Tuberculosis is one of the top ten causes of death worldwide, killing nearly two million people every year. An estimated two billion people carry a chronic infection, the only available vaccine was developed almost a century ago and offers limited protection, and drug resistance is growing. Despite this enormous global burden, remarkably little has been understood about how the disease actually develops and spreads inside the human body at the molecular level. A new study from researchers at the Gladstone Institutes, UC San Francisco, and UC Berkeley has now produced an entirely new map of how the bacterium interacts with human proteins, revealing 187 potential drug targets and opening new directions for treatment and vaccine development. The findings were published in the journal Molecular Cell.
A New Approach to Understanding Tuberculosis Infection
The bacterium carries approximately 4,000 genes, a scale of genetic complexity that dwarfs the 10 to 15 genes found in most viruses. During infection, those genes produce roughly 100 proteins inside human cells. Until this study, scientists knew virtually nothing about what those proteins do once they enter the body or which human proteins they interact with.
Senior investigator Nevan J. Krogan, PhD, of the Gladstone Institutes and his colleague Jeffery S. Cox, PhD, from UC Berkeley used a mass spectrometry based approach to systematically identify physical interactions between the pathogen’s proteins and human proteins. The technique works by attaching a molecular hook to bacterial proteins, then fishing them out of human cells along with any human proteins attached to them. This allowed the team to directly observe which human proteins each bacterial protein connects with, an approach applied to tuberculosis for the first time.
187 Tuberculosis Protein Interactions Mapped as Drug Targets
Targeting 34 bacterial proteins, the vast majority of which had never been studied before, the team identified 187 distinct interactions between the pathogen and human proteins. According to Krogan, each of those connections represents a potential drug target, a new way to intervene against the disease that does not rely solely on attacking the bacterium directly.
This is a critical distinction. Most existing therapies target the bacterium itself, which means that as it mutates and develops resistance, drugs lose effectiveness. By targeting human proteins involved in the infection process instead, researchers could develop therapies less vulnerable to the resistance problem that is increasingly limiting existing antibiotic treatments. You can read more about how FOMAT approaches infectious disease research on the FOMAT blog.
The CBL Protein and What It Reveals About Tuberculosis and Viral Defense
After completing the broad interaction map, Krogan and Cox focused on one specific connection that revealed an unexpected dimension of the disease’s biology. They studied the physical interaction between the human protein CBL and a bacterial protein called LpqN. When LpqN was removed, the infection lost much of its ability to spread inside human cells. When CBL was also deleted, the infection resumed its normal growth pattern, suggesting that CBL plays an active role in limiting bacterial infections.
The finding carried an additional surprise. When CBL was removed, cells also became more resistant to viral infections, including herpes. This led the researchers to conclude that CBL functions as a molecular switch that toggles the cell between anti bacterial and anti viral defense modes, a discovery that would not have emerged from a more narrowly focused study. As Cox noted, studying protein interactions without preconceptions is essential precisely because unexpected connections like this one are impossible to anticipate.
Tuberculosis Research as a Model for Treating Multiple Diseases
The broader implications of this work extend well beyond this single pathogen. Krogan and Cox co founded the Tuberculosis Research Host Pathogen Mapping Initiative with investigators from Gladstone, UCSF, UC Berkeley, and UC San Diego to comprehensively map the gene and protein networks underlying infectious disease. They also helped launch the BioFulcrum Viral and Infectious Disease Research Program at Gladstone in 2017, which focuses on developing host directed therapies that target human proteins rather than pathogens directly.
The rationale is compelling. The human genes hijacked by the bacterium during infection are the same genes mutated in a range of other disease states, including cancer and autism. A single drug targeting a commonly hijacked human pathway could theoretically be effective against multiple pathogens simultaneously. As Krogan put it, the goal is to find the cell’s Achilles heel and target it to fight many diseases at once.
FOMAT conducts infectious disease clinical trials at sites across the United States. To learn more about active studies, visit FOMAT’s patient studies page.