Progressive Host-Directed Strategies to Potentiate BCG Vaccination Against Tuberculosis

The pursuit to improve the TB control program comprising one approved vaccine, M. bovis Bacille Calmette-Guerin (BCG) has directed researchers to explore progressive approaches to halt the eternal TB pandemic. Mycobacterium tuberculosis (M.tb) was first identified as the causative agent of TB in 1882 by Dr. Robert Koch. However, TB has plagued living beings since ancient times and continues to endure as an eternal scourge ravaging even with existing chemoprophylaxis and preventive therapy. We have scientifically come a long way since then, but despite accessibility to the standard antimycobacterial antibiotics and prophylactic vaccine, almost one-fourth of humankind is infected latently with M.tb. Existing therapeutics fail to control TB, due to the upsurge of drug-resistant strains and increasing incidents of co-infections in immune-compromised individuals. Unresponsiveness to established antibiotics leaves patients with no therapeutic possibilities. Hence the search for an efficacious TB immunization strategy is a global health priority. Researchers are paving the course for efficient vaccination strategies with the radically advanced operation of core principles of protective immune responses against M.tb. In this review; we have reassessed the progression of the TB vaccination program comprising BCG immunization in children and potential stratagems to reinforce BCG-induced protection in adults

Understanding the host epigenetics in Mycobacterium tuberculosis infection

Epigenetics denotes to study the heritable changes occurred in the gene function without any changes in DNA sequence. These epigenetic changes are known to be governed by various factors viz. stress, infection, nutrients, drugs and toxicological agents etc. Recently, it has been identified that different microorganisms can cause the epigenetic changes in host. In this review we intend to address about the epigenetic changes occurred in host by Mycobacterium tuberculosis (M.tb) infection and then elaborate the current state of research about how Mtb. modulates host epigenome. M.tb induced epigenetic modifications which either leads to promote host defense or M.tb survival. Therefore, M.tb can be considered as potential modulator of host epigenome and consequently, these epigenetic changes can be beneficial or disastrous to M.tb. Currently, there is huge advances in sequencing technology and this can lead to a better understanding of the roles of epigenetics in the tuberculosis and other infectious diseases. Subsequently, therapeutic targeting of the epigenome can be potentially helpful in treatment of Mtb infection

The uncharted territory of host-pathogen interaction in tuberculosis

Mycobacterium tuberculosis (M.tb) effectively manipulates the host processes to establish the deadly respiratory disease, Tuberculosis (TB). M.tb has developed key mechanisms to disrupt the host cell health to combat immune responses and replicate efficaciously. M.tb antigens such as ESAT-6, 19kDa lipoprotein, Hip1, and Hsp70 destroy the integrity of cell organelles (Mitochondria, Endoplasmic Reticulum, Nucleus, Phagosomes) or delay innate/adaptive cell responses. This is followed by the induction of cellular stress responses in the host. Such cells can either undergo various cell death processes such as apoptosis or necrosis, or mount effective immune responses to clear the invading pathogen. Further, to combat the infection progression, the host secretes extracellular vesicles such as exosomes to initiate immune signaling. The exosomes can contain M.tb as well as host cell-derived peptides that can act as a double-edged sword in the immune signaling event. The host-symbiont microbiota produces various metabolites that are beneficial for maintaining healthy tissue microenvironment. In juxtaposition to the above-mentioned mechanisms, M.tb dysregulates the gut and respiratory microbiome to support its replication and dissemination process. The above-mentioned interconnected host cellular processes of Immunometabolism, Cellular stress, Host Microbiome, and Extracellular vesicles are less explored in the realm of exploration of novel Host-directed therapies for TB. Therefore, this review highlights the intertwined host cellular processes to control M.tb survival and showcases the important factors that can be targeted for designing efficacious therapy

N-acetylglucosamine (GlcNAc-inducible gene GIG2 is a novel component of GlcNAc metabolism in Candida albicans

Candida albicans is an opportunistic fungal pathogen that resides in the human body as a commensal and can turn pathogenic when the host is immunocompromised. Adaptation of C. albicans to host niche-specific conditions is important for the establishment of pathogenicity, where the ability of C. albicans to utilize multiple carbon sources provides additional flexibility. One alternative sugar is N-acetylglucosamine (GlcNAc), which is now established as an important carbon source for many pathogens and can also act as a signaling molecule. Although GlcNAc catabolism has been well studied in many pathogens, the importance of several enzymes involved in the formation of metabolic intermediates still remains elusive. In this context, microarray analysis was carried out to investigate the transcriptional responses induced by GlcNAc under different conditions. A novel gene that was highly upregulated immediately following the GlcNAc catabolic genes was identified and was named GIG2 (GlcNAc-induced gene 2). This gene is regulated in a manner distinct from that of the GlcNAc-induced genes described previously in that GlcNAc metabolism is essential for its induction. Furthermore, this gene is involved in the metabolism of N-acetylneuraminate (sialic acid), a molecule equally important for initial host-pathogen recognition. Mutant cells showed a considerable decrease in fungal burden in mouse kidneys and were hypersensitive to oxidative stress conditions. Since GIG2 is also present in many other fungal and enterobacterial genomes, targeted inhibition of its activity would offer insight into the treatment of candidiasis and other fungal or enterobacterial infections

Simultaneous inhibition of T helper 2 and T regulatory cell differentiation by small molecules enhances bacillus Calmette-Guerin vaccine efficacy against tuberculosis

Tuberculosis affects nine million individuals and kills almost two million people every year. The only vaccine available, Bacillus Calmette-Guerin (BCG), has been used since its inception in 1921. Although BCG induces host-protective T helper 1 (Th1) cell immune responses, which play a central role in host protection, its efficacy is unsatisfactory, suggesting that additional methods to enhance protective immune responses are needed. Recently we have shown that simultaneous inhibition of Th2 cells and Tregs by using the pharmacological inhibitors suplatast tosylate and D4476, respectively, dramatically enhances Mycobacterium tuberculosis clearance and induces superior Th1 responses. Here we show that treatment with these two drugs during BCG vaccination dramatically improves vaccine efficacy. Furthermore, we demonstrate that these drugs induce a shift in the development of T cell memory, favoring central memory T (Tcm) cell responses over effector memory T (Tem) cell responses. Collectively, our findings provide evidence that simultaneous inhibition of Th2 cells and Tregs during BCG vaccination promotes vaccine efficacy

Mycobacterium tuberculosis directs T helper 2 cell differentiation by inducing interleukin-1β production in dendritic cells

Mycobacterium tuberculosis (M. tb), the causative agent of tuberculosis (TB), resides and replicates within phagocytes and persists in susceptible hosts by modulating protective innate immune responses. Furthermore, M. tb promotes T helper 2(Th2) immune responses by altering the balance of T cell polarising cytokines in infected cells. However, cytokines that regulate Th2 cell differentiation during TB infection remain unknown. Here we show that IL-1β produced by phagocytes infected by virulent M. tb strain H37Rv directs Th2 cell differentiation. In sharp contrast, the vaccine strain BCG as well as RD-1 and ESAT-6 mutants of H37Rv failed to induce IL-1β and promote Th2 cell differentiation. Furthermore, ESAT-6 induced IL-1β production in dendritic cells, and CD4+ T cells co-cultured with infected DCs differentiated into Th2 cells. Taken together our findings indicate that IL-1β induced by RD-1/ESAT-6 plays an important role in the differentiation of Th2 cells, which in turn facilitates progression of TB by inhibiting host protective Th1 responses

Small molecule-directed immunotherapy against recurrent infection by Mycobacterium tuberculosis

Tuberculosis remains the biggest infectious threat to humanity with one-third of the population infected and 1.4 million deaths and 8.7 million new cases annually. Current tuberculosis therapy is lengthy and consists of multiple antimicrobials, which causes poor compliance and high treatment dropout, resulting in the development of drug-resistant variants of tuberculosis. Therefore, alternate methods to treat tuberculosis are urgently needed. Mycobacterium tuberculosis evades host immune responses by inducing T helper (Th)2 and regulatory T (Treg) cell responses, which diminish protective Th1 responses. Here, we show that animals (Stat-6−/−CD4-TGFβRIIDN mice) that are unable to generate both Th2 cells and Tregs are highly resistant to M. tuberculosis infection. Furthermore, simultaneous inhibition of these two subsets of Th cells by therapeutic compounds dramatically reduced bacterial burden in different organs. This treatment was associated with the generation of protective Th1 immune responses. As these therapeutic agents are not directed to the harbored organisms, they should avoid the risk of promoting the development of drug-resistant M. tuberculosis variants

Transforming growth factor-β protein inversely regulates in vivo differentiation of interleukin-17 (IL-17)-producing CD4<SUP>+</SUP> and CD8<SUP>+</SUP> T Cells

TGF-β is a pleiotropic cytokine that predominantly exerts inhibitory functions in the immune system. Unexpectedly, the in vitro differentiation of both Th17 and Tc17 cells requires TGF-β. However, animals that are impaired in TGF-β signaling (TGF-βRIIDN mice) display multiorgan autoimmune disorders. Here we show that CD4+ T cells from TGF-βRIIDN mice are resistant to Th17 cell differentiation and, paradoxically, that CD8+ T cells from these animals spontaneously acquire an IL-17-producing phenotype. Neutralization of IL-17 or depletion of CD8+ T cells dramatically inhibited inflammation in TGF-βRIIDN mice. Therefore, the absence of TGF-β triggers spontaneous differentiation of IL-17-producing CD8+ T cells, suggesting that the in vivo and in vitro conditions that promote the differentiation of IL-17-producing CD8+ T cells are distinct

Mycobacterium tuberculosis TlyA protein negatively regulates T helper (Th) 1 and Th17 differentiation and promotes tuberculosis pathogenesis

Mycobacterium tuberculosis, the causative agent of tuberculosis, is an ancient pathogen and a major cause of death worldwide. Although various virulence factors of M. tuberculosis have been identified, its pathogenesis remains incompletely understood. TlyA is a virulence factor in several bacterial infections and is evolutionarily conserved in many Gram-positive bacteria, but its function in M. tuberculosis pathogenesis has not been elucidated. Here, we report that TlyA significantly contributes to the pathogenesis of M. tuberculosis. We show that a TlyA mutant M. tuberculosis strain induces increased IL-12 and reduced IL-1β and IL-10 cytokine responses, which sharply contrasts with the immune responses induced by wild type M. tuberculosis. Furthermore, compared with wild type M. tuberculosis, TlyA-deficient M. tuberculosis bacteria are more susceptible to autophagy in macrophages. Consequently, animals infected with the TlyA mutant M. tuberculosis organisms exhibited increased host-protective immune responses, reduced bacillary load, and increased survival compared with animals infected with wild type M. tuberculosis. Thus, M. tuberculosis employs TlyA as a host evasion factor, thereby contributing to its virulence

CD4<SUP>+</SUP> T Cell-derived novel peptide Thp5 induces interleukin-4 production in CD4<SUP>+</SUP> T cells to direct T helper 2 cell differentiation

The differentiation of naïve CD4+ T cells into T helper 2 (Th2) cells requires production of the cytokine IL-4 in the local microenvironment. It is evident that naïve/quiescently activated CD4+ T cells produce the IL-4 that drives Th2 cell differentiation. Because early production of IL-4 in naïve T cells leads to preferential Th2 cell differentiation, this process needs to be tightly regulated so as to avoid catastrophic and misdirected Th2 cell differentiation. Here, we show that Thp5, a novel peptide with structural similarity to vasoactive intestinal peptide, regulates production of early IL-4 in newly activated CD4+ T cells. Induction of IL-4 in CD4+ T cells by Thp5 is independent of the transcription factor STAT6 but dependent on ERK1/2 signaling. Furthermore, cytokines (IL-12 and TGF-β) that promote the differentiation of Th1 or Th17 cells inhibit Thp5 induction, thus suppressing Th2 cell differentiation. We further showed that Thp5 enhances Th2 responses and exacerbates allergic airway inflammation in mice. Taken together, our findings reveal that early activated CD4+ T cells produce Thp5, which plays a critical role as a molecular switch in the differentiation of Th cells, biasing the response toward the Th2 cell phenotype