Can Breakthrough Infections Lead to Long COVID?
Not only could tuberculosis have dangerous consequences, but many of the bugs that cause multidrug-resistant strains had undergone a significant evolutionary step at least a decade ago that took them from a fairly lethal illness to one that is relatively easy to kill. In an ominous trend, researchers have seen this shift in pathogen evolution happen in HIV, HIV and hepatitis C, which are also considered drug-resistant.
Dr. Jenny Kay, a microbial ecologist at the Scripps Research Institute in California, found the first signs of this rise in multidrug-resistant TB in 1999 and has kept an eye on it ever since. She teamed up with biomedical engineer Dustin Meister and computational biologist Jon Page to try to understand just how multidrug-resistant it really is and why. To find out, they would need to see what genetic mutations were responsible for making multidrug-resistant strains so resistant to conventional drugs. To see how important mutations were, and whether they have long-term effects, the team sampled hundreds of TB isolates from around the world, looking for mutations. It turned out that since the turn of the century, mutations have become the most important factor when it comes to strains becoming multidrug-resistant.
Dr. Kay describes it as the “American Revolution.” That was the year in the early 1800s that one of the most powerful genomics companies was founded: DNA pioneer J. Craig Venter’s Synthetic Genomics Corporation, which created artificial DNA that could then be used to study the human genome. Prior to this, Sam Lynch of Princeton University had sequenced the top of the genome and then noted a shift in mutations: different mutations having different effects on the pathogens. Lynch and others made a major statement with these discoveries, revealing a sort of subtle, but significant divergence between bacteria that showed that the majority of TB genes shared common structural rules and proteins — so they were not equivalent.
Now, scientists at Scripps researchers were wondering if the shift that occurred after the American Revolution was also responsible for some of the broader shifts in bacteria evolution — that is, mutations that helped evolve the weapons needed to create drug-resistant strains. It turned out that Dr. Kay and her colleagues had already made a preliminary discovery that it was possible to see subtle shifts in the structure of TB genes by looking at plant genome sequences, and now they wanted to see if these were genetic signatures of TB evolution. It turned out they were.
And that is another way these mutations, known as dynamic helicase genes, are changing the world. Dr. Kay and her colleagues found that many of these mutations were likely due to changes in the way the organism’s antennae rewires with the genes, which are intricately folded into the membrane that surrounds the bacteria. Over time, the helicase genes responded to environmental factors such as genes that made sure the yeast developed well in cold weather or genes that made sure if bacteria could turn the vitamin B7 receptor into part of their skin, which allowed them to better ward off disease.
Her team managed to look at these changes for a long period of time. Interestingly, they found that these were more than slight alterations. Many of the changes were subtle yet in some cases big changes in the fungi. It turns out that DNA changes in the TB-related helicase genes resulted in changes in the fungus which could make them more resistant to drugs, like the common antibiotic tetracycline. Dr. Kay believes the changes made these changes happen for good, with less chance of drug resistance.
“If we see the same mutation over and over, that’s pretty clear that we have introduced drugs that have curbed resistance,” she said. That may not be the case in many other species. Yet the simple fact that TB became significantly more drug-resistant in recent years provides an early warning that in the future, multidrug-resistant strains may also infect people and spread easily. Dr. Kay is trying to figure out whether there are some bacteria that more likely move on this path of evolution, though, without showing that yet. What she does know for sure is that more work is necessary to understand what is going on with TB.
“Deeper sequencing is always something that we are interested in,” she said. “We are moving in the right direction, but there is a lot more to know before I can say definitively that drug resistance is a thing of the past.”