The Role of the Mycobacterial Cell Wall in Disease Pathogenesis

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 The cell wall of the Mycobacterium species, specifically Mycobacterium tuberculosis, Mtb, plays a critical role in its success as a pathogen, in its ability to resist treatment, and in its persistence in the host organism. Unlike most other bacterial cell walls, the mycobacterial cell wall is unusually complex and studied, and this contributes to the pathogen’s resilience to antibiotics and host immune responses. Such a unique structure not only provides physical protection to the bacterium from external attacks but is also actively involved in the pathogenesis of TB through interactions with host cells and modulation of the host’s immune response. Knowing the structure and functions of the cell wall of mycobacteria is therefore crucial in developing new therapeutic strategies against TB, which remains one of the most deadly infectious diseases worldwide. 

Mycobacterial cell wall composition and structure

The mycobacterial cell wall is a complex assembly of lipids, proteins, and polysaccharides, hence much different from any other known bacterial cell walls. It is composed of three major layers: a peptidoglycan layer, an arabinogalactan layer, and a mycolic acid layer, making the bacterium impermeable and therefore resistant to many antibiotics. The peptidoglycan refers to structural rigidity, while the arabinogalactan links the peptidoglycan to the outer layer of mycolic acid, which is responsible for the cell wall’s hydrophobicity and resistance to chemical damage.

Mycolic acids are long-chain fatty acids that form a waxy coating around the cell, making the mycobacterial cell wall among the most lipid-enriched structures in nature. The waxy coat is crucial for the survival of the bacterium in hostile environments encountered inside immune cells, the macrophages, within the host. Other than that, other kinds of lipids are also present on the cell wall, such as phosphatidylinositol mannosides and lipoarabinomannan, which are essential in the modulation of immunity.

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Role in Disease Pathogenesis

The mycobacterial cell wall acts as not only a protective barrier but also plays an active role in the pathogenesis of TB. The complex structure of the cell wall enables Mtb to evade the host immune system, survive under hostile conditions, and persist in latent form for years. Partly, this is because the cell wall prevents phagosomes, vesicles that engulf bacteria, from fusing with lysosomes, vesicles containing digestive enzymes, in the macrophages. Such inhibition in fusion prevents the killing of Mtb; instead, it replicates within the macrophage.

Moreover, cell wall components such as mycolic acids, LAMs, and other glycolipids modulate the host immune response. For instance, LAMs have been shown to downregulate the production of pro-inflammatory cytokines, which play an important role in mounting an efficient immune response. If the host’s immune response is damaged, the Mtb will not be detected and thus will not be destroyed, finally establishing itself, thereby establishing persistent infection. Owing to its potential interference with the induction of protective immunity, TB becomes a chronic, previous complication with high mortality if untreated.

Cell Wall Biosynthesis as a Drug Target

Since the cell wall plays such a cardinal role in the survival and pathogenicity of Mtb, it is an attractive drug target. Inhibiting the biosynthesis of cell wall components can render the bacterium more susceptible to antibiotics and the host immune system. The current drugs against TB, including isoniazid and ethambutol, act against enzymes involved in mycolic acid and arabinogalactan biosynthesis, respectively. It is in view of emerging strains of drug-resistant TB that new drugs targeting other aspects of the cell wall biosynthesis process need to be developed. With the acidity of recent advances in molecular genetics and biochemistry, several potential targets within the cell wall biosynthesis pathway have been identified over the past decade.

These include enzymes involved in the early stages of peptidoglycan synthesis and others responsible for mycolic acid and LAM biosynthesis. Inhibitors of these enzymes could, therefore, disrupt the formation of the cell wall and result in bacterial death. The next strategy is the development of drugs that target the transport and assembly of components of the cell wall. If key lipids are unable to transport efficiently to the cell surface, it may be possible to weaken the cell wall and enhance the efficacy of existing treatments for TB.

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Challenges of Targeting Mycobacterial Cell Walls

While the mycobacterial cell wall represents an attractive drug target, there are formidable challenges to be overcome. The cell wall biosynthetic pathways themselves are intrinsically complex and redundant, so inhibiting one enzyme or pathway alone may not be sufficient to kill the bacterium. Mtb has developed compensatory mechanisms that enable it to survive even in the presence of drugs by compensating for the inhibition of one pathway. Furthermore, one of the major problems associated with drug delivery is the impermeability of the cell wall. Many potentially useful drugs will not be able to go through the layers of lipids that comprise the cell wall and therefore will not work.

Researchers are trying out combination therapies that target more than one component of cell wall biosynthesis pathways in an effort to prevent the bacterium from compensating for the inhibition of a single target. Novel delivery systems, such as nanoparticles, could be developed to ensure better penetration of drugs into the mycobacterial cell wall; this could probably improve their efficacy.

Conclusion

It is the mycobacterial cell wall, one of the most powerful structures in the pathogenesis of tuberculosis. Its complex structure and functions give Mycobacterium tuberculosis resistance to a wide range of antibiotics and equip it with the possibility of including the host’s immune system, allowing this typical opportunity pathogen to persist in the human body for years. In such a scenario, knowledge of the intricacies of cell wall biosynthesis and its involvement in disease pathogenesis is very important for developing new therapeutic strategies against TB. Though the challenges in this research area are huge, continuous study on the molecular mechanisms of cell wall assembly and function give hope for a more effective mode of therapy against this killing disease.

References

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