Researchers at Baylor College of Medicine and collaborating institutions have identified a mechanism driving the long-term decline in immune response observed after successful tuberculosis (TB) treatment. Their findings, published in the Proceedings of the National Academy of Sciences, suggest a potential new way to restore immune responsiveness and reduce mortality risk after severe infections.
“Sepsis 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 result in persistent, long-lasting epigenetic changes. These changes refer to alterations in chemical markings on DNA that tell cells 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. This results in decreased production of proteins mediating immune defense and increased susceptibility to infections. However, the mechanisms inducing epigenetic changes were not clear.
Previous studies identified the tricarboxylic acid (TCA) cycle 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 with bacterial lipopolysaccharide, a bacterial product, and Mycobacterium tuberculosis became immune tolerant. They found that patients diagnosed with both sepsis and TB have increased TCA activation correlating with DNA methylation. When TB patients were given standard therapy plus everolimus, an inhibitor of TCA activation, damaging methylation changes to their DNA were reduced.
“Tuberculosis is an interesting disease. By the time a person is diagnosed, they have had symptoms for over three months. By adding everolimus to standard TB antibiotic treatment, the number of detrimental DNA methylation marks is reduced six months into the disease process. It’s promising that we can induce epigenetic healing,” DiNardo said.
“What we found is going to lead to a paradigm shift,” said Dr. Cristian Coarfa, co-author and associate professor of molecular and cellular biology at Baylor. “Our approaches are not limited to tuberculosis. The evidence we have suggests these strategies might play a role in other infectious diseases.”
The next step for researchers is identifying which post-TB epigenetic marks lead to increased morbidity and mortality. From there, they aim to determine which individuals would benefit most from host-directed therapy that can heal epigenetic scars.
Other contributors 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 ,Reinout van Crevel .They are affiliated with one or more institutions: Baylor College of Medicine ,Texas Children’s Hospital ,Columbia University Irving Medical Center ,UTHealth School Public Health-Houston ,Research Center Borstel ,Aurum institute ,Radboud University Medical Center ,University Bonn ,University Oxford Case Western Reserve University Vanderbilt University University Johannesburg Texas A&M School Medicine .
See publication for full list funding.
