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Remodeling The Immune System To Fight Tuberculosis
Tuberculosis, caused by the bacterium Mycobacterium tuberculosis (Mtb) kills upwards of 1.6 million people a year, making it one of the leading causes of death by an infectious agent worldwide -- and that number is only growing larger. How, exactly, Mtb evades the immune system isn't yet known, but a collaborative team of researchers from the University of Massachusetts Amherst and Seattle Children's Research Institute recently discovered something surprising: prior exposure to a genus of bacteria called Mycobacterium seems to remodel the first-line defenders in the body's immune system. Furthermore, how those cells are remodeled depends on exactly how the body is exposed. These results, published recently in PLOS Pathogens, suggest that a more integrated treatment approach that targets all aspects of the immune response could be a more effective strategy in the fight against tuberculosis.
"We breathe in thousands of liters of air every day," says Alissa Rothchild, assistant professor in the Veterinary and Animal Sciences Department at UMass Amherst and the paper's senior author. "This essential process makes us incredibly vulnerable to inhalation of all sorts of potentially infectious pathogens that our immune systems have to respond to."
Systems, plural. When we think of immunity, we typically think of the adaptive immune system, which is when prior exposure to a pathogen -- say, a weakened version of chickenpox -- teaches the immune system what to guard against. Vaccination is the most common tool that we use to teach our adaptive immune systems what to look out for.
While the adaptive immune system is the major focus of most vaccine research (think protective antibodies induced by COVID-19 vaccines), it is not the body's first responder -- that would be the innate immune system and its ranks of macrophages. The macrophages are the first-line defenders in the tissues that recognize and destroy pathogens and also call for backup. One way they do this by turning on different inflammatory programs that can change the tissue environment.
In the case of the lungs, these macrophages are called alveolar macrophages (AMs). They live in the lung's alveoli, the tiny air sacs where oxygen passes into the bloodstream -- but, as Rothchild has shown in a previous paper, AMs don't mount a robust immune response when they're initially infected by Mtb. This lack of response seems to be a chink in the body's armor that Mtb exploits to such devastating effect. "Mtb takes advantage of the immune response," says Rothchild, "and when they infect an AM, they can replicate inside of it for a week or longer. They effectively turn the AM into a Trojan Horse in which the bacteria can hide from the body's defenses."
"But what if we could change this first step in the chain of infection?" Rothchild continues. "What if the AMs responded more effectively to Mtb? How could we change the body's innate immune response? Studies over the last 10 years or so have demonstrated that the innate immune system is capable of undergoing long-term changes, but we are only beginning to understand the underlying mechanisms behind them."
To test conditions where the innate immune response might be remodeled, Dat Mai, a research associate at Seattle Children's Research Instituteand the first author of the paper, Rothchild and their colleagues designed an experiment using two different mouse models. The first model used the BCG vaccination, one of the world's most widely distributed vaccines and the only vaccine used for tuberculosis. In the second model, the researchers induced a contained Mtb infection, which they previously showed protects against subsequent infections in a form of concomitant immunity.
Weeks after exposure, the researchers challenged the mice with aerosolized Mtb and infected macrophages were taken from each mouse model for RNA sequencing. There were striking differences in the RNA from each set of models.
While both sets of AMs showed a stronger pro-inflammatory response to Mtb than AMs from unexposed mice, the BCG-vaccinated AMs strongly turned on one type of inflammatory program, driven by interferons, while the AMs from the contained Mtb infection turned on a qualitatively different inflammatory program. Other experiments showed that the different exposure scenarios changed the AMs themselves, and that some of these changes seem to be dependent on the greater lung environment.
"What this tells us," says Rothchild, "is that there's a great deal of plasticity in the macrophage response, and that there's potential to therapeutically harness this plasticity so that we can remodel the innate immune system to fight tuberculosis."
FAQ: What Is Tuberculosis And Can It Be Caught Easily?
Who might develop active tuberculosis?Tuberculosis is transmitted through respiratory droplets from an infected person.
It is spread through "close and prolonged exposure", usually days to weeks, said Mr Ong. A person may get tuberculosis if they live or work daily with a person who is infected.
"They cannot get (tuberculosis) by sharing cups, utensils or food, through hand shaking, or having the occasional meal at the hawker centre," said Mr Ong in a Facebook post on Sunday.
According to MOH, the risk of progression from latent tuberculosis to active tuberculosis is higher in people who have underlying medical conditions such as HIV infection and diabetes.
Those who have a weakened immune system - due to drugs or sickness - or have poor nutritional status may also develop active tuberculosis. Substance abusers and drug addicts are also at risk.
The World Health Organization (WHO) states that babies and children are at higher risk and may develop symptoms.
How do I know I have tuberculosis?Unlike infection, a person who develops tuberculosis disease will have symptoms. These may be mild for many months, said the WHO.
Some common symptoms of tuberculosis disease are chest pain or a prolonged cough, sometimes with blood. The person may also feel weak or fatigued, and get fever and night sweats. They may also lose weight.
The WHO urges those at increased risk to get tested.
"Early detection is key. If you have a persistent cough that lasts three weeks or longer, you should consult a doctor immediately," said MOH.
The doctor may ask the person to go for a chest x-ray or they may be referred to a specialist for further clinical and lab investigations.
Mr Ong said that the screening exercise in Bukit Merah was a precautionary measure to identify cases among those who live and work in the area.
People who frequently visit – or have spent more than 12 hours per month between November 2021 and January 2024 – the market can also voluntarily go for screening.
This is to ensure that those who are infected can be treated to further reduce the risk of transmission.
"The vast majority of us don't fall into this category so please go ahead and enjoy the good food at ABC. Let's support our hawkers," said Mr Ong.
What Are The Stages Of Tuberculosis?
Many people with tuberculosis stay in the latent infection stage, but some develop the active disease. Both stages are treatable.
Tuberculosis (TB) is a bacterial infection that usually affects the lungs but can also attack other parts of the body. However, it can be fatal without correct treatment.
After the primary infection, most people enter an inactive infection stage where they experience no symptoms and cannot spread the disease. Others develop TB disease, or an active infection, which causes symptoms and can spread. Medication regimens can treat TB at both stages, although drug-resistant TB requires special approaches.
This article discusses the primary, latent, and active stages of TB and describes how the disease generally progresses.
The bacterium Mycobacterium tuberculosis causes the TB infection.
Someone can contract TB when they breathe in the bacterium after a person with an active infection coughs, sneezes, sings, or speaks. However, according to the American Lung Association, TB does not spread easily.
The primary infection usually occurs in the middle part of the lungs. From there, the infection typically enters a latent, or inactive, stage but can sometimes quickly develop into active TB disease. Treatments are available for both stages.
Those with a higher risk of contracting a TB infection include anyone near someone with TB, such as:
A latent TB infection occurs when someone gets a TB infection, but their immune system makes it inactive and stops the bacterium from growing. People with a latent infection do not feel ill and cannot spread TB to others.
Many individuals with latent TB infection never develop TB disease, and the TB bacterium remains inactive for a lifetime. In others, especially those with weakened immune systems, the bacterium become active, multiply, and cause disease.
In this stage, blood or skin tests can indicate whether someone has TB.
While latent TB does not spread or cause symptoms, treatment is important for making sure it does not become active.
Treatment involves either 3–4 months or 6–9 months of one or more of the following medications:
Read more about latency TB.
An active TB infection, or TB disease, occurs when the TB bacterium grows and attacks the lungs or other parts of the body. This happens because the immune system cannot fight the bacterium effectively. TB disease causes symptoms and can spread to others.
For some people, an active TB infection can come from a latent infection that progresses. In other cases, TB disease can occur soon after exposure to the bacterium.
An active TB infection usually makes someone feel sick and can be fatal. Symptoms can include:
Treatment involves using one or multiple medications across several months. Some first-line medications include:
In some cases, TB disease may be resistant to drugs or unresponsive to one or multiple medications. Treating drug-resistant TB disease can be complicated. It requires specialized approaches from a healthcare team, which take much longer to complete.
TB progresses differently for people. The primary infection usually becomes a latent TB infection first. In many cases, the latent infection never progresses, but for some people, TB may be latent for weeks, months, or years before becoming active.
An active TB infection occurs when someone's immune system is not strong enough to fight the bacterium. Those at a higher risk of developing TB disease include anyone with weakened immune systems, including:
Tuberculosis is a disease that spreads when someone inhales the Mycobacterium tuberculosis bacterium from someone with an active infection.
The primary infection usually occurs in the center of the lungs. From there, the infection can enter a latent stage, or in fewer cases, become an active infection.
Latent TB causes no symptoms and cannot spread. Treatment involves a medication regimen. Some people will have a latent infection for weeks or years before it progresses into an active infection, but many will only stay in the latent stage.
An active TB infection, or TB disease, occurs when someone's immune system cannot fight the bacterium effectively, and the bacterium attacks the body. TB disease can spread to others and can be fatal without treatment. Treatment involves a medication regimen over several months. In some cases, TB disease can be resistant to drugs and requires special treatment approaches.
TB can progress in different ways. While TB usually enters and stays in the latent infection stage, some people will eventually develop an active infection when their immune system weakens. Occasionally, some people develop an active TB infection right away.
Those with weakened immune systems face a higher risk of developing TB disease. This includes babies and young people, those with HIV, AIDS, or chronic conditions, people receiving chemotherapy or treatments for autoimmune disorders, and organ transplant recipients. Proper treatment can cure a TB infection.
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