A lethal strain of cholera bacteria, first identified in Indonesia in 1961, continues to spread globally, causing thousands of deaths and infecting millions annually. This persistent strain has puzzled scientists for decades. However, a recent study published in Nature by researchers from The University of Texas at Austin reveals how this virulent strain has managed to survive.
The strain of Vibrio cholerae (V. cholerae) responsible for the seventh global cholera pandemic has long been a mystery due to its ability to outperform other pathogenic variants. The research team from UT discovered a unique aspect of the immune system that shields the bacteria from a significant driver of bacterial evolution.
"This component of the immune system is unique to this strain, and it has likely given it an extraordinary advantage over other V. Cholerae lineages," said Jack Bravo, a UT postdoctoral researcher in molecular biosciences and corresponding author on the paper. "It has also allowed it to defend against parasitic mobile genetic elements, which has likely played a key part in the ecology and evolution of this strain and ultimately contributed to the longevity of this pandemic lineage."
Like all living organisms, cholera and other bacteria evolve through mutations and adaptations over time, leading to new developments such as antibiotic resistance. One key driver of microbial evolution is plasmids—tiny DNA structures that infect, exist within, and replicate inside bacteria in ways that can alter bacterial DNA.
Using laboratory analysis combined with cryo-electron-microscope imaging, the research team identified a unique two-part defense system within these bacteria that effectively destroys plasmids, thereby protecting and preserving the bacterial strain.
According to World Health Organization estimates, cholera infects between 1.3 million and 4 million people annually, resulting in between 21,000 and 143,000 deaths each year. The bacterium typically spreads through contaminated water or food or contact with an infected person's fluids. Severe cases are characterized by diarrhea, vomiting, and muscle cramps that can lead to dehydration and sometimes death. Outbreaks predominantly occur in areas with poor sanitation and drinking water infrastructure.
Although a vaccine exists to combat cholera, protection against severe symptoms diminishes after only three months. With the need for new interventions, researchers believe their study offers a potential new path for drugmakers to investigate.
"This unique defense system could be a target for treatment or prevention," said David Taylor, associate professor of molecular biosciences at UT and an author on the paper. "If we can remove this defense, it could leave it vulnerable, or if we can turn its own immune system back on the bacteria, it would be an effective way to destroy it."
The defense system detailed in the paper consists of two parts that work together. One protein targets the DNA of plasmids with remarkable precision, while a complementary enzyme shreds the DNA of the plasmid.
Researchers also noted that this system bears similarities to some CRISPR-Cascade complexes based on bacterial immune systems. The discovery of CRISPR has revolutionized gene-editing technologies leading to significant biomedical breakthroughs.
Delisa A. Ramos, Rodrigo Fregoso Ocampo and Caiden Ingram of UT were also authors on the paper. The research was funded by the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health and a Welch Foundation research grant.