New genetic element linked to virulence of plague pathogen

The origins of the plague can be traced back to the Neolithic Age, with the oldest evidence of the causative pathogen Yersinia pestis found in human bones dating back around 5,000 years. Throughout history, two notable outbreaks stand out: the late antique Justinianic plague in the sixth century and the infamous Black Death during the late Middle Ages. Both were unequivocally caused by Y. pestis and are estimated to have decimated up to half of Europe’s population.

Over the centuries, smaller outbreaks occurred regionally on different continents. One of the most devastating pandemics was the third plague pandemic, which spanned from the mid-19th to the early 20th century. Initially affecting Asia, particularly India, it later spread globally and claimed around 15 million lives, making it one of the deadliest pandemics in human history. Even today, the plague continues to emerge regionally and is nearly always fatal if not treated promptly with antibiotics.

Throughout its long existence, Y. pestis has evolved into numerous strains through gene acquisition and loss. Scientists worldwide are dedicated to studying the evolution of Y. pestis to understand the causes of historical pandemics and the ongoing risks posed by the plague.

Researchers are particularly interested in the genetic characteristics of the pathogen that govern its transmission, geographical distribution, and disease severity. A recent study conducted by a team from Kiel University and the Max Planck Institute for Evolutionary Biology in Plön (MPI-EB) examined ancient and modern Y. pestis genomes, spanning from the Neolithic era to the modern pandemic.

Led by Dr. Daniel Unterweger, a research group leader at MPI-EB and Kiel University, and Professors Almut Nebel and Ben Krause-Kyora from the Institute of Clinical Molecular Biology (IKMB) at Kiel University, the team discovered that Y. pestis must have acquired a new genetic element called the YpfΦ prophage sometime between the Middle Ages and the modern pandemic. This genetic element is linked to the pathogen’s virulence, i.e., its ability to cause disease.

The YpfΦ prophage produces a protein that closely resembles certain toxins found in other pathogens, such as those in the cholera pathogen. The study, in collaboration with colleagues from the University of Southern Denmark in Odense (SDU), was recently published in the journal Proceedings of the Royal Society B: Biological Sciences. These findings contribute to the ongoing research conducted by the Kiel Evolution Center (KEC) at Kiel University and shed light on the evolutionary history and characteristics of Y. pestis.

New genetic elements increased the virulence of the pathogen

The Kiel research team collaborated with the Department of Forensic Medicine at SDU, which oversees skeletal material from various Danish museums. This partnership allowed the scientists to examine the genetic samples of 42 individuals buried in two Danish parish cemeteries between the 11th and 16th centuries.

The genetic material obtained from the skeletal remains was subjected to sequencing, and the Y. pestis genes contained within were compared to other published genomes from the Neolithic, medieval, and modern periods.

Dr. Joanna Bonczarowska, the first author of the paper and a researcher who conducted this study as part of her Ph.D. at the IKMB with support from the International Max-Planck-Research School for Evolutionary Biology (IMPRS), explains that previous research revealed that early in its evolution, Y. pestis lacked the genetic components necessary for efficient transmission through fleas, which is characteristic of today’s bubonic plague. Over time, the pathogen underwent significant evolution, acquiring a high level of virulence that contributed to some of the deadliest pandemics in history.

The recent study shows that all known Y. pestis strains before the 19th century lacked a specific genetic element known as the YpfΦ prophage. It appears that the prophage was obtained through lateral gene transfer from the environment. This genetic information significantly influences the pathogen’s virulence, determining the severity of the disease resulting from an infection. Strains of Y. pestis containing the YpfΦ prophage were demonstrated to require a much lower lethal dose compared to those without it. This acquisition of new genetic elements could have provided Y. pestis with an advantage during the modern plague pandemic.

How has the increased virulence since the Middle Ages come about?

The specific mechanisms through which the prophage contributes to the heightened virulence of the modern plague pathogen have not yet been extensively studied. However, previous research indicates that such newly acquired genetic information may aid the pathogen in infecting distant body tissues from the original site of infection. In their quest to understand this mechanism, the Kiel researchers conducted a thorough examination of all proteins encoded by the newly acquired DNA.

During their investigation, they made a significant discovery. One of the proteins closely resembled a toxin found in other pathogens, namely the zonula occludens toxin (ZOT). ZOT is known to facilitate the exchange of harmful substances between infected cells and has a damaging effect on mucosal and epithelial tissues. This similarity to ZOT was first observed in the cholera pathogen, where it causes the characteristic symptoms of gastroenteritis.

Dr. Joanna Bonczarowska elaborates on this finding, stating that the identified protein in Y. pestis shares a structural resemblance to ZOT. This observation provides a potential explanation for the increased virulence of the plague pathogen in both present and recent times. However, further research is needed to fully explore and understand the role of this ZOT-like protein in Y. pestis.

In the future, the Kiel researchers aim to delve deeper into the investigation of this protein to gain insights into how it contributes to the pathogen’s heightened virulence. Understanding these mechanisms could offer valuable knowledge for combating the plague and potentially lead to new strategies for managing and preventing the spread of this deadly disease.

Further research into the evolution of the plague and other pathogens

The rapid evolution of Y. pestis poses an ongoing pandemic threat that demands attention. The acquisition of new genetic elements by the pathogen can introduce novel symptoms of infection. These new and misleading signs of illness make it challenging to diagnose plague promptly, leading to delays in crucial treatment, which is vital for survival. Dr. Daniel Unterweger emphasizes the urgency of rapid treatment and how it can be hindered by the evolving nature of the pathogen.

Moreover, the concerning aspect is that some strains of the plague pathogen are already displaying resistance to various antibiotics, further escalating the potential danger of this disease. The development of antibiotic resistance is a worrisome trend that could complicate treatment options and increase the risk of uncontrollable outbreaks.

An essential aspect of the research is the discovery of similarities between genetic elements in YpfΦ and other bacterial species. Similar elements have been found in other bacteria, indicating the potential for these pathogens to evolve towards increased virulence. This finding sheds light on the broader picture of bacterial evolution and its implications for public health.

The research outcomes underscore the significant knowledge modern science and medicine can gain by studying the historical evolution of diseases using ancient DNA (aDNA) dating back hundreds or even thousands of years. Understanding how the pathogen has historically increased its harmfulness, sometimes through rapid leaps in evolution, provides valuable insights. These insights are crucial in detecting new forms of the disease and in devising measures to prevent and manage potential future pandemics. Professor Ben Krause-Kyora summarizes the importance of this research in our ongoing battle against infectious diseases.

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