They identify a key protein for tuberculosis bacteria to cause disease

Tuberculosis, caused by the bacteria Mycobacterium tuberculosis, remains one of the deadliest infectious diseases in the world. Despite the fact that there are effective antibiotics against it and a vaccine that offers global protection of 50%, around 1.5 million people died from this disease in 2020. The lack of access to treatment in developing countries or the increase Progressive resistance to multiple first-line antibiotics complicates the prognosis of tuberculosis. In addition, the COVID-19 pandemic has further worsened the control of this disease, due to the difficulty in detecting and treating patients early.

The bacteria M.tuberculosis It is characterized by almost always attacking the lungs, where it causes most of the damage. Like many other pathogenic bacteria for humans, this bacillus (rod-shaped bacteria) needs iron to perform various functions and multiply (several enzymes need this ion to catalyze chemical reactions). To get it, M.tuberculosis It has a sophisticated system for sequestering iron from host tissues. In essence, the tubercle bacillus releases iron-carrying molecules (siderophores), called mycobactin and carboxymycobactin, which allow this precious metal ion to be captured inside.

Unlike other bacteria that have been extensively studied in the laboratory, such as Escherichia colithe machinery involved in the secretion of siderophores in M.tuberculosis and other bacteria of the same family (such as the bacterium that causes leprosy) have very particular and little-known characteristics. Now, researchers in the United States have discovered the role of an essential protein in “stealing” iron from the surrounding environment. The results of their study have recently been published in the journal Nature Communications.

The newly identified protein is called Rv0455c and its function was unknown prior to this study. This molecule acts as a pump that releases the siderophores through the membranes of the tuberculosis bacteria. Thanks to it, the bacillus that causes tuberculosis can grow in low-iron media and release both mycobactins and carboxymycobactins.

In addition, the gene for this protein bears virtually no resemblance in sequence to the genes for proteins involved in siderophore secretion systems of other, unrelated bacteria that had been studied before (such as E. coli). Instead, the gene for this protein is also highly conserved in other bacteria of the same family of mycobacteria that M.tuberculosisWhat M. leprae (causes leprosy). This fact suggests that the Rv0455c protein plays a valuable role among these microorganisms.

To check what would happen if this protein was not present in the bacteria, the scientists generated mutant strains in which the gene responsible for producing this molecule had been eliminated. These mutant bacteria not only secreted much less siderophores, but were also unable to grow in iron-poor media and suffered from toxic effects in the presence of these iron-carrier molecules.

Through various experiments, the authors verified that the Rv0455c protein was functional both in its mature and water-soluble form (located in the periplasm, the compartment between the plasma membrane and the cell wall), as well as anchored in the membrane (through genetic engineering). This supports the idea that this protein works inside the tubercle bacillus. However, it is still unknown through which mechanisms this molecule works to release the siderophores.

In mice, the absence of the Rv0455c protein in the mutant strain of M.tuberculosis it prevented their multiplication and also caused a much milder disease than in those mice infected with the original strain (and said functional protein). In fact, this molecule was necessary, especially at an early stage, for the bacteria to be able to infect the lungs. Those mice infected by bacteria without the functional protein had far fewer lung lesions and fewer lymphocytes in the lungs at 70 days. This effect was due to siderophore poisoning of the bacteria, which were unable to release these iron-carrying molecules to the outside.

Together, the authors point out that the Rv0455c protein is necessary for the secretion of iron transporters and for the tuberculosis bacteria to attack with all their virulence in mice. This advance is not simply limited to a better understanding of the siderophore secretion system. The special characteristics of the Rv0455c protein make it an interesting therapeutic target. This opens the door to develop drugs with a new mechanism of action, aimed at blocking the function of this protein.

Esther Samper

Reference: «A periplasmic cinched protein is required for siderophore secretion and virulence of Mycobacterium tuberculosis», Lei Zhang et al. in Nature Communications, vol. 13, art. #2255, April 26, 2022.

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