Tuberculosis, an ancient infectious disease that afflicted Old Testament Israelites and even pharaohs, has been historically curtailed by vaccinations, antibiotics, and public health measures such as isolation. However, a complete cure has remained elusive, and over a million people worldwide still succumb to TB each year.
Recently, a team of researchers led by Boston University has made significant strides in enhancing the body’s immune response against TB. By pinpointing the genetic characteristics distinguishing TB-susceptible and TB-resistant white blood cells, known as macrophages, the researchers conducted experiments to transform vulnerable cells into more robust counterparts using various compounds.
The promising findings have raised hopes, with the research team asserting that, with adequate support and funding, their approach could advance to clinical trials as early as the next year. This breakthrough holds the potential to revolutionize TB treatment and significantly reduce the global burden of this ancient disease.
“The TB vaccine is not really 100 percent efficient and antibiotic resistance is becoming more prevalent,” said Igor Kramnik, the study’s corresponding author and a BU Chobanian & Avedisian School of Medicine associate professor of medicine.
The strategy employed by his team might contribute an additional tool in the fight against TB: a host-directed therapy that assists the body in managing infections more effectively and minimizing inflammation related to the disease.
“It’s a way of treating the host, the patient, rather than focusing on the pathogen.”
The project combined laboratory experiments conducted at BU’s National Emerging Infectious Diseases Laboratories (NEIDL) with a comprehensive analysis of potential compounds using big data techniques by scientists at University College Dublin, Ireland.
“Tuberculosis, as one of my colleagues used to say, has studied us much longer than we have studied it,” Kramnik, who’s also a NEIDL investigator, shared. “It’s a serious and complex disease and our standard interventions are only partially efficient-;none of them are sufficient to eradicate the disease.”
However, recent research conducted by Shivraj M. Yabaji, a postdoctoral researcher at NEIDL, suggests that this could soon change.
“We hope that our research will contribute to the development of more effective treatments for TB by better understanding how to fine tune the activation states of immune cells,” Yabaji, the paper’s lead author, said. “This could potentially lead to therapies that target host immunity to tuberculosis.”
Weak TB Vaccine, Increasing Antimicrobial Resistance
Tuberculosis, caused by the bacterium Mycobacterium tuberculosis, is a highly contagious disease. The bacterium, a minute rod-shaped germ measuring less than 0.5 micrometers in diameter, spreads through actions as simple as a cough, sneeze, or conversation. Common symptoms include fever, weight loss, and chest pain. In 2021, over 10 million people worldwide were afflicted by TB, primarily affecting their lungs.
For a century, the bacille Calmette-Guérin (BCG) vaccine has served as the primary defense against TB, albeit imperfectly. Recent research from Boston University revealed its limitations, showing a mere 37 percent effectiveness in children under five and offering no protection for adolescents and adults. Antibiotics, the fallback for the infected, are losing efficacy. The World Health Organization warns that drug-resistant tuberculosis significantly contributes to global antimicrobial resistance, causing approximately 500,000 deaths yearly.
Kramnik, who initially intended to study TB briefly before shifting focus to tumor biology, has dedicated three decades to TB research.
“I thought that tuberculosis would be a nice stepping stone, but I’m still here, trying to understand it,” he said. “It’s a disease that’s very different from others. Thinking about tuberculosis as a battle between a pathogen and a host isn’t really productive. What we’re probably dealing with is an evolutionarily refined coexistence of a pathogen and a host that eventually leads to incurable disease at its terminal stage.”
A new treatment to enhance natural defenses against TB
One of the most significant enigmas in tuberculosis (TB) research revolves around the puzzling phenomenon of why certain individuals fall ill while the majority remain unaffected. Specifically, scientists are intrigued by the process wherein many patients initially resist infection, only to later succumb to the disease. Additionally, researchers like Kramnik are keen to unravel the bacteria’s specific targeting of the lungs, a tactic that facilitates its transmission through infectious aerosols. In recent research endeavors, Kramnik’s laboratory has employed experimental mouse models that replicate the human experience of contracting TB, aiming to shed light on these mysteries.
“It all led us to identify the importance of macrophage cells as major determinants, and regulators and controllers, of local immune response in the lung,” he stated, “and a major cell that affects susceptibility in cases of growing infection.”
Kramnik explains that macrophages usually operate in two modes to combat diseases: an active mode, where they eliminate harmful intruders, and a regenerative mode, aiding tissue repair after infection. In the case of tuberculosis (TB), these cells can become hyperactive but ineffective, leading to a damaging inflammatory response that harms the body without eliminating the pathogen. In their recent study, Kramnik, Yabaji, and their colleagues used mouse models to find ways to switch off this response and enhance macrophage effectiveness.
They employed RNA sequencing, a technique that identifies active genes, to pinpoint the genetic differences between normal/resistant and aberrant/susceptible activation states. Kramnik mentioned they hoped this method would help identify the specific “genetic signature” distinguishing these states. The team collaborated with Alexander A. Gimelbrant, an investigator at the Altius Institute for Biomedical Sciences in Seattle, to simultaneously analyze the expression of 46 genes representing this signature. “This allowed us to look at gene expression patterns rather than individual genes to characterize the cell states and their changes in response to treatments.”
After experimenting with various drugs to alter gene expression, the researchers discovered that certain molecules were more effective than others. However, none of these drugs alone could transform a macrophage from a susceptible to a resistant state against TB. To find a potential synergistic combination, the team shared their data with researchers at University College Dublin, Ireland. These researchers had developed a machine learning algorithm capable of predicting the effectiveness of specific drug combinations. “We then went back to the bench and tested those predictions,” Kramnik said.
Two promising molecules for cancer treatment, Rocaglamide A (RocA) and a c-Jun N-terminal kinase (JNK) inhibitor, were discovered to form a highly effective combination. Together, they impeded cell signals associated with inflammation and stress, while enhancing pathways that transmit stress resistance signals. “They would be good candidates for clinical trials, so it could change the medical treatment of tuberculosis,” Kramnik said.
The researchers found that combining the two substances enabled them to reduce the necessary dose of RocA, which can become harmful at elevated levels due to its potential toxicity. Kramnik said that their results show how to increase “therapeutic efficacy at lower drug doses and decrease toxic side effects. This is particularly important for chronic diseases that require long course treatments, such as tuberculosis.”
Even though the team is prepared to advance the research, securing support for conducting a trial, be it from a pharmaceutical company or another institution, is essential. “We will be in position,” Kramnik said, “to partner with people who can bring it to the clinic. This is our goal.”
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