Author interview: Dr. Debraj Koiri is a Ph.D. scholar in the Membrane Biology Lab at the School of Biological Sciences, NISER. He earned his B.Sc. in Microbiology from the University of Kalyani and his M.Sc. in Biotechnology from Jadavpur University. His research focuses on understanding the role of Mycobacterium secretory components in evading phagosomal maturation through host membrane modulation.
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Lab: Dr. Mohammed Saleem, National Institute of Science Education and Research, Bhubaneshwar
Research Summary: This study highlights that Mycobacterium tuberculosis ESAT-6 disrupts phagosomal membranes through fibril-mediated vesiculation, enabling bacterial escape. These findings challenge traditional pore-formation theories and provide new insights into Mtb’s immune evasion mechanisms.
What was the core problem you aimed to solve with this research?
This research focused on uncovering how Mycobacterium tuberculosis (Mtb) employs the ESAT-6 protein to breach the phagosomal membrane inside host cells, a crucial step in its ability to survive and replicate within the human body. The phagosome is a specialized compartment where immune cells attempt to contain and destroy invading bacteria. However, Mtb has evolved mechanisms to escape this confinement, allowing it to establish infection. Previous studies suggested that ESAT-6 might act like a pore-forming toxin, meaning it could create holes in the phagosomal membrane to facilitate bacterial escape. However, the precise way ESAT-6 interacts with the membrane and whether it truly forms conventional pores remained uncertain. This study aimed to clarify this mechanism, providing a deeper understanding of how Mtb subverts immune defenses at the molecular level.
How did you go about solving this problem?
To solve the problem of understanding how Mycobacterium tuberculosis (Mtb) ESAT-6 disrupts the phagosomal membrane, we used a combination of real-time imaging, biophysical assays, and structural analysis to track the dynamics of ESAT-6 with the membrane.
- Real-Time Imaging and Microscopy
- We used super-resolution and live-cell imaging to visualize how ESAT-6 interacts with the phagosomal membrane inside host cells.
- This allowed us to observe in real-time how ESAT-6 leads to the formation of membrane deformations, such as tubules and vesicles.
2. Biophysical and Structural Analysis
- We performed in vitro membrane interaction assays to see how ESAT-6 binds and alters synthetic lipid membranes, mimicking the phagosome.
- Using electron microscopy and thin-section electron microscopy we studied the structural organization of ESAT-6 when interacting with membranes, revealing its fibril formation and vesiculation properties both in vitro and in-cellulo.
How would you explain your research outcomes (Key findings) to the non-scientific community?
Imagine your immune system as a security team in a building, constantly on the lookout for intruders. When a bacterium like Mycobacterium tuberculosis (Mtb) enters, your immune cells (like security guards) capture it in a “security room” called a phagosome, where it’s supposed to be contained and destroyed.
However, Mtb has a sneaky trick up its sleeve. It uses a protein called ESAT-6 to weaken and break down the walls of this security room, allowing it to escape and continue spreading inside the body.
Furthermore, it is not a Traditional Breakout, but a Clever One– Instead of punching holes in the phagosome like other bacteria, ESAT-6 gently reshapes and weakens the membrane by forming tiny fibrils (like pulling threads), making small vesicles that eventually cause the phagosome to break apart and help the bacterium to escape the security room.
Our findings provide novel insights into the mechanism of ESAT-6 mediated phagosomal membrane deformation that remained elusive so far. The findings also potentially provide a fresh perspective in understanding the observed heterogeneity in the residency time of Mtb inside the vacuole. – Dr. Mohammed Saleem
What are the potential implications of your findings for the field and society?
This research uncovers a new way that Mtb manipulates human macrophages, opening the door to better treatments, improved vaccines, and broader applications in infectious disease control.
What was the exciting moment during your research?
One of the most exciting moments in the research was likely when we observed, in real time, how ESAT-6 disrupts the phagosomal membrane in a completely unexpected way. Instead of punching holes like traditional bacterial toxins, ESAT-6 formed fibrils that reshaped the membrane into tiny vesicles, leading to its breakdown. It becomes more thrilling when it challenges previous assumptions, previously, it was believed that ESAT-6 formed simple pores but using advanced microscopic techniques, we observe ESAT-6 in action, directly witnessing how it manipulates the host membrane revealing a completely new mechanism.
Reference: Koiri, Debraj, et al. “Real-time visualization reveals Mycobacterium tuberculosis ESAT-6 disrupts phagosome-like compartment via fibril-mediated vesiculation.” Cell Reports 44.3 (2025). https://doi.org/10.1016/j.celrep.2025.115328
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