Understanding the biology of 16 kDa antigen of Mycobacterium tuberculosis: scope in diagnosis, vaccine design and therapy

Heat Shock Proteins (HSPs) are conserved and ubiquitous house keeping entities that act as molecular chaperones, which protect the cell from damage during stress. One such HSP, the 16 kDa antigen, from Mycobacterium tuberculosis (Mtb) has received considerable attention due to its importance in tuberculosis latency and immunodominant property. In this article, we discuss about the potential role of 16 kDa antigen of Mtb in latency, its expression, regulation and implication in host immune response. We also highlight the scope of employing 16 kDa in early diagnosis, development of vaccine and as a potential drug target

Innate immunity holding the flanks until reinforced by adaptive immunity against Mycobacterium tuberculosis infection

T cells play a cardinal role in imparting adaptive immunity against Mycobacterium tuberculosis (Mtb). However, ample time is required before T-cells are able to evoke efficient effector responses in the lung, where the mycobacterium inflicts disease. This delay in T cells priming, which is termed as lag phase, provides sufficient time for Mtb to replicate and establish itself within the host. In contrast, innate immunity efficiently curb the growth of Mtb during initial phase of infection through several mechanisms. Pathogen recognition by innate cells rapidly triggers a cascade of events, such as apoptosis, autophagy, inflammasome formation and nitric oxide production to kill intracellular pathogens. Furthermore, bactericidal mechanisms such as autophagy and apoptosis, augment the antigen processing and presentation, thereby contributing substantially to the induction of adaptive immunity. This manuscript highlights the role of innate immune mechanisms in restricting the survival of Mtb during lag phase. Finally, this article provides new insight for designing immuno-therapies by targeting innate immune mechanisms to achieve optimum immune response to cure TB

T-cell exhaustion in tuberculosis: pitfalls and prospects

T-cells play an important role in immunity but when these cells are overexposed to specific antigens, their function may decline. This state is usually referred to as exhaustion and the T-cells show reduced proliferation and functions such as cytokine release. T-cell exhaustion has been observed in several cancers as well as in chronic infections such as Tuberculosis (TB). In chronic Mycobacterium tuberculosis (Mtb) infection, T-cells may express the exhaustion phenotype and show a progressive loss of secretion of IL-2, IFN-γ and TNF-α. In some cancers and chronic infection models, blocking the exhaustion phenotype can be achieved with the so-called checkpoint inhibitors. This results in tumor control and more effective immunity. However, in the case of TB, the T-cell exhaustion results are quite ambiguous. Hence, there is a need to investigate and explain the contribution of checkpoint at a molecular level to the outcome of events in chronic TB. Such information could help to guide the success of new therapies against chronic TB. This review highlights the mechanism through which T-cells undergo exhaustion and the approaches that can avert such events. This will help to design immunotherapies that can reinvigorate T-cell potency to protect patients from TB

Alteration in the gut microbiota provokes susceptibility to tuberculosis

AbstractThe microbiota that resides in the gastrointestinal tract provides essential health benefits to the host. In particular, they regulate immune homeostasis. Recently, several evidences indicate that alteration in the gut microbial community can cause infectious and non-infectious diseases. Tuberculosis (TB) is the most devastating disease, inflicting mortality and morbidity. It remains unexplored, whether changes in the gut microbiota can provoke or prevent TB. In the current study, we have demonstrated the antibiotics driven changes in the gut microbial composition and their impact on the survival of Mtb in the lungs, liver and spleen of infected mice, compared to those with intact microbiota. Interestingly, dysbiosis of microbes showed significant increase in the bacterial burden in lungs and dissemination of Mtb to spleen and liver. Further, elevation in the number of Tregs and decline in the pool of IFN-γ and TNF-α releasing CD4 T cells was noticed. Interestingly, fecal transplantation in the gut microbiota disrupted animals exhibited improved Th1 immunity and lesser Tregs population. Importantly, these animals displayed reduced severity to Mtb infection. This study for the first time demonstrated the novel role of gut microbes in the susceptibility to TB and its prevention by microbial implants. In future, microbial therapies may help in treating patients suffering from TB

The impact of aging-induced gut microbiome dysbiosis on dendritic cells and lung diseases

ABSTRACTAging is an inevitable natural process that impacts every individual, and understanding its effect on the gut microbiome and dendritic cell (DC) functionality in elderly subjects is crucial. DCs are vital antigen-presenting cells (APCs) that orchestrate the immune response, maintaining immune tolerance to self-antigens and bridging innate and adaptive immunity. With aging, there is a shift toward nonspecific innate immunity, resulting in a decline in adaptive immune responses. This alteration raises significant concerns about managing the health of an elderly population. However, the precise impact of aging and microbiome changes on DC function and their implications in lung-associated diseases remain relatively understudied. To illuminate this subject, we will discuss recent advancements in understanding the connections between aging, gut dysbiosis, DCs, and lung diseases. Emphasizing the key concepts linking age-related gut microbiome changes and DC functions, we will focus on their relevance to overall health and immune response in elderly individuals. This article aims to improve our understanding of the intricate relationship between aging, gut microbiome, and DCs, potentially benefiting the management of age-associated diseases and promoting healthy aging

Caerulomycin A suppresses the differentiation of naïve T cells and alleviates the symptoms of experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is a highly detrimental autoimmune disease of the central nervous system. There is no cure for it but the treatment typically focuses on subsiding severity and recurrence of the disease. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS. It is characterized by frequent relapses due to the generation of memory T cells. Caerulomycin A (CaeA) is known to suppress the Th1 cells, Th2 cells, and Th17 cells. Interestingly, it enhances the generation of regulatory T cells (Tregs). Th1 cells and Th17 cells are known to aggravate EAE, whereas Tregs suppress the disease symptoms. Consequently, in the current study we evaluated the influence of CaeA on EAE. Intriguingly, we observed by whole body imaging that CaeA regressed the clinical symptoms of EAE. Further, there was reduction in the pool of Th1 cells, Th17 cells, and CD8 T cells. The mechanism involved in suppressing the EAE symptoms was due to the inhibition in the generation of effector and central memory T cells and induction of the expansion of Tregs. In essence, these findings implicate that CaeA may be considered as a potent future immunosuppressive drug

Fiction and Facts about BCG Imparting Trained Immunity against COVID-19

The Bacille Calmette-Guérin or BCG vaccine, the only vaccine available against Mycobacterium tuberculosis can induce a marked Th1 polarization of T-cells, characterized by the antigen-specific secretion of IFN-γ and enhanced antiviral response. A number of studies have supported the concept of protection by non-specific boosting of immunity by BCG and other microbes. BCG is a well-known example of a trained immunity inducer since it imparts ‘non-specific heterologous’ immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the recent pandemic. SARS-CoV-2 continues to inflict an unabated surge in morbidity and mortality around the world. There is an urgent need to devise and develop alternate strategies to bolster host immunity against the coronavirus disease of 2019 (COVID-19) and its continuously emerging variants. Several vaccines have been developed recently against COVID-19, but the data on their protective efficacy remains doubtful. Therefore, urgent strategies are required to enhance system immunity to adequately defend against newly emerging infections. The concept of trained immunity may play a cardinal role in protection against COVID-19. The ability of trained immunity-based vaccines is to promote heterologous immune responses beyond their specific antigens, which may notably help in defending against an emergency situation such as COVID-19 when the protective ability of vaccines is suspicious. A growing body of evidence points towards the beneficial non-specific boosting of immune responses by BCG or other microbes, which may protect against COVID-19. Clinical trials are underway to consider the efficacy of BCG vaccination against SARS-CoV-2 on healthcare workers and the elderly population. In this review, we will discuss the role of BCG in eliciting trained immunity and the possible limitations and challenges in controlling COVID-19 and future pandemics