New approach to mapping tuberculosis paves way for new treatments
Thursday, August 30, 2018
Tuberculosis is one of the world’s deadliest diseases. More than 10 million people worldwide became infected with tuberculosis (TB) in 2016, according to the Centers for Disease Control and Prevention, and there were 1.7 million deaths associated with TB that year.
The Bacille Calmette-Guérin (BCG) vaccine is not widely available in the United States, and vaccination with BCG does not always provide complete protection from TB.
Increasing drug resistance is also a concern. TB currently has about an 83 percent treatment success rate, according to the World Bank, so there is still room for improvement.
Despite the significant effect TB has on human health, researchers know relatively little about the transmission and pathogenesis of tuberculosis.
A group of researchers recently provided a new look at an old adversary. The team discovered interactions between tuberculosis and human proteins that could someday help in the development of new approaches to combating TB infection.
The research team published their findings in Molecular Cell.
"With a better understanding of the mechanisms used by tuberculosis to disrupt our immune response, we could eventually optimize vaccine strategies, as well as explore therapies to supplement antibiotics," said Dr. Nevan J. Krogan, senior investigator at the Gladstone Institutes and director of the Quantitative Biosciences Institute at the University of California, San Francisco.
Researchers Investigate the Pathogenesis of Mtb, Looking for a New Way to Fight Tuberculosis
The genome of Mycobacterium tuberculosis (Mtb) contains around 4,000 genes, which means the bacteria that causes TB infection is significantly more complex than viruses, which typically have only 10 to 15 genes.
The genes produce approximately 100 proteins inside human cells during a TB infection, but researchers new very little about the resulting effects of these proteins.
The researchers identified interactions between the TB proteins and human proteins using an innovative mass spectrometry-based approach. Specifically, they used mass spectrometry to create an Mtb-host protein-protein interaction map.
The interaction map revealed the two main factors involved in the pathogenesis of Mtb — the secreted Mtb protein known as LpqN and its binding partner, the human ubiquitin ligase CBL. It is the first time scientists have applied this approach to tuberculosis.
The technology essentially works by placing a "hook" on the tuberculosis proteins. When the scientists fish the hook out of the human cells, the attached human proteins come with it. This allows the researchers to determine which human proteins are interacting with the TB proteins.
The researchers used this method to target 34 tuberculosis proteins; very few of these proteins have been studied. They found 187 interactions between the tuberculosis proteins and human proteins, and each of those interactions present potential opportunities for targeted drug therapy.
One of these connections responds to both bacterial and viral infections. Following their initial discovery, the research team focused on physical interaction between CBL and LpqN.
They found that removal of the LpqN protein interferes with infection of human cell. When they deleted the CBL protein, however, the infection could resume its normal growth. This finding suggests that CBL plays a role in limiting bacterial infections.
"Interestingly, we discovered that when CBL is removed, cells also become more resistant to infections by viruses, such as herpes," said co-author of the study, Dr. Jeffery S. Cox. "We believe that CBL acts as a switch to toggle between anti-bacterial and anti-viral responses in the cell. That’s why it’s important to study the interactions between proteins in an unbiased way; you never know what you’ll find!"
Using the Approach to Investigate Other Diseases
Studying the interaction of proteins and the mapping of proteins onto pathways can help scientists find unexpected connections, compare protein interactions across a number of pathogens, and identify similarities. The mapping of gene and protein networks underlying infectious diseases can help researchers develop novel and targeted therapies for TB and other serious diseases.
"Most therapies to fight infection currently target the virus or bacteria," said Krogan. "But viruses and bacteria mutate quickly and develop resistance to existing treatments. Instead, we want to target human host proteins involved in common pathways. This could allow us to develop therapies that use a single drug to treat multiple pathogens."
Tuberculosis "hijacks" the same human genes as other do other diseases, such as autism and cancer. Krogan adds, "It’s about finding the cell’s Achilles’ heel, and targeting it to fight many diseases at once."
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