cells (DCs) are highly specialized innate cells involved in immune response to Mycobacterium tuberculosis (Mtb) infection. The gut-lung axis is a potential therapeutic target in tuberculosis; however, understanding of the innate immune mechanism underlying the interaction of gut microbiota and lung still remains obscure. We investigated if antibiotics (Abx) induced gut dysbiosis is able to affect the activation of innate receptor, macrophage inducible C-type lectin (mincle) in lungs during Mtb infection. We found that dysbiosis reduced the lung mincle expression with a concomitant increase in Mtb survival. Further, Abx diminished the effector and memory T cell population, while elevating frequency of regulatory T cells (Tregs) in the lungs. Here, we show that dysbiotic mice exhibited low mincle expression on lung DCs. These DCs with impaired phenotype and functions had reduced ability to activate naïve CD4 T cells, and thus unable to restrict Mtb survival. In vivo administration of trehalose-6,6-dibehenate (TDB: mincle ligand) efficiently rescued this immune defect by enhancing lung DCs function and subsequent T cell response. Further, gut microbial profiling revealed augmentation of Lactobacillus upon mincle stimulation in microbiota depleted animals. Accordingly, supplementation with Lactobacillus restored mincle expression on lung DCs along with anti-Mtb response. Our data demonstrate that gut microbiota is crucial to maintain DC-dependent lung immune response against Mtb, mediated by mincle. Abx interrupt this process to induce impaired T cell-response and increased susceptibility to Mtb.

Reinforcing the Functionality of Mononuclear Phagocyte System to Control Tuberculosis.

The mononuclear phagocyte system (MPS) constitutes dendritic cells, monocytes, and macrophages. This system contributes to various functions that are essential for maintaining homeostasis, activation of innate immunity, and bridging it with the adaptive immunity. Consequently, MPS is highly important in bolstering immunity against the pathogens. However, MPS is the frontline cells in destroying Mycobacterium tuberculosis (Mtb), yet the bacterium prefers to reside in the hostile environment of macrophages. Therefore, it may be very interesting to study the struggle between Mtb and MPS to understand the outcome of the disease. In an event when MPS predominates Mtb, the host remains protected. By contrast, the situation becomes devastating when the pathogen tames and tunes the host MPS, which ultimately culminates into tuberculosis (TB). Hence, it becomes extremely crucial to reinvigorate MPS functionality to overwhelm Mtb and eliminate it. In this article, we discuss the strategies to bolster the function of MPS by exploiting the molecules associated with the innate immunity and highlight the mechanisms involved to overcome the Mtb-induced suppression of host immunity. In future, such approaches may provide an insight to develop immunotherapeutics to treat TB.