Tuberculosis and role of antioxidants in it’s management

Introduction :

Tuberculosis (TB) is caused by mycobacterium tuberculosis. Mycobacterium tuberculosis is a highly aerobic bacterium that requires high levels of oxygen. so it primarily effects lungs of human beings. Macrophages serve as a natural habitat to mycobacterium tuberculosis (Mtb). Mtb corrupts the macrophage’s mechanism of intercellular killing and antigen presentation, leading to development of tuberculosis (TB). Here we describe mechanism of Mtb uptake by the macrophages and address key macrophage functions that are targeted by Mtb specific effecter molecules enabling this pathogen to escapes host immune response. The macrophage function described in this review include fusion between phagosomes and lysosomes , which leads to the production of free radicals or reactive oxygen species(ROS) which causes immunosupression. Free radicals are highly reactive and are capable of damaging almost all types of biomolecules , (proteins, carbohydrates, lipids and nucleic acids) by lipid peroxidation, oxidation of proteins, DNA damage and cytoskeleton damage. Use of anti tubercular drugs also leads to the production of reactive oxygen species which causes the destruction of hepatocytes leading to drug induced liver injury (DILI). Anti oxidants are the drugs that can neutralize the free radicals or reactive oxygen species (ROS) produced by the Mtb or during the anti tubercular therapy. So use of anti oxidants along with the anti tubercular drugs can inhibit the effects of free radicals or reactive oxygen species (ROS). In majority of the TB cases, mycobacterium tuberculosis is latent (inactive) it becomes active only when our immunity is suppressed, to avoid this we should use anti oxidants to neutralize the free radicals or (ROS) formed.

**Understanding Tuberculosis (TB) and Oxidative Stress**

Tuberculosis (TB) remains one of the most significant infectious diseases globally, with Mycobacterium tuberculosis (Mtb) as its causative agent. This bacterium is uniquely adapted to thrive in the human host, primarily targeting the lungs due to its aerobic nature. Within the host, Mtb interacts with various immune cells, most notably macrophages, which play a crucial role in the body's defense against pathogens.

Macrophages are specialized immune cells responsible for engulfing and destroying invading microbes through a process called phagocytosis. However, Mtb has evolved mechanisms to evade destruction by macrophages, allowing it to survive and replicate within these cells. One such mechanism involves interfering with the fusion of phagosomes (vesicles containing engulfed pathogens) and lysosomes (organelles containing digestive enzymes), which are essential for the degradation of pathogens. This evasion tactic enables Mtb to establish a niche within macrophages, where it can evade immune surveillance and persist for extended periods.

A significant consequence of Mtb infection is the generation of reactive oxygen species (ROS) by activated macrophages. ROS are highly reactive molecules derived from oxygen metabolism, and they serve as crucial mediators of the immune response against pathogens. While ROS are effective in killing microbes, they can also inflict collateral damage to host tissues if not regulated properly. The excessive production of ROS during TB infection leads to oxidative stress, which can cause damage to proteins, lipids, nucleic acids, and cellular structures within the lungs. This oxidative damage contributes to tissue injury, inflammation, and immunosuppression, further exacerbating the progression of TB.

Moreover, the treatment of TB with anti-tubercular drugs can exacerbate oxidative stress. Some anti-tubercular drugs, such as isoniazid and rifampicin, are known to induce the production of ROS as part of their mechanism of action against Mtb. However, the increased ROS levels can also lead to unintended side effects, including drug-induced liver injury (DILI), which poses a significant challenge in TB management.

Given the detrimental effects of oxidative stress in TB pathogenesis and treatment, there is growing interest in exploring antioxidant therapies as adjunctive treatments. Antioxidants are substances that can neutralize ROS and prevent oxidative damage to cells and tissues. By scavenging excess ROS, antioxidants may help alleviate tissue injury, reduce inflammation, and enhance the efficacy of anti-tubercular drugs.

**Potential Role of Antioxidants in TB Management**

The potential role of antioxidants in TB management stems from their ability to counteract oxidative stress and its associated detrimental effects. Antioxidants act through various mechanisms, including scavenging free radicals, inhibiting ROS production, and repairing oxidative damage to biomolecules. By restoring redox balance, antioxidants help maintain cellular homeostasis and promote tissue repair and regeneration.

Several studies have investigated the efficacy of antioxidants in mitigating TB-related oxidative stress and improving treatment outcomes. For example, studies have shown that administration of antioxidants, such as vitamin C, vitamin E, and N-acetylcysteine (NAC), can reduce oxidative damage to lung tissues in animal models of TB. Furthermore, clinical studies have suggested that supplementation with antioxidants may enhance the efficacy of anti-tubercular drugs and reduce the risk of adverse drug reactions, including DILI.

However, the use of antioxidants in TB management is not without challenges. The optimal dosage, timing, and duration of antioxidant therapy remain unclear, and further research is needed to elucidate their precise mechanisms of action and therapeutic potential. Additionally, the potential interactions between antioxidants and anti-tubercular drugs need to be carefully evaluated to ensure safety and efficacy.

Despite these challenges, the use of antioxidants holds promise as a complementary approach to TB treatment, particularly in individuals at risk of oxidative stress-related complications, such as severe TB disease or drug-induced toxicity. Integrating antioxidant therapy into existing TB treatment regimens could potentially improve patient outcomes, reduce treatment-related complications, and enhance overall treatment success rates.

In conclusion, oxidative stress plays a significant role in TB pathogenesis and treatment, contributing to tissue injury, inflammation, and drug-induced toxicity. Antioxidants offer a promising avenue for mitigating oxidative stress and enhancing the efficacy of TB treatment. However, further research is needed to establish the safety, efficacy, and optimal use of antioxidants in TB management. By addressing oxidative stress, we can potentially improve outcomes for individuals affected by this devastating disease and move closer to achieving global TB control and elimination goals.

Methods & Materials

Methods of detecting free radicals: the detection of free radicals generated within the body may contribute to clarifying the pathophysiological role of free radicals in disease process .

1): Electron spin resonance (ESR): (ESR) is an appropriate procedure to examine the generation of free radicals in the biological system, (ESR) has emerged as an important tool for detection and identification of free radicals

2)Spin trapping technique: in this technique some of the reagents are used for the detection of free radicals. In this oxygen radicals are trapped by 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) or alpha-phenyl-N-t-butylnitrone (PBN), and the DMPO and PBN spin adduct signal was measured quantitatively by an ESR spectrometer.

With these methods it is possible to specify the radicals or the location at which the radicals are produced.

Results :

Upon detection of the free radicals, the use of drugs called anti oxidants played an important role in neutralizing them and there by inhibiting the effects of free radicals and helps in protecting the cells , minimizing oxidative stress induced immunosupression , and reducing hepatotoxicity.

Some of the examples of anti oxidants are

Vitamin-E and C ,

Acetyl Cysteine ,

Melatonin,

Alpha Lipoic Acid,

Reduced Glutathione,

Silymarin ,

Carvedilol ,

Pirfenidone

These drugs can be used along with anti tubercular drugs as they do not have any interactions among them. Use of these drugs will also decreases the incidence of hepatotoxicity induced by anti tubercular drugs