New mechanism uncovered behind immune decline after tuberculosis treatment
· News-Medical"Sepsis, the body's extreme response to an infection, and TB are associated with loss of protective immune responses and increased mortality post successful treatment," said Dr. Andrew DiNardo, corresponding author and associate professor in the section of infectious diseases and division of pediatric global and immigrant health at Baylor College of Medicine and Texas Children's Hospital. "In the current study, we investigated what mediated the perturbation of immune function after severe infections."
Researchers knew that severe and chronic infections in humans and animals result in persistent epigenetic changes. These changes refer to alterations in chemical markings on the DNA that tell cells in the body which genes to turn on or off.
For instance, TB dampens immune responsiveness by adding extra methyl chemical tags (DNA methylation) to certain genes involved in immune responses. Consequently, the body produces fewer proteins mediating immune defense which increases susceptibility to infections. However, the mechanisms inducing epigenetic changes in infections were not clear.
TCA plays a role in epigenetic changes
Previous studies have identified the tricarboxylic acid (TCA) cycle, a key part of cellular metabolism, as a metabolic driver of the epigenetic landscape in cancer. DiNardo and his colleagues wanted to see if TCA also regulated epigenetics, specifically DNA methylation, after infection-induced immune tolerance.
The team reported that human immune cells treated in the lab with bacterial lipopolysaccharide, a bacterial product, and Mycobacterium tuberculosis, the bacteria that cause TB, became immune tolerant.
"Tuberculosis is an interesting disease. By the time a person is diagnosed, they have had symptoms for over three months. But seeing that adding everolimus to standard TB antibiotic treatment reduces the number of detrimental DNA methylation marks six months into the disease is promising that we can induce epigenetic healing," DiNardo said.
Other contributors to this research include Abhimanyu, Santiago Carrero Longlax, Tomoki Nishiguchi, Malik Ladki, Daanish Sheikh, Amera L. Martinez, Emily M. Mace, Sandra L. Grimm, Thaleia Caldwell, Alexandra Portillo Varela, Rajagopal V. Sekha, Anna M. Madalakas, Mandla Mlotshwa, Sibuse Ginidza, Jeffrey Cirilo, Robert S. Wallis, Mihai G. Netea and Reinout van Crevel. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Texas Children's Hospital, Columbia University Irving Medical Center, UTHealth School of Public Health-Houston, Research Center Borstel, the Aurum institute, Radboud University Medical Center, University of Bonn, University of Oxford, Case Western Reserve University, Vanderbilt University, University of Johannesburg and Texas A&M School of Medicine.
Source:
Journal reference: