How small genetic change in Yersinia pestis changed human history

In a paper published in Nature Communications, Lathem and first author Daniel Zimbler, Ph.D., a Feinberg post-doctoral fellow, demonstrated how the acquisition of a single gene caused the shift of Y. pestis from causing a primarily gastrointestinal infection to a more serious and often fatal respiratory disease. They further showed how later modifications of this gene enhanced infections associated with the bubonic plague.

"Our findings demonstrate how Y. pestis had the ability to cause a severe respiratory disease very early in its evolution. This research helps us better understand how bacteria can adapt to new host environments to cause disease by acquiring small bits of DNA," Lathem said.

The team examined ancestral strains of the bacteria in mouse models to learn when Y. pestis gained the ability to infect the lungs and cause the severe form of the disease known as pneumonic plague.

In the most ancestral of all currently existing Y. pestis strains, they showed how the bacteria could successfully colonize the lungs but could not cause the severe disease associated with pneumonic plague. The biggest difference they found between this strain and closely related strains that could cause pneumonic plague was a gene for the surface protein Pla.

Lathem proposed that the bacteria's acquisition of the gene Pla enhanced its ability to cause infection in the lungs and was all that this ancestral strain of Y. pestis needed to produce a fatal lung infection.

So Lathem and his team inserted the Pla gene into this strain to observe changes in the health of the lungs. They found the newly mutated strain had gained the ability to cause respiratory infection identically to modern strains of Y. pestis that cause disease today, demonstrating that the Pla gene was necessary for Y. pestis to infect the lungs. In addition, they found that no other changes to Y. pestis were required, even though the bacteria has continued to gain and lose genes over the last several thousand years.

The lab also looked at variations of the gene Pla and discovered that a single modification only found in modern strains of Y. pestis was a critical adaptation for the bacteria to spread in the body and infect the lymph nodes, a form of the infection that causes bubonic plague. According to Lathem, the surprising conclusion from this aspect of the study is that, contrary to current thinking in the field, Y. pestis may have first evolved as a respiratory pathogen before it could cause the more common form of disease, bubonic plague.

Lathem said the new research may explain how Y. pestis transitioned from causing only localized outbreaks of plague to the pandemic spread of Y. pestis such as the sixth century's Justinian Plague and the fourteenth century's Black Death.

"Our data suggests that the insertion and then subsequent mutation of Pla allowed for new, rapidly evolving strains of disease," Lathem said. "This information can show how new respiratory pathogens could emerge with only small genetic changes."

This work was supported by funding from National Institutes of Health grants R01AI093727, R21652A103658 and T32AI007476.