Researchers uncover how Bartonella causes deadly Oroya fever

The so-called "Oroya fever" is an extremely severe infectious disease, yet it is classified among the so-called neglected tropical diseases. This is because the infection occurs - so far - exclusively in high-altitude valleys of the South American Andes, primarily in Peru, but also in Ecuador and Colombia. As a result, it has received little attention from research and pharmaceutical development. Oroya fever is caused by the bacterium Bartonella bacilliformis, which is transmitted through the bite of infected sandflies of the genus Lutzomyia. The disease typically begins with high fever and massive destruction of red blood cells (erythrocytes), resulting in a severe hemolytic anemia. Without antibiotic treatment, Oroya fever is fatal in up to 90 percent of cases. Already 26 percent of the pathogens are resistant to the standard antibiotic ciprofloxacin, making antibiotic treatment significantly more difficult.

Lutzomyia sandflies are so far found only in South America. However, due to global warming and increasing travel, experts expect that the habitat of these sandflies could expand to other continents and even into Europe.

An international research team led by Professor Volkhard Kempf from Universitaetsmedizin Frankfurt and Goethe University has now generated and analyzed more than 1,700 genetic variants of the pathogen, identifying two proteins that Bartonella requires for the destruction of red blood cells: a so-called porin, which enables the exchange of substances such as ions with the environment, and an enzyme called α/β-hydrolase. Together, these two proteins are responsible for hemolysis. Structural analyses and targeted point mutations showed that the hemolytic activity of Bartonella bacilliformis strictly depends on the enzymatic integrity of the α/β-hydrolase.

Both proteins work together to destroy human erythrocytes and thereby provide an explanation for the characteristic clinical presentation of Oroya fever. This makes the α/β-hydrolase a suitable target protein for therapeutic agents."

Dr. Alexander Dichter, first author of the study

In laboratory experiments, the researchers also identified an inhibitor - a phospholipase inhibitor - that blocks the activity of the α/β-hydrolase and can also prevent the hemolysis of erythrocytes. "If we succeed in selectively disabling the disease-causing effect of the bacterium in the human body in this way, we may have a therapy against which resistance is unlikely to develop," Dichter is convinced.

"Oroya fever is a serious public health problem in Peru and South America, killing hundreds of people every year without drawing attention from the rest of the world. The disease is poverty-related and belongs to the neglected tropical diseases, which receive far too little attention says Professor Volkhard Kempf, Director of the Institute of Medical Microbiology and Hospital Hygiene, which also hosts the German Consiliary Laboratory for Bartonella Infections (appointed by Robert Koch Institute, Berlin). "We are therefore all the more pleased that we have laid the foundation for developing novel therapeutic approaches for Oroya fever and thus made an important contribution to the fight against this deadly neglected tropical disease."

With the project's funding period now ended, efforts are underway to secure further financial support to continue the research, Kempf explains. "Now that we have elucidated the mechanisms of hemolysis, our next goal is to understand how the pathogen binds to erythrocytes, since adhesion of pathogens to host cells is always the first step in any infection. We were able to elucidate the adhesion mechanisms of a related pathogen, the bacterium Bartonella henselae, several years ago."pical diseases.