The diseases cat scratch fever and trench fever are both caused by parasitic bacteria from the genus Bartonella. Animals can transmit these pathogens to people through bites and scratches, and it causes an infection called bartonellosis, forms of which cause the fevers. Bartonella bacteria infections can lead to lesions on the skin and internal organs. The microbes cause an increase in the number of cells that line the insides of blood vessels, called vascular endothelial cells to hide from the host immune system, which generates the lesions. They also trigger the generation of new blood vessels, a process called angiogenesis.
Previous work has indicated that a type of Bartonella called B. henselae, which causes cat scratch fever, can release proteins that interfere with programmed cell death, called apoptosis, in endothelial cells. B. henselae also encourage angiogenesis without contacting endothelial cells directly. New work reported in Nature Communications has shown that the microbe does so by releasing a protein called Bartonella angiogenic factor A (BafA). This is the first time researchers have identified a bacterial protein that can also function like a vascular endothelial growth factor (VEGF).
In this study, the researchers exposed human endothelial cells growing in culture to B. henslae, which caused the endothelial cells to proliferate. The researchers systematically introduced mutations into the microbe's DNA to find the portion that was essential for this result. They determined that human endothelial cells would only multiply if B. henslae had a gene that encodes for BafA. They also found that by itself, the BafA protein caused the endothelial cells to grow.
The researchers collected samples of a mouse aorta, and exposed it to solutions that did and did not contain BafA. Only the BafA-treated samples grew vessels (picture above). Additional experiments showed that BafA was activating receptors on the surface of human endothelial cells that attach to VEGF. When BafA bound to the receptors, a pathway called MAPK/ERK was activated, which is involved in angiogenesis.
"In the last set of experiments, we performed similar studies in a related bacterium called Bartonella quintana, the bacterium that causes trench fever, and we found that it produces its own version of BafA that also causes human endothelial cells to multiply," said Senior Assistant Professor Kentaro Tsukamoto of Fujita Health University.
This research can help explain how these pathogenic microbes are causing lesions in the infected. "We believe that BafA proteins can be leveraged as tools for studying angiogenesis, and we also consider potential medical benefits," said Professor Yohei Doi of Fujita Health University,. "Most importantly, BafA is a potential target for the development of diagnostic and therapeutic strategies for bartonellosis."