In a new study, published in Nature, CSSB researchers and international collaborators reveal new insights into the structure of a key system of the tuberculosis pathogen:Type VII secretion systems are molecular machines that play key roles in the infection cycle of many pathogenic mycobacteria, including the notorious Mycobacterium tuberculosis. A deeper understanding of the structure and function of these systems can enable the development of novel therapies for the treatment of tuberculosis.
Prior to the corona virus pandemic, tuberculosis was the leading cause of death worldwide from a single infectious agent. Mistakenly considered by many to be a disease of the past, tuberculosis is a disease that still kills four thousand people every day (approximately 1.4 million every year). With the spotlight placed on combatting COVID-19, the fight against tuberculosis has now suffered additional difficulties, due to decreased options for testing and treatment during lockdown periods. WHO models are currently estimating an excess of half a million TB deaths in 2020 and a decade-long setback in the fight against TB.
To infect a human host cell, Mycobacterium tuberculosis must transport bacterial proteins across its own impermeable cell envelope. “The pathogen possesses an arsenal of dedicated molecular machines, called type VII secretion systems (T7SS), that facilitate this transport,” explains Wilbert Bitter from the Vrije Universiteit Amsterdam/Amsterdam UMC “In fact, the five different types of these systems in Mycobacterium tuberculosis are not only central for virulence but are also critical for nutrient uptake which makes them ideal drug targets to fight the disease.”
The high-resolution structure, created based on data collected by Jiri Wald at the CSSB cryo-EM facility, confirms that four components of T7SS do in fact form a six-sided star-shaped complex. The structural model also revealed that this complex is stabilized by an additional fifth component, the enzyme MycP, which the researchers discovered is essential for T7SS functioning. A group of three MycPs cap a dome-like chamber sitting at the top of T7SS’s star-shaped complex. Each MycP sits on top, like an inverted cherry, and provides stability by increasing the overall number of contact points. “In the absence of MycP the entire complex becomes more flexible, and the arms of the star begin to wobble,” explains CSSB researcher and first author Catalin Bunduc “The complex with MycP is like a stable suspension bridge and when the suspenders (MycP) are removed, the complex lacks support and sways like an unsteady footbridge.”
The data also provided new insights into how T7SSs could be able to secrete proteins in a controlled manner without allowing other molecules to leak in and out. Proteins are usually transported in an unfolded state, meaning that prior to traveling through a secretion channel the protein is untangled into a chain-like structure, reducing its width. T7SS, however, secretes proteins in at least a partially folded manner which requires a relatively large opening in the bacterial membrane. “The T7SS molecular machinery seems to form two communicating chambers, one on each side of the inner membrane which could potentially prevent leakage when a pore is opened.” notes CSSB researcher Dirk Fahrenkamp.
While tuberculosis can be treated with antibiotics, drug resistant strains are becoming increasingly more prevalent and in 2019 these represented 3.5% of new TB cases and 17.7% of previously treated cases. The structural insights gained by the researchers provide a starting platform for the identification of domains and interactions that could be targets for drug development. “Our results are a huge step forward in understanding T7SSs and Mycobacterium tuberculosis itself” explain the authors “we can now investigate potential drug binding sites that inhibit the function of T7SS and prevent the spread of infection.”
“This breakthrough not only reveals new possibilities in the fight against tuberculosis but also emphasizes the societal importance of fundamental research. Breakthroughs, like this one, can ultimately lead to practical applications that save lives,” emphasizes CSSB investigator Thomas Marlovits.
Featured image: Atomic structure of the complete type 7 secretion system of the tuberculosis pathogen Mycobacterium tuberculosis determined by cryo-electron microscopy (picture: CSSB).
Catalin M. Bunduc, Dirk Fahrenkamp, Jiri Wald, Roy Ummels, Wilbert Bitter, Edith N. G. Houben & Thomas C. Marlovits: Structure and dynamics of a mycobacterial type VII secretion system; Nature 2021; DOI: 10.1038/s41586-021-03517-z
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