Fig. 3.-High-resolution computed tomography of the chest shows...

Why Some Tuberculosis Bacteria Prove DeadlyScienceDaily

People who fall sick with drug-resistant tuberculosis (TB) face daunting odds. Only about two in three survive the illness, unlike people with drug-sensitive TB, of whom more than 90 percent survive.

Part of the reason drug-resistant TB is so lethal is because some antibiotics of first choice don't kill the TB bacteria, forcing doctors to treat the infection with second-line medications that are often more toxic and less effective.

But the TB bacteria also may be undermining the body's ability to defend itself. Researchers at Washington University School of Medicine in St. Louis have found that the same mutation that makes TB bacteria withstand a first-line drug also elicits a different -- and probably weaker -- immune response in mice.

"As the bacteria become drug resistant, they change physiologically and trick the immune system to behave differently," said Shabaana A. Khader, PhD, an associate professor of molecular microbiology and the study's senior author. "If we're going to fight TB bacteria effectively, we're going to have to understand what the drug-resistant bacteria are doing to the immune system to elicit protection."

The findings are published Sept. 17 in Nature Microbiology.

There have been hints for years that drug-resistant bacteria might interact with the body differently than drug-sensitive strains. Anecdotal reports suggest that resistant TB bacteria cause more damage to the lungs and spread more widely through the body.

Khader, working with graduate student and first author Nicole Howard and colleagues, analyzed the immune response in mice infected with Mycobacterium tuberculosis, the bacteria that cause TB. They compared a strain that is resistant to all first- and many second-line antibiotics with a drug-sensitive strain of TB.

The mice's immune systems battled the sensitive bacteria by releasing a powerful immune molecule known as IL-1 beta and ramping up the ability of their immune cells to burn sugar. Both actions are crucial for an effective immune assault on the TB bacteria.

But when infected with the drug-resistant strain, the mice failed to pull out the big guns. Their immune cells did not burn more sugar, and they failed to produce much IL-1 beta. Instead, they released a different immune molecule, IFN beta, which is associated with a feeble and sometimes detrimental immune response to TB.

"People always thought that development of drug resistance just meant that there's a change in how bacteria respond to antibiotics," Khader said. "But this shows that the whole immune environment is changing in ways that we haven't been fully aware of."

To find out why drug-resistant bacteria elicit a different immune response, the researchers scanned the whole genomes of several drug-resistant strains. They found that a change of one letter in the genetic code gave bacteria the ability to withstand rifampicin, an important first-line antibiotic, and also altered the immune response.

Treating TB is a long, drawn-out process. The bacteria grow slowly and are wrapped in a protective shell, so it takes a combination of four antibiotics given repeatedly over six months to eradicate them. Boosting the immune response would be like sending in fresh troops to a protracted battle -- it could put an end to the fight, quickly and decisively. Clinical trials are already underway to find out whether immune-enhancing drugs combined with antibiotics improves outcomes for people with TB. But because of the inherent dangers of working with drug-resistant bacteria, nearly all research into strengthening the immune response has been conducted using drug-sensitive strains.

"If you're going to do host-directed therapeutics, we need to know what immune pathways to target," Khader said. "And these pathways may turn out to be different for drug-sensitive and drug-resistant TB."

Howard and Khader's findings suggest that the people most in need of better therapeutics -- those infected with drug-resistant strains -- may not benefit from immune enhancers that are designed based on drug-sensitive bacteria.

"We don't know enough about the differences between resistant and sensitive TB to be confident that the therapeutics and vaccines we're designing are going to work," Khader said. "We're going to have to do those studies."

Study Could Explain Tuberculosis Bacteria Paradox - ScienceDaily

Tuberculosis bacteria have evolved to remember stressful encounters and react quickly to future stress, according to a study by computational bioengineers at Rice University and infectious disease experts at Rutgers New Jersey Medical School (NJMS).

Published online in the open-access journal mSystems, the research identifies a genetic mechanism that allows the TB-causing bacterium, Mycobacterium tuberculosis, to respond to stress rapidly and in manner that is "history-dependent," said corresponding author Oleg Igoshin, a professor of bioengineering at Rice.

Researchers have long suspected that the ability of TB bacteria to remain dormant, sometimes for decades, stems from their ability to behave based upon past experience.

Latent TB is an enormous global problem. While TB kills about 1.5 million people each year, the World Health Organization estimates that 2-3 billion people are infected with a dormant form of the TB bacterium.

"There's some sort of peace treaty between the immune system and bacteria," Igoshin said. "The bacteria don't grow, and the immune system doesn't kill them. But if people get immunocompromised due to malnutrition or AIDS, the bacteria can be reactivated."

One of the most likely candidates for a genetic switch that can toggle TB bacteria into a dormant state is a regulatory network that is activated by the stress caused by immune cell attacks. The network responds by activating several dozen genes the bacteria use to survive the stress. Based on a Rice computational model, Igoshin and his longtime Rutgers NJMS collaborator Maria Laura Gennaro and colleagues predicted just such a switch in 2010. According to the theory, the switch contained an ultrasensitive control mechanism that worked in combination with multiple feedback loops to allow hysteresis, or history-dependent behavior.

"The idea is that if we expose cells to intermediate values of stress, starting from their happy state, they don't have that much of a response," Igoshin explained. "But if you stress them enough to stop their growth, and then reduce the stress level back to an intermediate level, they remain stressed. And even if you fully remove the stress, the gene expression pathway stays active, maintaining a base level of activity in case the stress comes back."

In later experiments, Gennaro's team found no evidence of the predicted control mechanism in Mycobacterium smegmatis, a close relative of the TB bacterium. Since both organisms use the same regulatory network, it looked like the prediction was wrong. Finding out why took years of follow-up studies. Gennaro and Igoshin's teams found that the TB bacterium, unlike their noninfectious cousins, had the hysteresis control mechanism, but it didn't behave as expected.

"Hysteretic switches are known to be very slow, and this wasn't," Igoshin said. "There was hysteresis, a history-dependent response, to intermediate levels of stress. But when stress went from low to high or from high to low, the response was relatively fast. For this paper, we were trying to understand these somewhat contradictory results. "

Igoshin and study co-author Satyajit Rao, a Rice doctoral student who graduated last year, revisited the 2010 model and considered how it might be modified to explain the paradox. Studies within the past decade had found a protein called DnaK played a role in activating the stress-response network. Based on what was known about DnaK, Igoshin and Rao added it to their model of the dormant-active switch.

"We didn't discover it, but we proposed a particular mechanism for it that could explain the rapid, history-dependent switching we'd observed," Igoshin said. "What happens is, when cells are stressed, their membranes get damaged, and they start accumulating unfolded proteins. Those unfolded proteins start competing for DnaK."

DnaK was known to play the role of chaperone in helping rid cells of unfolded proteins, but it plays an additional role in the stress-response network by keeping its sensor protein in an inactive state.

"When there are too many unfolded proteins, DnaK has to let go of the sensor protein, which is an activation input for our network," Igoshin said. "So once there are enough unfolded proteins to 'distract' DnaK, the organism responds to the stress."

Gennaro and co-author Pratik Datta conducted experiments at NJMS to confirm DnaK behaved as predicted. But Igoshin said it is not clear how the findings might impact TB treatment or control strategies. For example, the switch responds to short-term biochemical changes inside the cell, and it's unclear what connection, if any, it may have with long-term behaviors like TB latency, he said.

"The immediate first step is to really try and see whether this hysteresis is important during the infection," Igoshin said. "Is it just a peculiar thing we see in our experiments, or is it really important for patient outcomes? Given that it is not seen in the noninfectious cousin of the TB bacterium, it is tempting to speculate it is related to survival inside the host."

Tuberculosis Has Overtaken COVID As World's Deadliest Infectious Disease

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Tuberculosis (TB) is once again the infectious disease responsible for the most deaths worldwide, according to a Tuesday announcement from the World Health Organization (WHO).

The contagious disease was responsible for 1.25 million global deaths in 2023, WHO reported, including 161,000 people with HIV.

COVID-19 had overtaken TB as the world's leading infectious killer for the previous three years.

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What to know about tuberculosis

TB is a preventable and curable disease caused by bacteria that typically impacts the lungs, according to WHO.

This 2006 electron microscope image provided by the Centers for Disease Control and Prevention shows Mycobacterium tuberculosis bacteria, which causes the disease tuberculosis.  (Janice Carr/CDC/AP)

It is an airborne contagion that can be spread through coughing, sneezing or saliva.

While around 25% of people have likely been infected with the bacteria, only 5% to 10% will experience symptoms and develop the disease, the same source stated.

Only people with symptoms can spread the disease.

Who is at risk?

"If you breathe, you can catch TB — so all people are at risk," Masae Kawamura, M.D., a former TB control director in San Francisco and a tuberculosis clinician, told Fox News Digital. 

Kawamura calls TB a "social disease of crowding and mobility." 

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"Since TB is airborne, congregate settings like hospitals, nursing homes, prisons, jails, classrooms and homeless shelters are places TB is more easily spread, especially if multiple risks are involved," she said.

Those at the highest risk of developing TB disease after exposure include people who have diabetes, have weakened immunity, are malnourished, use tobacco and/or drink excess amounts of alcohol.

Babies and children are also at higher risk.

"If a person has latent TB infection, TB disease activation varies from 5% to 15% over a lifetime, but can be higher if a person has multiple risks, such as being an elderly person and/or being malnourished, having diabetes and/or having other diseases that weaken the immune system," said Kawamura.

Symptoms, diagnosis and treatment

Those who get sick with TB may experience mild symptoms, including coughing, chest pain, fatigue, weight loss, weakness, fever and night sweats, according to WHO.

Symptoms will vary depending on which organs are affected. 

"If you breathe, you can catch TB — so all people are at risk."

In addition to the lungs, the disease can also affect the kidneys, spine, skin and brain.

"TB can affect any organ of the body, but it causes disease in the lung in over 80% of cases," said Kawamura.

"This is dangerous because it causes cough, the mechanism of airborne spread."

TB is an airborne contagion that can be spread through coughing, sneezing or saliva. (iStock)

In more severe cases, patients may cough up blood, noted Kawamura, who serves on the board of directors of Vital Strategies, a global public health organization. 

"Often there are minimal symptoms for a long time and people mistake their occasional cough with allergies, smoking or a cold they can't shake off," she added.

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TB can be identified with rapid diagnostic tests, WHO noted.

The disease is treated with antibiotics that are taken every day for four to six months, the same source stated. Some of the most common include isoniazid, rifampicin, pyrazinamide and ethambutol.

"TB can affect any organ of the body, but it causes disease in the lung in over 80% of cases," an expert said. "This is dangerous because it causes cough, the mechanism of airborne spread." (iStock)

Failing to take the complete course of medications can cause the bacteria to become drug-resistant.

Cases of drug-resistant TB need to be treated with different medications.

When TB becomes deadly

If TB goes untreated, it is fatal in about half of its victims, according to Kawamura. 

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"About 25% recover on their own and another 25% persist as chronic active TB cases," she said.  

 In the U.S., most active TB cases are detected at an earlier stage, the expert noted, but the death rate is still "shockingly high" at 10%, and much higher if the patient is over 65 years old.  

Prevention of the disease

There is a childhood vaccine called Bacille-Calmette-Guerin (BCG) that is given in most of the world to infants, Kawamura noted.

"It reduces death, meningitis and organ dissemination by 75% in children under 5 — however, it does not prevent TB infection and is ineffective in adults," the doctor told Fox News Digital. 

The best means of prevention is testing those at risk and treating latent tuberculosis infection (LTBI), a doctor advised. (iStock)

"Overall, BCG is considered ineffective, hence, TB's title as the greatest infectious disease killer of all time."

BCG was never used in the U.S. Because of the country's lower rates of TB, its ineffectiveness and its interference with TB tests, she added.

"Our best chance to end the TB epidemic is to kill TB while it sleeps."

The best means of prevention is testing those at risk and treating latent tuberculosis infection (LTBI), according to the doctor.

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"Our best chance to end the TB epidemic is to kill TB while it sleeps," Marc Destito, head of global health for QIAGEN, a Netherlands-based company that provides tuberculosis testing solutions, told Fox News Digital. 

"To do that, we need to identify, test and treat the estimated millions of Americans — and many more around the world — who are infected with the bacteria that causes TB disease. More aggressive testing, contact tracing and education are the keys to ending TB." 

Melissa Rudy is senior health editor and a member of the lifestyle team at Fox News Digital. Story tips can be sent to melissa.Rudy@fox.Com.

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