How Tuberculosis Manipulates Human Genes for Survival

Medical News: Tuberculosis (TB) remains a global health threat, claiming millions of lives despite ongoing efforts to combat it. Researchers from Amrita Vishwa Vidyapeetham in India, CHRIST University in India, and the University of Florida in the USA have collaborated on a study uncovering how the TB-causing bacteria, Mycobacterium tuberculosis (Mtb), manipulates the human immune system using epigenetic mechanisms. The study’s findings could reshape our understanding of TB and open pathways for new therapies.


How Tuberculosis Manipulates Human Genes for Survival

The Power of Epigenetics in Bacterial Survival
Mtb’s survival relies heavily on altering the host's immune system through a complex interplay of epigenetic changes. Epigenetics, which involves changes in gene expression without altering DNA sequence, is a powerful tool that the pathogen uses to evade immune responses. By modifying the host's immune genes, Mtb can silence or activate specific genes that assist in its survival. This Medical News report highlights the various methods Mtb employs to manipulate immune responses and the implications for potential treatments.
 
Key Mechanisms: Histone Modifications and DNA Methylation
Mtb uses multiple epigenetic strategies, primarily focusing on two mechanisms: histone modifications and DNA methylation. Histones are proteins that package DNA into a compact structure, and modifications to them can activate or silence genes involved in immune responses. Researchers discovered that Mtb manipulates these histone modifications, causing an imbalance that prevents immune cells from attacking the bacteria.
 
-Histone Modifications: Mtb’s protein ESAT-6 is known to acetylate histones, promoting the release of anti-inflammatory cytokines like IL-10, which calms the immune response. Additionally, proteins such as Rv2966c modify histones to suppress the production of reactive oxygen species (ROS), a critical immune response. These alterations significantly reduce the body’s ability to control and clear Mtb infection.
 
-DNA Methylation: Another tactic Mtb uses is DNA methylation, which silences genes that play a role in immune responses. By adding methyl groups to specific areas of the host DNA, Mtb effectively silences crucial immune-related genes. This strategy allows the bacteria to evade immune surveillance and continue replicating within the host cells.
 
MicroRNA Manipulation: A Hidden Tool in Bacterial Defense
MicroRNAs (miRNAs) are small molecules that regulate gene expression. Mtb manipulates these miRNAs in a way that directly impacts the immune system’s response. For example, Mtb can increase levels of miR-155, which suppresses the initial stages of autophagy - a process the body uses to destroy harmful invaders. This alteration helps Mtb avoid destruction within immune cells.
 
Moreover, Mtb alters miR-889 levels, targeting the TWEAK protein. By suppressing TWEAK, Mtb hinders t he body’s ability to initiate autophagy, allowing the bacteria to continue thriving. Another significant miRNA change includes miR-17 downregulation, which enhances Mtb’s ability to survive within immune cells by preventing cell death. These findings underscore how Mtb utilizes miRNA manipulation as a stealthy defense mechanism to thrive within the human body.
 
The Role of Cytokines: Suppression and Survival
Cytokines are signaling proteins that mediate immune responses. Mtb manipulates the production of cytokines to suppress immune activity. For instance, it promotes IL-10, an anti-inflammatory cytokine, while downregulating pro-inflammatory cytokines like TNF-α. By doing so, Mtb ensures that immune cells are less aggressive, allowing the bacteria to replicate within macrophages undetected. This cytokine manipulation proves advantageous for Mtb, as it prevents immune cells from mobilizing effectively against the infection.
 
In addition, Mtb’s ability to increase IL-10 through histone acetylation prevents the activation of MHC-II proteins, which are crucial for identifying and attacking foreign invaders. This further dampens the immune response, creating a favorable environment for Mtb within host cells. These findings highlight how Mtb orchestrates cytokine changes to foster its survival and replication within the human body.
 
Macrophage Polarization: Reprogramming Immune Cells
Macrophages are key players in the immune response, and Mtb has developed sophisticated methods to manipulate them. Normally, macrophages can polarize into two types: M1 (pro-inflammatory) and M2 (anti-inflammatory). Mtb encourages macrophages to adopt the M2 phenotype, which is less aggressive, by secreting specific proteins that influence polarization. This reprogramming enables Mtb to thrive in a less hostile environment, where immune responses are subdued.
 
One critical protein, ESAT-6, plays a dual role in polarization. Initially, it activates M1 macrophages, triggering an immune response. However, Mtb then swiftly changes tactics, pushing these macrophages to the M2 state, thereby dampening the immune response and allowing the bacteria to persist longer within the host.
 
Autophagy Inhibition: Halting the Body’s Cleanup Process
Autophagy is a natural process that cells use to remove damaged components and harmful invaders. However, Mtb halts this process by targeting autophagy-related genes. Mtb’s protein EIS plays a pivotal role in this, interfering with the host’s autophagy signaling pathways. This inhibition allows the bacteria to avoid being broken down by immune cells.
 
Mtb also regulates autophagy by manipulating specific miRNAs. For example, increased levels of miR-144 suppress autophagy, creating a safe niche for Mtb. These mechanisms underline how Mtb obstructs autophagy to protect itself, evading one of the immune system’s main defenses against intracellular infections.
 
Potential Treatments: Targeting Epigenetic Mechanisms
This groundbreaking research opens new avenues for treatment by targeting Mtb’s epigenetic manipulation. Host-directed therapies, which aim to modulate the host’s immune response rather than directly attacking the bacteria, show promise. By inhibiting histone deacetylases (HDACs), for instance, researchers have found ways to stimulate a stronger immune response. The HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) has shown effectiveness by reducing IL-10 levels and enhancing the pro-inflammatory response, thus making the host environment less hospitable to Mtb.
 
Another promising avenue involves targeting miRNAs. Using anti-miRNA compounds, researchers can inhibit the effects of Mtb-induced miRNAs, potentially restoring normal immune function. These approaches, although still in experimental stages, could lead to novel therapies that make the body’s immune system more resilient to Mtb infection.
 
Study Conclusions: A New Era in Tuberculosis Treatment
The study’s findings underscore the complexity of Mtb’s survival tactics. By hijacking the host’s epigenetic machinery, Mtb creates a favorable environment for its survival, outsmarting traditional immune responses. Understanding these epigenetic mechanisms provides insights into why TB remains so challenging to eradicate. The study suggests that targeting these epigenetic changes, either by using HDAC inhibitors or by regulating miRNAs, could pave the way for new treatments that help the immune system more effectively combat TB.
 
The intricate methods Mtb uses to manipulate host immune responses - spanning histone modification, DNA methylation, and miRNA regulation - highlight the pathogen’s adaptability and resilience. As researchers continue to unravel these complex interactions, host-directed therapies offer a promising frontier. This approach has the potential to transform TB treatment by focusing not on the bacteria itself but on strengthening the host's defense mechanisms.
 
The study findings were published in the peer-reviewed International Journal of Molecular Sciences.
https://www.mdpi.com/1422-0067/25/21/11801
 
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