Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the leading infectious disease in the world. Inflammation and immunity are host responses to infection that influence the progression and amelioration of the disease. The final outcome depends on the balance between effect or and regulatory immune mechanisms. Growing evidence indicates how anti-inflammatory or immunomodulatory agents improve the outcome of TB. In this communication, we propose that restraining inflammatory responses by host-directed therapies is necessary to control the overall progression and pathology of TB.

Globally, TB kills 2 million people and infects another 10 million every year. Approximately one-third of the world’s population is latently infected with Mycobacterium tuberculosis (Mtb) [1]. Despite more than 20 years of intensive research in this field, the current multifaceted TB epidemic continues to grow at an alarming rate. The lack of an effective vaccine [2], the lengthy treatment regimens with multiple chemotherapeutic agents that have serious side effects [3], the prevalence of co-infection with HIV and the increasing number of cases of multi/extensively/totally drug resistant tuberculosis (MDR/XDR/TDT-TB), have made the control of Mtb infection highly challenging [4,5]. There is a clear association between the immune status of an individual and the outcome of infection/ reactivation of active TB disease [6]. Consequently, alternative host immune-directed therapies can be exploited to improve the efficacy of treatment and the outcome of infection [7].

The most important roadblock in developing host immune-directed therapies for TB is the gap in understanding the complex interaction between bacterial virulence and host resistance, and the immune correlates responsible for ridding the body of TB infection. Mycobacteria attenuate and evade the bactericidal host immune response by surviving and/or proliferating within macrophages [8]. During the infection, mycobacterial components also trigger activation of innate immune cells through pathogen recognition receptors (PRRs) leading to the production of several inflammatory mediators including cytokines, chemokines and antibacterial effect or molecules (ROI/RNI etc.), which drive the local inflammatory responses, recruit immune cells and localize the infection in the form of granulomas with incomplete sterilization [9]. These localized granulomas contain not only mycobacteria, but also mediators of inflammatory responses including various lymphocytes [10]. These rigorous inflammatory responses may contribute to the stochastic nature of disease outcome after infection [11,12]. It is still a matter of debate whether granulomas, and associated inflammation, help to contain or promote the infection.

Immune responses can help to clear and contain a TB infection. However, tuberculosis is not only the result of inadequate immune responses that lead to increased multiplication of mycobacteria and consequent disease. Indeed, excessive or uncontrolled inflammatory immune responses also determine the progression of disease. Thus, inflammation is a doubleedged armament, which determines the susceptibility of a host to contract the disease and/or also worsens the complications of tuberculosis and its associated diseases [13].

Traditional approaches for treating TB have focused on using antibiotics to directly target and kill the bacterium after infection and eventually clear it from the body. However, an increasing body of evidence supports that dampening the excessive and harmful inflammatory responses may minimize mycobacterial dissemination and transmission without deleterious immunopathology [14-18]. For instance, fatal forms of disseminated TB, such as TB meningitis or miliary TB are treated with corticosteroids [19]. Treatment of TB meningitis with dexamethasone and prednisolone in conjunction with standard antibiotic regimens significantly reduced mortality and residual neurological deficit in patients [20]. Corticosteroids only suppress the proinflammatory cytokine responses without affecting antigen-specific T cell responses in the peripheral blood of TB patients [21]. Further, It has been shown that a range of immunosuppressive and immunomodulatory agents reduce mortality in TB-HIV co-infected patients presenting antiretroviral mediated immune reconstitution inflammatory disease [22,23]. It is believed that treatment with antiretrovirals leads to dysregulated recovery of host immune responses, which in turn result in the development of abnormal inflammatory responses or IRD (Immune Reconstitution Disease). IRD affects TB disease in two contradicting modes [24-27]. In 8-43% of the people, IRD results in recovery from TB disease. In the second form of IRD, recovery of host immune responses also leads to unmasking of the previously subclinical latent TB infection [28-32]. Therefore, inhibiting harmful inflammatory responses without affecting adaptive immunity may be an appropriate intervention to treat IRD associated active TB disease. Vilaplana et al. [33] have shown excellent effects with ibuprofen, anon-steroidal anti-inflammatory (NSAIDs) drug, in mouse model of active tuberculosis. Oral treatment with ibuprofen led to reduction in the number of lung lesions, bacillary load and improved survival of mice [34]. Interestingly, Gold et al. [35] have reported that an antiinflammatory drug, oxyphenbutazone can kill both non-replicating and actively replicating forms of mycobacteria within phagocytes. This suggests that drugs like oxyphenbutazone with dual anti-inflammatory as well as antimycobacterial activities provide new insights for TB drug development. However, the potentially beneficial role of treating humans with anti-inflammatory agent’s combined with anti-TB drugs remains elusive.

Recently, Cardona et al. [36] showed that oral administration of heatinactivated Mycobacterium manresensis modifies immune responses triggered by Mtb infection through induction of Tregs. As an adjunct to front-line drug, it protected C3HeB/FeJ mice infected with Mtb against the progression of active disease and relapse after TB treatment, by creating an anti-inflammatory milieu in the lungs [36].

Inflammatory cytokines produced during infection can modulate effect or and regulatory cellular responses. They also provide signals to by stander naïve T cells, which are not specific for Mtb antigens. Consequently, nonspecific by stander inflammation exacerbates both antigen-specific and non-specific immune responses and drives immunopathology [37]. Highlevels of pro-inflammatory cytokines and chemokines (IL-15, granzyme A, MCP-1, IL-1β, IL-9, MIP-1β, SAA and ferritin) have been reported in patients with active TB [38]. It has also been shown that non-specific stimulation of cytokines also increases the risk of type-2 diabetes mellitus in patients with active tuberculosis or vice versa [39].

Overall, these studies point towards the role of inflammatory responses in intensifying tuberculosis disease. To control the global TB epidemic, research should focus on developing novel host immune-directed therapies that inhibit excessive production of pro-inflammatory cytokines and prevent tissue damage and disease exacerbation. At the same time, this research could reveal a fine-tuned mechanism to induce regulated protective immune responses. Development of host-directed adjunct therapies, which can alter inflammatory vs. protective immune responses, would have immense promisein tackling current and future outbreaks of tuberculosis infections, reducing the duration of treatment, avoiding emergence of drug-resistance and preventing disease recurrence, while also controlling the reactivation of latent TB to active disease. Accelerated research efforts towards such an intervention must be made a global priority if we want to win the fight against this leading infectious disease in the world.

 

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Article Information

Article Type: Short Communication

Citation: Gupta N, Agrawal B, Kumar R (2016) Controlling Inflammation: A Superior Way to Control TB. J Infect Pulm Dis 2(2): doi http:// dx.doi.org/10.16966/2470-3176.113

Copyright: © 2016 Gupta N, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Publication history: 

Received date: 16 Mar 2016

Accepted date: 18 Apr 2016

Published date: 22 Apr 2016