New TB Study Has Hopeful Results

By August 28, 2018 disease, research
Tuberculosis (TB), an infectious disease targeting the lungs, is the second biggest killer, globally.  In 2015, 1.8 million people died from the disease, with 10.4 million falling ill, despite the development of vaccines and effective drug treatment.  At one point, the United Nations predicted that TB would be eliminated worldwide by 2025, but treatment options remain surprisingly sparse.  The only vaccine for TB was developed nearly a century ago, and offers limited protection.  Even worse,  patients are becoming increasingly resistant to available drugs.
Despite this significant impact on humankind, very little is known about the development and spread of tuberculosis in the body
A group of researchers from UC San Francisco (UCSF), and UC Berkeley have recently published a study in the journal Molecular Cell, providing insight on the mode of TB infection in people.  Their research discovered interactions between tuberculosis and proteins present in the human body that could provide new targets for TB drugs.

Tuberculosis is caused by bacteria consisting of 4,000 genes, making it a difficult target for gene based therapies and small  molecule treatments.  During infection, these genes produce approximately 100 proteins inside human cells, each one of which could be a potential target for medications. Until recently, scientists lakced a basic understanding of the actions these proteins had in the body.  Krogan, along with his colleague Jeffery S. Cox, PhD, from UC Berkeley, utilized mass spectrometry-based to identify interactions between tuberculosis and human proteins.
“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,” –Nevan J. Krogan, PhD, Director of the Quantitative Biosciences Institute at UCSF

 

Basically, the TB proteins are modified in order to make extraction from human cells easier.  Once the TB proteins are inside human cells, they can be removed, and the proteins they were bound to in the human cells analyzed and studied.  Using this method, 34 tuberculosis proteins were targeted, with most of them never having been studied previously.  The research revealed 187 interactions between the TB and human proteins, with each interaction a potential point to target TB through treatment.  

After the initial discovery, the researchers focused their attention on one specific connection between the human protein CBL and a tuberculosis protein called LpqN.  When the LpqN protein was removed, tuberculosis was unable to infect human cells.  When the CBL protein was also deleted, the tuberculosis infection can resume growth, suggesting that CBL is involved in limiting bacterial infections.  The scientists believe that CBL acts as a switch of sorts, acting between antibacterial and anti-viral responses in the cell. 
 

By studying proteins interactions, scientists can map proteins pathways and discover connections that can be compelling drug targets. They can also compare interactions across multiple pathogens and identify similarities, potentially expanding treatment options for patients.

Krogan and Cox recently founded the Host Pathogen Mapping Initiative with investigators from Gladstone, UCSF, UC Berkeley, and UC San Diego. Through this initiative, they will comprehensively map the gene and protein networks underlying infectious disease and develop technologies to lead to novel and targeted therapies.  The scientists have already identified common pathways in human cells that bacteria and viral agents often attack. The human genes targeted by tuberculosis, for instance, are the same mutated genes present in other disease states, such as cancer and autism.

This discovery could potentially provide expanded treatment options for patients suffering from TB and other conditions, and allow for specific targeting of diseased cells in people, while leaving healthy cells unharmed.

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