TB is primarily acquired following inhalation of aerosolized Mycobacterium tuberculosis bacilli and the majority of TB cases are pulmonary in nature. In 1882 Dr. Robert Koch announced his discovery of Mycobacterium tuberculosis, the bacillus that causes tuberculosis (TB). Tuberculosis (TB) remains a major threat to human health with approximately one-third of the world’s population being affected. Significant progress has been seen over the last decades, still, TB continues to be the top infectious killer worldwide, claiming over 4500 lives a day. In 2016 WHO reported 10.4 million people falling ill due to TB and 1.8 million TB deaths. World TB Day is celebrated on March 24 to educate the public about the impact of TB around the world. On this annual event successes in TB prevention and control is shared and awareness is raised about the challenges that hinder progress toward the elimination of this devastating disease. Up to 13 million people in the United States have latent TB infection who will convert to active disease in the future. The emergence of multidrug-resistant TB (MDR-TB) poses a major health security threat and could risk gains made in the fight against TB.

  1. tuberculosis is a gram-variable, contagious rod-shaped pathogen varying in diameter and length between 0.3–0.5 μm and 1.5–4.0 μm, respectively (1). These aerobic-to-facultative anaerobes are metabolically very adaptable and can readily switch from a carbohydrate to a fat diet in an attempt to adjust to the evolving host cell conditions. Human alveolar macrophages which are the first line of innate defense for pathogen encounter is the primary target of M. tuberculosis. The acquired host defense against M. tuberculosis is mainly controlled by cell-mediated immune responses. In the molecular structure, M. tuberculosis is surrounded by thick and waxy cell envelope containing interconnected polymers of mycolic acids (MAs), arabinogalactan (AG) and peptidoglycan (PG). The uniqueness of this envelope is hydrophobicity primarily due to Mas, which are long chain fatty acids of up to 90 carbon atoms in length. M. tuberculosis is inherently resistant to antibiotics due to this hydrophobic membrane which acts as a permeability barrier towards various hydrophilic and lipophilic compounds. Apart from this impermeable membrane other virulence factors such as efflux pumps and drug degrading enzymes also act towards the intrinsic resistance. M. tuberculosis is primarily an intracellular pathogen and the macrophage is the major host cell. The bacterium possesses an innate ability to suppress the antimicrobial response of the macrophage. It survives within macrophages, preventing phagosome maturation and attenuation of pro-inflammatory responses. In an additional pathway, it enters a non-replicating persistent (NRP) state (2). NRP enables it to survive within the host until unfavorable conditions persist. A term used for tubercle bacilli within the NRP state is Persister cells, which are phenotypically and reversibly tolerant towards antibiotics. A small number of bacterial cells enter the NRP state. This low generation frequency together with their transient nature is the reason for limited knowledge about persister cells. Various factors attributed to their formation are the presence of an acidic environment, growth-limiting by-products such as acetate and nutrient and oxygen depletion. Persisters are believed to be the cause of latent TB infections (LTBI) which is a non-contagious and clinically asymptomatic state. LTBI proves to be a major obstacle in the TB control due to the chances of disease activation once the cells exit the NRP state and proliferate. As a result, latently infected persons are the pool of future infections. Approximately 5–10% of persons infected with M. tuberculosis will eventually develop primary active TB and 90–95% will remain latently infected, not because the bacilli gets eradicated but is effectively controlled within granulomatous structures (3). Conventional antibiotics which are targeted towards the cellular functions important for microbial growth and proliferation, fail to eliminate Persisters as they remain metabolically quiescent. NRP state is characterized by a thickening of cell walls, a decrease in protein synthesis and transcription rates, and a low metabolic state with ATP levels up to 5-fold lower compared to actively replicating cells. This automatically eliminates common antibiotic targets which render these cells tolerant towards various antibiotics if they remain within the NRP state.

In spite of the plethora of knowledge about the survival strategies employed by M. tuberculosis, a rise in drug-resistant strains has led to revived interest in developing immunotherapies for TB. This approach encompasses compounds with immune modulating activity to ‘activate’ immune cells and make a hostile environment for intracellular M. tuberculosis. Immune modulating compounds (IMCs) ranging from lipids and polysaccharides, cytokines and drugs such as metformin and albendazole are at various stages of development. Engineered nanoparticles (NPs) have been employed to effectively deliver IMCs to immune cells. Developing a TB vaccine ranks among the highest global health priorities from a medical needs perspective (4). Bacillus Calmette-Guerin (BCG) vaccine, is the only available vaccine and has very limited effect against adult pulmonary TB. Therefore, new treatment modalities are a promising strategy to eradicate TB globally. With numerous vaccine candidates for TB in the pipeline, most do not show strong immunogenicity and lack innate ability to be delivered to appropriate sites for optimal immune stimulation. To develop a robust innate and adaptive immune responses and to target antigens to immune cells and facilitate transfection NPs are being applied. Presently, a ‘cocktail’ of several antibiotics is administered to patients. In the cocktail, each antibiotic target various mycobacterial functions at relatively high doses as a preventative measure against the acquisition of resistance. The course of treatment for TB is a 6-month regimen based on a minimum of 4 first-line antibiotics (INH, RIF, ethambutol, and pyrazinamide) during the initial 2-month intensive phase. A major patient non-compliance and consequently failure of TB treatment and the manifestation of drug resistance has been observed as a result of the current lengthy treatment regimens.

A huge amount of literature available documenting various aspects of the immune response to M. tuberculosis infection is available. However, plausible target-based therapeutic approaches require a more complete understanding of the processes involved. The most important requirement is a system level understanding of the signaling processes during infection, and the influence of the temporal evolution of cytokines and chemokines as the host attempts to clear the infection. An understanding of the interplay between autophagy, apoptosis, and necrosis, and their balance during infection will be an advantage. The current imperative is to improve our understanding of the type of immunological responses needed to provide robust protection against Mtb infection and to use this information to efficiently develop new, safe and effective TB vaccines.

References

  1. Eleanor MG, Kumar AE, Dan MM. Review on Mycobacterium Tuberculosis. RRJMB 2016. p. 2320–3528.
  2. Dube A, Reynolds JL. Modulation of innate immune responses using nanoparticles for infectious disease therapy. Curr Bionanotechnol 2016;2:60–5
  3. Gideon HP, Flynn JL. Latent tuberculosis: what the host "-sees"? Immunol Res NIH Public Access 2011;50:202–12. 
  4. Khademi F, Derakhshan M, Yousefi-Avarvand A, Tafaghodi M. Potential of polymeric particles as future vaccine delivery systems/adjuvants for parenteral and non-parenteral immunization against tuberculosis: a systematic review. Iran J Basic Med Sci Mashhad University of Medical Sciences 2018;21:116–23.