- Press Release Distribution

Potential therapeutic target found to combat tuberculosis, a disrupted NAD(H) homeostasis

Tuberculosis, the world’s leading infectious disease killer, caused 1.6 million deaths in 2021, along with 10 million new cases of tuberculosis every year

Potential therapeutic target found to combat tuberculosis, a disrupted NAD(H) homeostasis
( BIRMINGHAM, Ala. – It has been uncertain how Mycobacterium tuberculosis deflects the immune response in humans, though evidence has pointed to host immunometabolism — the intrinsic link between metabolism in immune cells and their immune function. The pathogen M. tuberculosis is known to disrupt a metabolic pathway called glycolysis in infected myeloid cells, which include macrophages, through an unclear mechanism.

A more accurate understanding of this pathogenic mechanism could provide a target against the bacterium that caused 1.6 million deaths in 2021, along with 10 million new cases of tuberculosis every year.

Now a study published in Nature Communications by researchers at the University of Alabama in Birmingham and the Africa Health Research Institute, or AHRI, shows how M. tuberculosis perturbs homeostasis of the high-energy molecule NADH and reprograms glycolysis in myeloid cells. This highlights glycolysis as a potential therapeutic target to combat the world’s leading infectious disease killer.

Glycolysis is the pathway that converts glucose into pyruvate while forming the high-energy molecules ATP and NADH. But the pathway can run in either direction, and researchers took advantage of that to apply a more selective approach to inhibiting glycolytic flux. Previous experiments have taken a more sledgehammer-like approach, such as using an inhibitor that blocks uptake of glucose into myeloid cells.

The reversible process of lactate fermentation is catalyzed by the enzyme lactate dehydrogenase, or LDH. LDH has of four subunits, a mix of LDHA and LDHB subunits. When LDH is made mostly of LDHA subunits, a subunit that is predominantly expressed in myeloid cells, it preferentially converts pyruvate to lactate, and NADH to NAD+. However, an LDH made of LDHB subunits favors the opposite reaction.

The role of LHDA in tuberculosis pathogenesis is unknown. The UAB and AHRI researchers looked at resected lung tissue from patients with tuberculosis and found that myeloid, bronchial epithelial cells and lymphocytes stained positive for LDHA as they engaged in distinctive immunological phenomena like granuloma formation and alveolitis. “These data implicate LDHA as an important metabolic protein in the immune response in human tuberculosis lesions,” said Adrie Steyn, Ph.D., senior author of the research.

Knowing that NADH/NAD+ regulates glycolysis at defined steps, Steyn and colleagues hypothesized that NAD(H)-mediated glycolytic flux in myeloid cells protects the host against M. tuberculosis infection. To test this, they created mice that lack the LDHA subunit in myeloid cells. These cells have a reduced glycolytic capacity because the altered LDH function, composed only of LDHB subunits, decreases their ability to regenerate NAD+ from NADH in the presence of pyruvate.

The LDHA-deficient mice, when infected with a low dose of M. tuberculosis, were more susceptible to infection and had a significantly reduced survival time. Also, gross pathology and histopathology of the lungs were worse in the LDHA-deficient mice. Furthermore, wild-type mice initially mount a robust inflammatory response against the M. tuberculosis infection as a protective immune response, while the LDHA-deficient mice had a striking absence of early inflammation.

“This suggests that LDHA is necessary for protection against tuberculosis and that glycolytic flux in myeloid cells is essential for the control of M. tuberculosis infection and disease,” Steyn said.

Despite evidence of a reduced immune response, when researchers quantified gene expression in the lungs of the LDHA-deficient mice, they found that mRNAs associated with inflammatory processes were among the most enriched, especially a robust interferon-gamma gene set. “The robust interferon-gamma gene expression signature in more susceptible mice with a blunted immune response was particularly intriguing since interferon-gamma is an indispensable antimycobacterial cytokine widely considered to be protective in tuberculosis,” Steyn said.

This conundrum was solved through bioenergetics experiments that showed mouse macrophages require LDHA and its LDH-mediated NAD+ regeneration for their metabolic response to interferon-gamma.

Since NAD+ depletion appeared to be central to the glycolytic inhibition caused by M. tuberculosis, the researchers asked whether the addition of an NAD+ precursor, nicotinamide, would alter the ability of macrophages to mount an immune response.

Nicotinamide was found to increase the glycolytic capacity of M. tuberculosis-infected bone marrow-derived macrophages. The researchers hypothesized that nicotinamide acts as a host-directed therapy by enhancing glycolysis in M. tuberculosis-infected macrophages through its conversion to NAD(H) via the NAD+ salvage pathway.

They found that nicotinamide was an effective treatment for tuberculosis in in vitro experiments where they infected macrophages with luciferase-expressing M. tuberculosis. The infected macrophages showed that nicotinamide reduced luminescence at 48 hours post-infection dose dependently, and this reduction of the pathogenic bacteria depended on glycolysis. In a mouse model, feeding the mice nicotinamide for four weeks, beginning either three days or 28 days post-infection, showed a tenfold reduction of the M. tuberculosis burden in the lungs, and it also reduced inflammation in the lungs.

Nicotinamide was first described as a treatment for tuberculosis in the 1940s, via a different mechanism; but it was largely abandoned when much more effective drugs were discovered in the golden age of antibiotics.

However, the landscape of tuberculosis has shifted dramatically in the last 60 years. The incidence of tuberculosis has increased to more than 10 million new cases annually, and the pathogen has developed resistance to the frontline drugs that displaced nicotinamide, Steyn says.

“We have provided further evidence of a host-dependent effect of nicotinamide, the metabolic requirements for its activity and a modern-day demonstration of its efficacy as a treatment for tuberculosis, using two treatment regimens in vivo,” Steyn said of the current study. “Logistically, nicotinamide satisfies many of the criteria for an optimal novel tuberculosis treatment regimen set forth by the World Health Organization. It is inexpensive, orally bioavailable, shelf-stable, remarkably safe and tolerable, and it is well studied and routinely used in humans for various indications. Ultimately, these characteristics make nicotinamide appealing as an old tool in a modern setting.”

An unanswered question remains, Steyn says. How does M. tuberculosis deplete NAD(H) levels? A partial explanation, the researchers say, may be the secretion by M. tuberculosis of tuberculosis necrotizing toxin, or TNT, an NAD+ glycohydrolase. This toxin, reported by UAB’s Michael Niederweis, Ph.D., in 2015, is the first toxin ever found in M. tuberculosis during 132 years of study. TNT in wildtype M. tuberculosis significantly reduces NAD+ abundance in infected macrophages.

Steyn is a UAB professor of microbiology and oversees labs at UAB and at the AHRI, in Durban, KwaZulu Natal, South Africa, an area that is the worldwide epicenter for tuberculosis infections. Niederweis is a professor in the UAB Department of Microbiology.

First author of the study, “NAD(H) homeostasis underlies host protection mediated by glycolytic myeloid cells in tuberculosis,” is Hayden T. Pacl, M.D., Ph.D., UAB Department of Microbiology.

Co-authors with Steyn and Pacl are Krishna C. Chinta, Vineel P. Reddy, Sajid Nadeem, Ritesh R. Sevalkar and Joel N. Glasgow, UAB Department of Microbiology; Anupam Agarwal, UAB Department of Medicine, Division of Nephrology; and Kievershen Nargan, Kapongo Lumamba and Threnesan Naidoo, AHRI, University of KwaZulu Natal, Durban, South Africa. Naidoo also has an appointment at Walter Sisulu University, Eastern Cape, South Africa.

Support came from National Institutes of Health grants Al111940, AI134810, AI137043, AI138280, A127182 and DK079337. Partial funding came through Wellcome Strategic Core award 201433/Z/16/A.

At UAB, Microbiology and Medicine are departments in the Marnix E. Heersink School of Medicine, and Niederweis holds the Triton Endowed Professorship in Bacteriology. Agarwal is dean of the Heersink School of Medicine at UAB. Pacl, a graduate of the UAB Medical Scientist Training Program, is currently a resident in Internal Medicine with the Physician Scientist Training Program, Yale School of Medicine, New Haven, Connecticut.


[Attachments] See images for this press release:
Potential therapeutic target found to combat tuberculosis, a disrupted NAD(H) homeostasis


Global Neuroanatomy Network (GNN): Creating a new resource for neuro educators

In a leap forward for neuroanatomy education, the Global Neuroanatomy Network (GNN) is about to launch, creating a new, accessible, peer-reviewed collection of resources for instructors around the world. Developed as a response to the challenges faced in transitioning neuroanatomy education to an online format during the pandemic, the GNN represents a collaborative effort by educators globally. The initiative began as a conversation on social media, recognizing the need for better resources and support for teaching neuroanatomy online. As educators ...

New research demonstrates more effective method for measuring impact of scientific publications

Newly published research reexamines the evaluation of scientific findings, proposing a network-based methodology for contextualizing a publication’s impact. This new method, which is laid out in an article co-authored by Alex Gates, an assistant professor with the University of Virginia’s School of Data Science, will allow the scientific community to more fairly measure the impact of interdisciplinary scientific discoveries across different fields and time periods. The article was published ...

UCSB scientists will eliminate bottlenecks to breakthroughs with a newly acquired synthetic biology robotics system

Researchers in UC Santa Barbara’s newly designated Biological Engineering (BioE) Department have received a significant boost from the U.S. Army, which awarded the university a $9.85 million grant to design and purchase state-of-the-art equipment that project leader Michelle O’Malley, a professor of chemical engineering and biological engineering, says “allows UCSB scientists to do things that we never thought were possible.” The funding, awarded through the Department of Defense’s Defense University Research ...

NASA’s Webb reveals new features in heart of Milky Way

NASA’s Webb reveals new features in heart of Milky Way
The latest image from NASA’s James Webb Space Telescope shows a portion of the dense center of our galaxy in unprecedented detail, including never-before-seen features astronomers have yet to explain. The star-forming region, named Sagittarius C (Sgr C), is about 300 light-years from the Milky Way’s central supermassive black hole, Sagittarius A*. “There’s never been any infrared data on this region with the level of resolution and sensitivity we get with Webb, so we are seeing lots of features here for the first time,” said the observation team’s principal investigator Samuel Crowe, an undergraduate student at the University ...

UC Irvine-led study is first to find brain hemorrhage cause other than injured blood vessels

Irvine, Calif., Nov. 20, 2023 — A first-of-its-kind study led by the University of California, Irvine has revealed a new culprit in the formation of brain hemorrhages that does not involve injury to the blood vessels, as previously believed. Researchers discovered that interactions between aged red blood cells and brain capillaries can lead to cerebral microbleeds, offering deeper insights into how they occur and identifying potential new therapeutic targets for treatment and prevention.   The ...

AI outperforms expert plastic surgeon in rhinoplasty consultations

AI outperforms expert plastic surgeon in rhinoplasty consultations
In a new study, artificial intelligence in the form of ChatGPT outperformed an expert rhinoplasty surgeon in answering preoperative and postoperative patient questions related to nasal surgery. ChatGPT earned significantly higher ratings in accuracy, completeness, and overall quality, according to the study published in Facial Plastic Surgery & Aesthetic Medicine. Click here to read the article now. Kay Durairaj, MD, and Omer Baker, from Pasadena, California , Dario Bertossi, MD, from University of Verona, Steven Dayan, MD, from University of Illinois, Chicago, Kian Karimi, MD, from Los Angeles California, Roy Kim, MD, from San Francisco, California, Sam ...

People watched other people shake boxes for science. Here’s why

People watched other people shake boxes for science. Here’s why
When researchers asked hundreds of people to watch other people shake boxes, it took just seconds for almost all of them to figure out what the shaking was for. The deceptively simple work by Johns Hopkins University perception researchers is the first to demonstrate that people can tell what others are trying to learn just by watching their actions. Published today in the journal Proceedings of the National Academy of Sciences, the study reveals a key yet neglected aspect of human cognition, and one with implications for artificial intelligence. “Just by looking ...

AI finds formula on how to predict monster waves

AI finds formula on how to predict monster waves
Long considered myth, freakishly large rogue waves are very real and can split apart ships and even damage oil rigs. Using 700 years’ worth of wave data from more than a billion waves, scientists at the University of Copenhagen and University of Victoria have used artificial intelligence to find a formula for how to predict the occurrence of these maritime monsters. The new knowledge can make shipping safer. EMBARGOED CONTENT UNTIL MONDAY 20 NOVEMBER 2023 3 PM US EASTERN TIME Stories about monster waves, called rogue waves, have been the lore of sailors for centuries. But when a 26-metre-high rogue wave slammed into the Norwegian oil ...

Study reveals bias in AI tools when diagnosing women’s health issue

Machine learning algorithms designed to diagnose a common infection that affects women showed a diagnostic bias among ethnic groups, University of Florida researchers found.  While artificial intelligence tools offer great potential for improving health care delivery, practitioners and scientists warn of their risk for perpetuating racial inequities. Published Friday in the Nature journal Digital Medicine, this is the first paper to evaluate fairness among these tools in connection to a women’s health issue. “Machine learning can be a great tool in medical diagnostics, but we found it can show bias toward different ethnic groups,” said Ruogu Fang, an associate ...

Anti-bias police training improved performance and reduced discrimination-based complaints significantly

In recent years, many police departments have mandated or encouraged anti-bias training. This has occurred in response to government-imposed measures such as consent decrees or as a proactive attempt to enhance public perceptions of police following actions that have raised concerns about racially motivated and other discriminatory practices. In a new study, researchers evaluated the effectiveness of an anti-bias training intervention in one Californian jurisdiction. The study found that officers who received the training had improved performance scores (measured by Body Worn Camera footage), decreased disparity in how they treated different groups of people, ...


USC medical school dean appointed to CIRM board

Antibiotic pollution disrupts the gut microbiome and blocks memory in aquatic snails 

Researchers expose new symbiosis origin theories, identify experimental systems for plant life

Q&A: How AI affects kids’ creativity

Virtual lab meetings improve undergraduate research experience and foster diversity in academia

Study shows effectiveness of updated COVID-19 vaccines wanes moderately over time, is lower against currently circulating variants

Researchers expose new ‘origin’ theories, identify experimental systems for plant life

Researchers honored for outstanding contributions to cancer care

A new Hungarian method may aid protein research

AIM algorithm enhances super-resolution microscope images in real time

Rice researchers uncover surprising role of opioid receptors in gut development

Cleveland Clinic and IBM researchers apply quantum computing methods to protein structure prediction

Blood flow makes waves across the surface of the mouse brain

More out-of-state patients seek abortions in Washington state

Researchers take step toward development of universal COVID-19 antibodies

Do epilepsy medications taken during pregnancy affect a child’s creativity?

First hints of memory problems associated with changes in the brain

Mass General Brigham study finds that memory complaints can predict biological changes in the brain

JPMorgan Chase, Argonne and Quantinuum show theoretical quantum speedup with the quantum approximate optimization algorithm

AI browser plug-ins to help consumers improve digital privacy literacy, combat manipulative design

Grant funds CU project to develop novel mechanism to expand NF1 treatments

A drying Salton Sea pollutes neighboring communities

Wild megalopolis: Study shows unexpected pockets of biodiversity pepper Los Angeles

Slugs and snails love the city, unlike other animals

Ideas that cross international borders may have powerful impact on elections

YouTube’s comments section: Political echo chamber or constructive cross-partisan forum?

Babies babble squeals and growls in clustering patterns observable from birth through the first year, suggesting this active vocal exploration is important to speech development

The sweat bee, H. rubicundus, is less sociable in Scotland than in Cornwall, but is genetically differentiated and genetically isolated too

Smartphone use may help adolescents feel better - at least in the moment, finds real-time survey of US teens

Public have no difficulty getting to grips with an extra thumb, study finds

[] Potential therapeutic target found to combat tuberculosis, a disrupted NAD(H) homeostasis
Tuberculosis, the world’s leading infectious disease killer, caused 1.6 million deaths in 2021, along with 10 million new cases of tuberculosis every year