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Lesions of Doom – How a parasitic bacterium disrupts blood vessels in the human body


Aortic tissues not exposed to BafA (left) did not germinate new vessels, whereas BafA-exposed aortic tissues (right) did. Credit: Kentaro Tsukamoto

Researchers gain insight into how pathogenic bacteria in the genus Bartonella cause damage to the human body, which opens up new avenues in modern medicine.

Bacteria of the genus Barton are parasites that can be transmitted to humans through insect bites and animal scratches, resulting in an infection called “bartonellosis.”

; Cat scratch disease and ditch fever are forms of bartonellosis caused by various Barton species that infect humans. Barton Bacteria can cause damage to appear in the skin and internal organs. To provide themselves with a safe habitat, the bacteria cause an increase in the number of “vascular endothelial cells” (cells located inside the blood vessels), which hide from the host’s immune system and stimulate the creation of new blood vessels through a process called “angiogenesis.”

Previous studies on Barton henselae (B. henselae in short), the bacterium responsible for feline scrapie, has shown that it can directly “inject” proteins that inhibit programmed cell death (apoptosis) into endothelial cells. In all cases, B. henselae can also promote angiogenesis without direct contact with endothelial cells, which means that the bacterium can secrete a bioactive substance that takes on the obligation to start angiogenesis.

In a new study published in nature Communications, a team of researchers led by Senior Assistant Professor Kentaro Tsukamoto and Professor Yohei Doi at Fujita Health University, Japan, have identified that this bioactive substance is in fact a protein. They have also referred to this protein as Barton angiogenic factor A, or “BafA” for short. This is the very first report of a vascular endothelial growth factor (VEGF for short) -like protein produced by bacteria.

Bartonella Angiogenic Factor A

This study identifies the molecular mechanism by which Bartonella bacteria cause lesions to appear across a patient’s body. Credit: Kentaro Tsukamoto

The researchers started their project by introducing B. henselae into human endothelial cells in petri dishes, and observed that the bacteria caused the endothelial cells to multiply. To identify the genes that give B. henselae this ability, the researchers began to induce random mutations in DNA of the bacteria and see if the mutated bacteria can still cause the endothelial cells to multiply. Through these experiments, the researchers decided B. henselae can stimulate angiogenesis in human endothelial cells only if it has a functional copy of the gene that “encodes”, or controls the synthesis of the BafA protein. They also observed that exposure of human endothelial cells to the isolated BafA protein caused the cells to multiply.

To confirm that BafA stimulates angiogenesis, the researchers extracted samples of a larger blood vessel called the aorta from mice and placed the samples in gels that contained or did not contain BafA. As shown in the image below, the aortic samples that were not exposed to BafA did not produce new blood vessels, but the aortic samples that were exposed to BafA outgrew vessels that extended into the gel. The researchers also found that surgical placement of a BafA-containing gel plug in live mice led to blood vessels growing from the surrounding tissue into the gel.

Additional experiments with human endothelial cells in petri dishes indicated that BafA-activated cell surface receptors that recognize VEGF. By binding to these receptors, BafA triggered the activation of a process inside the cells, with proteins called mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases (ERK). The MAPK / ERK pathway plays an important role in the multiplication of endothelial cells and angiogenesis. In the latest set of experiments, we conducted similar studies on a related bacterium called Barton quintana, the bacterium that causes ditch fever, and we found that it produces its own version of BafA that also causes human endothelial cells to multiply, explains Dr. Tsukamoto.

These findings provide valuable insight into the mechanisms by which infectious bacteria can produce damage in their hosts. “We believe that BafA proteins can be used as tools to study angiogenesis, and we are also considering potential medical benefits,” reports Prof Doi. “Most importantly,” he elaborates, “BafA is a potential target for the development of diagnostic and therapeutic strategies for bartonellosis.”

The researchers also speculate that BafA proteins may be used in regenerative medicine, which is a highly specialized medicine branch that is about replacing or regenerating lost or damaged parts of the body. Further research is needed to confirm the researchers’ findings, but of course BafA proteins will certainly be of enormous interest to the scientific community.

Reference: “The Barton autotransports BafA activates the host’s VEGF pathway to drive angiogenesis’ 16 July 2020, nature Communications.
DOI: 10.1038 / s41467-020-17391-2

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