Revisiting Host-Directed Adjunct Therapies in Tuberculosis

Review Article

J Bacteriol Mycol. 2020; 7(4): 1139.

Revisiting Host-Directed Adjunct Therapies in Tuberculosis

Fatima S1 and Dwivedi VP2*

1Department of Molecular Medicine, Jawaharlal Nehru University, New Delhi, India

2Department of Immunobiology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India

*Corresponding author: Dr Ved Prakash Dwivedi, Department of Immunobiology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India

Received: June 01, 2020; Accepted: June 29, 2020; Published: July 06, 2020


Tuberculosis (TB) is a deadly disease caused by the intracellular obligate pathogen, Mycobacterium tuberculosis (M.tb) and affects one-third of the world’s population. Of all the infected individuals only around 5-10% of the individuals develop active TB disease but there is an emergence of approximately 10 million total TB cases with 1.7 million deaths annually, globally. It leads to maximum number of deaths due to an infectious agent. The treatment of TB by conventional drugs requires multiple antibiotics, is lengthy and therefore most of the time leads to non-compliance with the treatment. The problem of TB treatment has become even more challenging after the emergence of multidrugresistant and extremely drug-resistant TB. Therefore, strengthened efforts to find new TB drugs and immunotherapies which could improve the effects of the drugs and reduce the side effects associated with them, are urgently required. A Th1/Th2 imbalance in TB patients caused by decrease in host protective Th1 response and an increase in Th2 response plays a substantial role in the pathogenesis and progression of TB. Immunotherapies could modulate the immune system in patients with active TB disease or latent TB infection, helping in controlling the replication of M.tb better. Immunotherapy against TB infection principally aims to restore the Th1/Th2 balance by augmenting the necessary Th1 response and subduing the undue Th2 response. Therefore, the emerging field of immunotherapy needs to be further improved and studied to maximize its potential as combination therapy. This review discusses several potential immunotherapies with special emphasis on immuno-modulators. These immunotherapies can be used to intensify the potential of the standard anti-TB drugs while eliminating their side effects in the host, when they are administered as an adjunct with the conventional anti-TB drugs.

Keywords: Mycobacterium tuberculosis; Immunotherapy; Adjunct Therapy; MDR; XDR


Tuberculosis (TB) remains a major public health concern. One fourth of the global population is estimated to have infected with M.tb. There are approximately 10 million new TB cases with 1.7 million deaths annually [1]. The only officially approved vaccine against M.tb is Mycobacterium bovis, Bacillus Calmette Güerin (BCG) that provides protection against miliary and childhood TB but proves to be unsuccessful in adults because of the absence of long lasting immunological memory. The only available treatment for TB is Directly Observed Treatment Short-course (DOTS) therapy [2]. Effective management of TB infection as well as the progression requires DOTS treatment, which is long, consists of several antibiotics and has multiple side-effects. These factors lead to noncompliance from the treatment, which ultimately results in the emergence of drug-resistant TB. It is noteworthy that drug-resistant TB is more challenging to treat and requires even a longer time [3]. This further increases the cost of TB control program in countries with a high percentage of infected population that have meager resources to invest in the control program. The World Health Organization (WHO) has reported a threefold increase in the incidences of Multiple Drug- Resistance (MDR) TB between 2013 and 2019. These M.tb strains are resistant to at least one of the antibiotics, isoniazid or revamping used in the treatment. XDR-TB (extensively drug resistant) is even more difficult to treat and the results of the treatment cannot be predicted. Therefore, the world is in extremely urgent need of developing new therapeutic strategies that has the potential of reducing the length of the Anti-Tuberculosis Therapy (ATT) and its associated side effects. Although, there are many new and efficient drugs in clinical trials but still the advancement in TB drug development is pretty slow and till date none of the drugs being tested so far has led to the shortening of the duration of the ATT [4]. Recent years have witnessed a huge interest in host directed therapies using immuno-modulators, which make the host immune system capable enough to fight against the bacteria on its own. This therapy mainly relies on maintaining a balance in the Th1/Th2 paradigm in the host organism by increasing the level of protective Th1 (T-helper 1) response and simultaneously reducing the level of Th2 response. It has also been established recently that Th17 host response also leads to protective immunity in TB disease [5]. Immunotherapies modulate the immune system in patients with both active and latent TB and thus assist in providing better control of M.tb replication [6]. The immuno-modulators are compounds derived naturally or synthesized and cytokines that have been reported to provide protection against TB by being used as an adjunct along with the DOTS therapy or even alone. These immuno-modulators target the biologically and clinically significant checkpoints in anti-mycobacterial directed pathways induced by the host [7]. They have also been described to reverse the side-effects of the DOTS therapy by providing lung protection and reducing the length of treatment of the DOTS therapy. Therefore, this hostdirected therapy using immuno-modulators is a promising approach which must be explored more elaborately for better control of the TB disease. This paper reviews the strategies and prospects for TB hostdirected therapy with the main focus on the immuno-modulators and their use in ATT as an adjunct therapy.

Host immune response to TB infection: The Th1/Th2 paradigm

Lungs are the primary organs, which gets infected by M.tb [8]. The encounter between M.tb and host immune response leads to the outcome of the TB disease- latent infection, active TB disease or complete eradication of the bacteria. T lymphocytes (CD4+) are the primary cell type that mediates the protective immune response to M.tb infection. This host immune response depends mainly on the cytokines secreted by the T helper (Th1) cells and Th17 cells, such as IFN-γ, IL-2, IL-12, IL-17 and IL-23. IFN-γ is the key factor in the containment of M.tb in the macrophages. These cytokines lead to the activation of macrophages. Activation of macrophages is important for the control of the disease by remarkably increasing the ability of macrophages to engulf and kill the pathogen by presenting the bacterial antigens to T-cells [9]. CD 8+ T-cells also produce similar cytokines as CD4+ T-cells and have cytolytic activity that can directly eliminate the pathogen. M.tb can evade the classical Th1-mediated response by inhibiting phagosomal maturation, lysosomal fusion, and MHC antigen presentation, resulting in its long-time survival in the host. At such a stage, CD8+ T-cells take the responsibility of getting rid of the bacteria by directly engulfing and killing the infected macrophages. Activated CD8+ T-cells can destroy the macrophages by releasing granzyme, which release intracellular bacteria and thus destroying the pathogen directly. Therefore, this dual strategy used by the host, which involves both macrophages and T-cells adequately, controls and eliminates M.tb infection. This mechanism of action is the immunological basis of TB treatment by Th1 cytokines [9]. Th2 cytokines, including IL-4, IL-10 and TGF-β, can impede the effect of Th1 cytokines. Thus, Th1 and Th2 cytokines interact and inhibit each other to maintain the T-cell homeostasis, killing the pathogen without significant damage to the host by a disproportionate and unbalanced immune response [10]. Remarkably, in TB patients, a Th1/Th2 imbalance with a decrease in Th1 cytokines and an increase in Th2 cytokines was observed, in the blood while Th1 cytokines were over-expressed in infected tissues [11]. This suggests that, the Th1/Th2 imbalance plays a significant role in the pathogenesis and expansion of TB disease, which could be explored for designing hostdirected immuno-therapeutics for an improved treatment of TB. The Th1/Th2 immune paradigm has been explained in Figure 1.

Tuberculosis: Pathogen burden and need for an alternative adjunct therapy

TB is a deadly disease causing approximately 1.7 million deaths each year [1]. The pathogenesis has become worse by the emergence of drug resistant strains. Treatment of drug-resistant TB is a major challenge in the prevention and eradication of TB. DOTS therapy is the only available treatment of the disease, which is characterized by long duration of treatment and administration of multiple drugs to achieve sterile cure of the infection and prevent occurrence of drug resistance [12]. The DOTS therapy characteristically is a 6 months treatment, comprising of an initial intensive period of 2 months followed by a 4 months continuation phase. During the first 2 months the patient is treated with four first line drugs namely, isoniazid (INH), rifampicin (Rif), ethambutol (ETH), and pyrazinamide. During the last 4 months the patient is given doses of Rif and INH. These drugs are accompanied by innumerable side effects, such as lung-toxicity, hepatitis, gastrointestinal problems, rashes, and renal failure [13]. These adverse effects coupled with the long duration of treatment often leads to non-compliance to the medications, and therefore increasing the risk of developing drug-resistant form of TB. The second-line of treatment of MDR patients, resistant to INH and Rif, consist of pyrazinamide, a fluoroquinolone along with an injectable antibiotic (amikacin or kanamycin), ethionamide, and cycloserine or para-aminosalicylic acid with the treatment, which lasts for 18-20 months [14]. Despite great efforts in finding new drugs for ATT, we still use the drugs which were discovered 40 years ago, except two new drugs, bedaquiline and delamanid that have been approved by FDA for treating MDR-TB patients [15-17]. We are in urgent need of novel drugs, which have enhanced efficacy as well as the ability to reduce the duration of the therapy while having an improved safety profile, compared to the currently available drugs [15]. With the decrease in the time taken for treatment, there would be a remarkable improvement and revolution in attaining cure of TB disease. This requires innovative efforts. Also, besides discovery of novel drugs, we need a therapy based on our understanding of the host-pathogen interactions. This would include not only the drugs that are bactericidal by themselves but also those which modulate the host immune pathways and clear the bacteria by a synergistic approach. This approach of eliminating the bacteria by enhancing the activity of the conventional drugs is known as adjunct therapy [18]. Adjunct therapies can be classified into host-directed or pathogendirected therapies based on their modulatory targets. Host-directed adjunct therapies are better to use, as they are not associated with emergence of antibiotic resistance. This dual approach of using standard drugs along with an adjunct therapy could enhance the effectiveness of ATT.

Citation: Fatima S and Dwivedi VP. Revisiting Host-Directed Adjunct Therapies in Tuberculosis. J Bacteriol Mycol. 2020; 7(4): 1139.