Turning the Tide on Tuberculosis

Tuberculosis (TB) has afflicted Homo sapiens since our species strode out of Africa 70,000 years ago. Over ensuing millennia, the lung disease has claimed an extraordinary number of lives — from ancient Egyptian pharaohs to U.S. Presidents James Monroe and Andrew Jackson. As of 2024, still more than 1 million people die annually from TB, making it the deadliest infectious disease of the modern day.

TB’s continuing scourge stands in contrast to numerous other historical maladies brought to heel by modern therapeutics. “I call TB a ‘standing pandemic,’” says Dr. Carl Nathan, a professor of microbiology and immunology, and of medicine. “It’s still creating havoc around the world.”

That havoc may yet grow. TB is increasingly acquiring resistance to drugs, foreshadowing a possible future where it runs rampant even in countries with currently low disease burden, such as the United States. TB rates have been on the rise domestically since 2021, with a significant ongoing outbreak in Kansas City, Kansas, racking up around 150 cases and counting.

Yet Dr. Nathan and colleagues at Weill Cornell Medicine — along with the broader international TB clinical and research communities — are hopeful that they are at last turning a corner against TB. Building on decades of research, they are making substantial headway in understanding the deadly bacterium, opening new avenues for better, faster-acting drugs and potentially game-changing vaccines.

“I think in the next 5-10 years, we’re really on the edge of making major advances if we continue to invest in basic science and clinical studies,” says Dr. Daniel Fitzgerald, director of the Center for Global Health at Weill Cornell Medicine, which conducts research and delivers health care in countries with high TB prevalence such as Haiti, Tanzania and India. “The fruits are on the vine, and we’re in the process of harvesting them, so it’s critical that we keep the pressure on.”

A key question driving many of Weill Cornell Medicine’s research endeavors is: What do all of TB’s genes do? Although one of the first organisms to ever have its genome sequenced, back in 1998, scientists still don’t know the function of about half of the bacterium’s 4,000 genes. Researchers are helping to discover essential roles some of these undeciphered genes play in enabling TB to transmit into the airways of its victims. Their work is also demonstrating which genes allow the hardy bacteria to withstand and dodge first-line drug treatments.

With technological innovations moving the overall field forward, the shared goal is to consign TB to the pandemics of the past before it explodes in our interconnected global society. Piece by piece, new treatments could address the deeply deleterious effects of TB in numerous countries, where the disease keeps people in poverty and stokes political instability.

“There’s no country in the world that does not have occasional TB cases, and like we’ve seen with COVID-19, anything that can get on a plane can become relevant to places where it’s not previously been an endemic problem,” says Dr. Vanessa Rouzier, assistant professor of pediatrics in medicine, who does scientific work in Haiti in collaboration with GHESKIO. That nonprofit medical organization was founded in 1982 by Dr. Jean Pape (M.D.’75), the Howard and Carol Holtzmann Professor in Clinical Medicine at Weill Cornell Medicine. “The benefits of our research are for everybody.”

Dr. Kyu Rhee, left, and Dr. Carl Nathan

Untangling TB transmission

Mycobacterium tuberculosis only reliably reproduces in humans, its natural animal host. The severe immune response TB elicits triggers its characteristic symptoms: persistent coughing up of sputum from deep in our lungs, accompanied by fever, chest pain, fatigue and weight loss. The chronic hacking launches infectious bacterial particles into the air.

Although people have long understood these basics of TB’s contagiousness, the transmission biology and genetics involved have only recently started coming to light. “A main reason for not knowing what many TB genes do is because people haven’t studied it in the air as it goes from Person One to Person Two,” says Dr. Nathan. “We think a lot of those genes are there in order to survive this journey.” Better understanding transmission, he says, could be lifesaving: “If it can’t go from me to you, it’s a goner.”

In a March study, Dr. Nathan and colleagues revealed that a family of several hundred genes is indeed required to protect exhaled TB from the drastic changes in temperature, carbon dioxide and oxygen levels encountered outside the lungs. Those overlooked genes offer a promising new suite of drug targets, Dr. Nathan says. The findings were facilitated by the creation of a novel fluid that accurately possesses the droplet composition, viscosity and surface tension of the aerosols TB-infected individuals expel.

Dr. Kyu Rhee has examined how exhaled TB survives intense desiccation, or drying out. “TB is transmitted in droplets that are so small, they often lack water, and yet our lungs and bodies are almost perfectly humid,” says Dr. Rhee, a professor of medicine and of microbiology and immunology.

In a preprint study, Drs. Rhee, Nathan and colleagues recently reported that TB particles undergo extensive DNA damage from airborne desiccation. DNA repair mechanisms kick in, though, restoring the bacterium, but in the process also introducing slight errors. These mutations serve as wellsprings of genetic diversification, and thus potential drug resistance, meaning TB manages to make evolutionary lemonade out of transmission lemons. “It’s a remarkable organism for sure and terrifying in many ways,” says Dr. Nathan.

Dr. Rhee is also leveraging technologies to advance drug development through deep biochemical analyses of TB. All too often, seemingly propitious drugs, screened out of millions of compounds, fail to make a dent in TB. Researchers used to assume the drug had failed to enter the bacterium. But Dr. Rhee is now illuminating the true fate of the compound of interest, using a technique that separates molecules based on chemical and physical properties, then precisely identifies them. As a result, Dr. Rhee can tell how much of a compound infiltrated a TB cell, and from there if TB neutralized the compound by breaking it down or pumping it out. “TB has its own ‘liver,’ though not literally,” says Dr. Nathan. “It detoxifies most of the compounds that we try to add to it.”

To learn more about why drugs work or fail, Dr. Rhee is pioneering the application of the tools of metabolomics and lipidomics to TB. The former method analyzes the smorgasbord of small molecules produced by a TB cell and how these levels change when genes are suppressed or “knocked out,” meaning rendered nonfunctional. The analysis of lipids or fats, called lipidomics, is highly relevant for TB, courtesy of the bacterium’s enormously thick and complicated lipid cell wall. That lipid-rich wall contributes to the bacterium’s integrity, virulence and ability to prevent drugs from penetrating. Monitoring the various lipids in the cell wall when genes are altered or drugs added could lead to new insights.

“Kyu’s technology is absolutely critical to contemporary drug development for TB, and it should be for all antibiotic development,” says Dr. Nathan.

Clockwise from left: Dr. Kayvan Zainabadi, Dr. Daniel Fitzgerald and Dr. Vanessa Rouzier.

Toward tailored treatments

New drugs are essential, given today’s dwindling and underperforming TB pharmaceutical armamentarium. Dr. Rouzier points out that the standard regimen of “RHZE” drugs — rifampin, isonaizid, pyrazinamide and ethambutol — hails from the 1950s and 1960s, and that bedaquiline and delamanid, the first new drugs since then, were not approved in some countries until 2012 and 2014, respectively, for increasingly common drug-resistant TB.

New therapies will seek to improve upon the typical six-month protocol used with RHZE drugs. The regimen is so long because TB is famously hard to completely root out, as drugs struggle to penetrate the lung lesions it forms. Further complicating matters, TB can temporarily enter a dormant, nonreplicating state that most first-line drugs miss because they only work on active or growing bacteria. Patients with dormant TB are said to have a latent TB infection and they don’t show symptoms, but their infections can suddenly reactivate and trigger disease relapse.

Overall, the standard regimen cures roughly nine out of 10 TB patients. But in addition to high costs and access issues, it poses significant side effects — most commonly gastrointestinal distress — that hinder compliance. For those who ultimately fail the regimen, sometimes years of harsher drug treatments are needed, which can thoroughly upend their and their family’s lives. “It’s not like taking penicillin for a week or two and ‘give me a call if you don’t feel better,’” says Dr. Fitzgerald. “It’s months of daily medicine with bad side effects.”

Part of improving drug regimens is figuring out who is demonstrably getting better from front-line treatment and thus may require only a month or two of medications, versus who is on a failing path and would benefit from additional drugs sooner rather than later. Toward this end, Dr. Kayvan Zainabadi — an assistant professor of molecular microbiology in medicine who works with Drs. Fitzgerald and Rouzier — is developing powerful new diagnostics for monitoring treatment. The decades-old standard for assessing treatment response is whether samples from patients’ sputum can grow bacterial colonies. The crude technique does not reveal dormant TB, though, which is nonculturable.

Instead, Dr. Zainabadi’s RNA-based assay aims to rapidly assess how patients are responding to therapy by offering a more accurate profile of TB in sputum. The test specifically detects 16S ribosomal RNA, part of TB’s protein-making cellular machinery. Tracking these RNA levels could offer insight into whose infection is being successfully treated.

Conveniently, the test could possibly extend to stool samples as well, which would be helpful for diagnostics and treatment monitoring in pediatric populations, because children tend to swallow sputum rather than spit it out. As a result, only around half of children with TB are successfully diagnosed, though many are put on the intensive antibiotic regimen if doctors suspect they’re infected, given TB’s higher mortality rates in children under 5.

“Children typically have been left behind in terms of progress in TB treatment,” says Dr. Rouzier, who specializes in pediatrics and care for pregnant women with TB. “Kayvan’s diagnostic could be an important step forward.”

Dr. Zainabadi recruited 41 Haitian patients with TB to initially develop the RNA diagnostic, reported in a 2022 study, and he is now engaged in follow-up work in India and Uganda with a grant from the TB-focused consortium, RePORT International.

“We have a chance here to predict patient outcomes, tell how well a drug is working, and tailor treatments, instead of a one-size-fits-all approach for everybody,” he says. “It could be a game changer for how we handle TB.”

Dr. Dirk Schnappinger, left, and Dr. Sabine Ehrt

Next-generation drugs

Additional research with an eye toward delivering new therapies is being pursued by the joint lab of Dr. Sabine Ehrt and Dr. Dirk Schnappinger.

Dr. Ehrt, who in July succeeded Dr. Nathan as chair of the Department of Microbiology and Immunology, focuses on ways to potentially trap dormant TB in a caged, inactive state, and thus unable to run amok in the lungs. Because hosts with latent TB infections do not experience symptoms and are not contagious, keeping TB tamped down in this way, although short of eradication, could still prove effective in slowing the simmering TB pandemic. “We’re hoping to turn these pathways the bacteria require to establish latency against them,” says Dr. Ehrt, who is also a professor of microbiology and immunology.

Dr. Schnappinger, meanwhile, is collaborating with Dr. Jeremy Rock, the Penrhyn E. Cook Associate Professor at The Rockefeller University, on an effort utilizing a relative of the well-known CRISPR gene editing technique that “silences” individual genes in TB’s genome. Inhibiting gene expression through CRISPR interference, or CRISPRi, and gauging how TB is affected serves as a trial run for potential drugs that target the same gene’s function. “If we silence a given gene, we can see if the bacterium is still able to establish an infection or persist in a chronic infection,” says Dr. Schnappinger, a professor of microbiology and immunology.

The collective work of Drs. Ehrt and Schnappinger and colleagues is also looking further ahead to potentially revolutionary vaccines. One initiative involves enhancing BCG (Bacille Calmette-Guérin), a kind of TB vaccine which debuted over a century ago that uses a weakened, live version of Mycobacterium bovis, a close relative of the human TB bacterium. Rarely used in countries with low rates of TB, BCG can slash the risk of TB infection by about 50% for babies and children in countries that administer the vaccine and is notably effective against severe manifestations such as meningitis (TB of the brain) and miliary TB (widespread in the lungs and blood) that have a high mortality rate or can leave patients severely disabled. Yet this vaccine — the longest in continuous use — does not significantly protect against typical, pulmonary TB in adults and adolescents.

Intriguingly, recent studies in nonhuman primates have revealed that high-dose BCG delivered directly into veins can provide robust immunity to pulmonary TB. To ensure that this high-dose approach could work safely in humans, Drs. Ehrt and Schnappinger have genetically engineered a “kill switch” for BCG, so the BCG bacteria can be immediately eliminated within a vaccine recipient, after inducing TB protection. The kill switch is essentially a bacterial self-destruct enzyme that rapidly expresses when another substance — in this case, an antibiotic — is withheld, as reported in a recent study.

To provide another level of safety for testing this controllable BCG and other vaccine candidates in human volunteers, the WCM researchers and colleagues have also developed a kill switch-equipped TB strain. That way, in any future clinical trial, participants’ voluntary TB infection could similarly be shut down at will.

If these levels of progress made by TB researchers worldwide can be sustained, the personal misery and societal upheaval that the bacterium has wrought for tens of thousands of years may at last abate.

“TB has been with us so long — there’s a moral obligation to better address it,” says Dr. Nathan. “We shouldn’t have a highly lethal, easily airborne-spread disease running rampant in the world.”