Scientists have discovered the mechanism that hijacks the immune system's response to tuberculosis, revealing an important new drug target for the disease that kills more than 1 million people each year. Herman Sintim, Purdue University's Drug Discovery Professor of Chemistry, collaborated with scientists at Johns Hopkins University to determine how tuberculosis turns off a human cell's signal to mount an immune response to the bacteria. Their findings were published in the journal Nature Chemical Biology.
Tuberculosis is a bacterial disease that results in coughing, fever, night sweats, weight loss and sometimes death.
When Mycobacterium tuberculosis enters a human cell, the presence of its DNA and a molecule that it makes called c-di-AMP alert the cell to the bacteria's presence. The human cell responds by creating a messenger molecule, cGAMP, which signals nearby cells to mount an immune response to kill the tuberculosis bacteria.
The human cell also produces another molecule, ENPP1, which degrades the cGAMP. That key step turns off the call for an immune response.
"Immune response can involve reactive oxygen and nitrogen species, which can kill the bacteria but at the same time cause collateral damage and also damage or kill the host cells as well," Sintim said. "There is a very delicate response to bacteria and stopping that response once bacteria have been taken care of."
But the tuberculosis bacterium has found a way to turn off the call for help. By producing a protein called cyclic dinucleotide phosphodiesterase (CdnP), the bacterium reduces the concentration of the cell's messenger molecule, cGAMP, a nucleic acid. This accentuates the effect of the human phosphodiesterase ENPP1, an enzyme that cleaves nucleic acids, to quickly degrade any already-made cGAMP and turn off the immune response early.
"The host cGAMP never gets to a high enough concentration to activate the immune response," Sintim said. "This is a very effective strategy the bacteria have developed to suppress an immune response."
Sintim and colleagues tested their hypothesis by creating a mutant of Mycobacterium tuberculosis that lacked the CdnP protein and tested it in a mouse model. On average, the mice with the mutant bacteria lived more than two times longer than mice with the wild type, suggesting that CdnP played a role in suppressing immune response.
They then artificially synthesized the cGAMP molecule and investigated if it was a substrate for CdnP. The CdnP degraded the human molecule as predicted.
Sintim said the CdnP protein in the tuberculosis bacteria now becomes an attractive target for a new drug. If a molecule could be developed that would inactivate or inhibit CdnP, it would improve immune response in tuberculosis patients.
Sintim's team identified several molecules that would bind with and inhibit CdnP, but they have not reached the potency level needed to create drugs. They will continue looking for new compounds that could potently inhibit this newly discovered CdnP drug target.
The National Institute of Allergies and Infectious Diseases, Howard Hughes Medical Institute, National Science Foundation, and Camille and Dreyfus Foundation funded the research.
Source: Purdue University
Dear Helpdesk: Working in a Toxic Health Care Environment
March 28th 2024Dear Helpdesk is your steadfast companion, offering life coaching and workplace advice from 2 seasoned IPs for some of your most challenging real-life situations. Let us help you navigate the intersection between work and life, guiding you to navigate the dynamic world of infection prevention with confidence and grace. This article is on handling a toxic health care environment.
Product Locator: Spring and Early Mother's Day Gift Guide for Infection Prevention Personnel
March 27th 2024Whether it's a spring holiday, birthdays, or no reason at all, infection prevention personnel love to give and receive gifts that help at the end of a stressful day. Infection Control Today® offers some gift ideas for infection prevention personnel and their families.
Catching Up With Vangie Dennis, AORN 2022-2023 President at AORN 2024
March 26th 2024Infection Control Today (ICT) had the privilege of catching up with Vangie Dennis, MSN, RN, CNOR, CMLSO, at the Association of periOperative Registered Nurses' (AORN’s) International Surgical Conference & Expo 2024. As the former president of AORN and an esteemed figure in perioperative services, Vangie Dennis shared insights into her recent endeavors and the exciting new chapter she's embarked upon.
How To Optimize Your Time Management Strategies for the Busy Infection Preventionist
March 25th 2024Is your calendar resembling a chaotic masterpiece of overlapping tasks? Join the club of infection preventionists striving to balance responsibilities. Dive into proven strategies from a fellow infection preventionist to reclaim control of your time, streamline tasks, and boost productivity effectively. This is an IP Lifeline article.