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Approximately 80 years ago, it was discovered that Mycobacterium tuberculosis (MTB), a lethal respiratory disease, has the ability to form cord-like structures. In a recent paper published in the journal Cell, researchers elucidate the biophysical principles governing the formation of these cords. They demonstrate how successive generations of dividing bacteria collaborate to construct these structures, granting them resistance to antibiotics.
Senior author Vivek Thacker, who spearheaded the research at the Global Health Institute at Ecole Polytechnique Federale de Lausanne (EPFL) in Switzerland and is now affiliated with the Department of Infectious Diseases at Heidelberg University in Germany, underscores the significance of cord formation in infection and its role in pathogenesis. The study employed a distinctive combination of technologies. One of these was a lung-on-chip model, providing a direct view of the initial interaction between MTB and host cells at the air-liquid interface in the lungs. This revealed that cord formation is prominent in the early stages of infection. Additionally, the researchers utilized a mouse model that develops pathologies resembling human tuberculosis. This enabled them to acquire tissue for examination through confocal imaging, confirming that cording also occurs early in infection in vivo.
The research yielded several novel insights into how these cords interact with and compress the cell nucleus, the impact of this compression on the immune system and the connections between host cells and epithelial cells. It also shed light on how cord formation influences the alveoli in the lungs. Moreover, the study unveiled how these cords maintain their structural integrity and enhance tolerance to antibiotic therapy.
Melanie Hannebelle, previously at EPFL’s Global Health Institute and now affiliated with Stanford University, highlights the increasing recognition of mechanical forces affecting cellular behavior and responses. She emphasizes the importance of understanding how these forces at various levels impact cell and tissue function for a comprehensive understanding of biosystems.
Thacker proposes a new perspective in pathogenesis, viewing MTB in infection as aggregates rather than individual bacteria. This opens up possibilities for novel interactions with host proteins, particularly those known to influence MTB pathogenesis. It introduces a paradigm shift where forces from bacterial architectures influence host function.
Future research will delve into whether cord formation imparts new functionalities to known effectors of MTB pathogenesis, many of which are situated on the MTB cell wall. Additionally, it will explore the consequences of tightly packed bacteria within the clump and how this may confer a protective effect against antibiotics.
Richa Mishra, the other first author, currently based at EPFL’s Global Health Institute, emphasizes the pressing need for host-directed therapies or interventions that target specific virulence mechanisms. These approaches have the potential to streamline and enhance antibiotic therapy, especially considering the challenges posed by prolonged and intricate therapeutic regimens and the growing threat of drug resistance in tuberculosis infections.
