Researchers have discovered that a protein complex that helps fight cancer cells also slows the growth of tuberculosis - a finding that could mean better treatments for both diseases.
The protein complex, which slows down the growth of tuberculosis (Mtb) bacteria in infected immune cells and enables them to survive infection, represents a newly discovered way human cells defend against bacterial infections.
Confocal microscopy image of macrophages infected with tuberculosis bacteria; colors indicate bacteria health status: green bacteria are healthy, while red ones are unhealthy or dying.
The protein complex, GID/CTLH, was known to control the degradation of glucose in yeast. Researchers had previously targeted this complex to starve human cancer cells, which are notoriously glucose-hungry. This is the first time the GID complex has been implicated in any infection.
"The GID complex is already a focus of drug discovery in cancer, so if people are out there looking for drugs to inhibit this complex, this could mean new opportunities for treatment of TB," said David Russell, the William Kaplan Professor of Infection Biology in the Department of Microbiology and Immunology in the College of Veterinary Medicine (CVM), and lead author of the paper.
The research, published Oct. 29 in Nature Communications, was conducted with Dr. Craig Altier, professor of population medicine and diagnostic sciences (CVM), and Christopher Sassetti, professor of microbiology at the University of Massachussets' Chan Medical School.
The team discovered the protein complex's role in antimicrobial defense through a screening that Nelson Simwela, a post-doctoral researcher in the Russell lab, did to find new biological targets that allow Mtb-infected cells to resist infection. To perform that screening, they used the CRISPR/Cas9 gene-editing technology to inactivate genes at random in primary macrophages, a type of immune cell. The team generated sufficient knockouts to provide extensive coverage of the full mouse genome
They then infected this macrophage population with Mtb and waited to see which macrophages died and which survived. "We waited until 50% of the macrophages had died from the infection," Russell said. "We took the other living 50% and analyzed them as the output of our screen. The hope was to find those cells that survive through controlling bacterial growth."
They found 259 knockout genes that promote cell survival. This list includes genes previously known to help cells resist infections, and genes that had never been associated with this function. Among these are five encoded protein subunits that form the GID complex. "With this overlap, we were confident we had hit a pathway relevant to our phenotype of interest," Russell said.
To see if their results applied to other bacterial infections in cells, the team tested their discovery on cells infected by salmonella. Cells lacking a functional GID complex were also better at controlling salmonella growth and had a higher survival rate, indicating that their discovery was not limited to Mtb.
In parallel with the genetic screening, Russell and his team are also screening for chemicals that could mimic the effects of the GID-knockout. "Genetic screening provides scientific information but chemical screening provides starting compounds for drug development," Russell said. "We have compounds that produce a comparable metabolic shift to the knockout and may help us develop new anti-TB drugs."
The Russell lab is interested chemicals that reprogram macrophages to be more resistant to infection, particularly compounds that help existing drugs works better or keep working. "This is particularly important for tuberculosis because these bacteria readily become less sensitive to drugs," he said.
Currently, other researchers are seeking chemicals that specifically affect the GID complex for cancer therapy, and Russell hopes to leverage the new findings for tuberculosis therapeutics. "We are monitoring the GID complex literature very closely," Russell said. "If new compounds are identified, we want to plug them immediately in our tuberculosis drug discovery platform."
Elodie Smith is a writer for the College of Veterinary Medicine.
