Pneumonia in Immunocompromised Patients: Overview, Causes of Pneumonia, HIV/AIDS

New Study Reveals How TB Bacteria May Survive In Human Tissues

Carbon monoxide is an infamous and silent killer that can cause death in minutes. But while it is deadly for us, some microorganisms actually thrive on it, by using this gas as an energy source.

Associate Professor Chris Greening and his team of microbiologists from the School of Biological Sciences, Monash University, have discovered that some pathogens depend on carbon monoxide to survive when other nutrients are not available.

The research focused on mycobacteria, a bacterial group that causes killer diseases such as tuberculosis (TB), leprosy, and Buruli ulcer. During infection, these microbes are in a hostile environment with very few nutrients to go around, meaning that anything they can do to get extra energy can be hugely advantageous.

"When microbial cells are starved of their preferred energy sources, one way they subsist is by scavenging gases such as carbon monoxide," said Monash PhD student Paul Cordero, the co-lead author of the study.

"They breakdown this gas into its fundamental components, which provide the cells just enough energy to persist."

The researchers showed that an enzyme called carbon monoxide dehydrogenase is what allows mycobacteria to obtain energy from this gas. While the energy gained is not enough to allow for growth, the researchers found that carbon monoxide consumption allowed mycobacteria to survive for longer periods of time.

The study, which was supported by the Australian Research Council (ARC) and National Health and Medical Research Council (NHMRC), was published today in the ISME Journal.

The group's findings suggest that Mycobacterium tuberculosis might be able to survive inside the human host by using carbon monoxide. Present in humans since ancient times, TB remains a major global health burden. This bacterium infects one quarter of the world's population and is now the leading cause of death from infectious disease worldwide.

"It has been known for years that Mycobacterium tuberculosis can use carbon monoxide, but nobody knew why," said fellow study co-first author, PhD candidate Katie Bayly.

"Based on these findings, we predict that it uses this gas to its advantage to persist inside human lungs," she said.

"Our immune cells actually make small amounts of carbon monoxide, which the bacterium may be able to use as an energy supply while dormant."

Dormancy allows Mycobacterium tuberculosis to stay alive inside patients for years. This dormant infection usually has no symptoms, but can advance into full-blown TB, for example when people become immuno-compromised.

This new discovery on the survival mechanism of mycobacteria could pave the way for new strategies to better fight communicable diseases such as tuberculosis.

Peat-bog Fungi Produce Substances That Kill Tuberculosis-causing Bacteria

An analysis of fungi collected from peat bogs has identified several species that produce substances toxic to the bacterium that causes the human disease tuberculosis. The findings suggest that one promising direction for development of better treatments might be to target biological processes in the bacterium that help maintain levels of compounds known as thiols. Neha Malhotra of the National Institutes of Health, U.S., and colleagues present these findings December 3 in the open-access journal PLOS Biology.

Every year, millions of people around the world fall ill from tuberculosis and more than 1 million people die, despite the disease being preventable and curable. However, treatment requires taking daily antibiotics for months, which can pose significant challenges, so new treatments that shorten the treatment period are urgently needed.

To explore potential targets for treatment-shortening strategies, Malhotra and colleagues turned to sphagnum peat bogs. These freshwater wetlands harbor abundant species of bacteria in the Mycobacterium genus -- the same genus as the tuberculosis-causing bacterium Mycobacterium tuberculosis. In these bogs, fungi compete with mycobacteria to grow within a decomposing "gray layer" that, similarly to lesions found in the lungs of tuberculosis patients, is acidic, nutrient-poor, and oxygen-poor.

In the lab, the researchers grew Mycobacterium tuberculosis alongside each of about 1,500 species of fungi collected from the gray layer of several peat bogs in the northeastern U.S. They identified five fungi that had toxic effects against the bacterium. Further laboratory experiments narrowed these effects down to three different substances produced by the different fungi: patulin, citrinin, and nidulalin A.

Each of the three compounds appears to exert its toxic effects on the tuberculosis bacterium by severely disrupting cellular levels of a class of compounds known as thiols -- several of which play essential roles in the molecular processes that help keep bacterial cells alive and functional.

The researchers note that these three compounds themselves are unlikely to be good drug candidates. However, especially given the similarity between the peat-bog environment and tuberculosis lesions, the findings provide support for a particular strategy for development of treatment-shortening drugs: targeting the biological processes that maintain thiol levels in the tuberculosis bacterium.

The authors add, "Pathogenic mycobacteria, like those causing the human diseases leprosy and tuberculosis, are found in abundance in sphagnum peat bogs where the acidic, hypoxic and nutrient-poor environment gives rise to fierce microbial competition. We isolated fungi from such bogs and screened for those that competed directly with mycobacteria by co-culture and discovered that these fungi all target the same physiological process in mycobacteria using several chemically distinct mechanisms."

Is There A Vaccine For Tuberculosis (TB)?

There's a vaccine available for tuberculosis. However, it's not commonly given in the United States. One reason why is that tuberculosis is no longer as common in the United States as it once was.

Tuberculosis (TB) is an infection caused by the bacteria Mycobacterium tuberculosis. It most often affects the lungs. It's contagious, meaning that it can be transmitted from person to person.

This article will go into more detail about the TB vaccine, who needs it, and what to know about its safety and effectiveness.

The TB vaccine is called Bacillus Calmette-Guérin (BCG). It's made from a weakened form of the bacterium Mycobacterium bovis, which causes a TB-like illness in cattle.

Exposure to BCG can help your body generate an immune response against M. Tuberculosis, which causes TB in humans.

the low risk of contracting TB in the United States

variations in the effectiveness of BCG to prevent TB in adults

the possibility of BCG interfering with tuberculin skin tests, which are used to detect TB infections

After a consultation with a doctor experienced in TB, BCG may be recommended for:

children who do not have TB but are often exposed to TB, or cannot be separated from an adult who:

hasn't been treated for TB, or

healthcare professionals who are working in areas where there's a high percentage of people with TB or ongoing TB transmission, especially of drug-resistant strains

In countries where TB is more common, BCG is still widely used. According to the World Health Organization (WHO), BCG is given to more than 80% of all newborns and infants in countries where it's a part of a national immunization program.

In countries where TB is common, BCG is mainly used to protect against two types of severe TB in infants and young children: TB meningitis and disseminated TB.

However, this protection doesn't last forever. A 2022 study found that BCG vaccination at birth only provided significant protection against any type of TB to children under 5 years old. It was not effective for older children and adults.

A 2016 study looked into the effectiveness of BCG in protecting against pulmonary (lung) TB. Researchers found that vaccine effectiveness against this specific type of TB became statistically insignificant 20 years after vaccination.

As you may have noticed, the vaccine effectiveness estimates for BCG in adults are highly variable. According to one 2021 review of research, studies have found that the effectiveness of BCG in adults has ranged from zero to 80%.

While more research is needed to help explain this large variation, scientists have some ideas about why this happens, such as:

exposure to other Mycobacterium species in the environment masking or blocking an immune response to BCG

immune system or genetic variations between people

differences between the strains of BCG used to make the vaccine

Like many vaccines, BCG can cause side effects. The most common are skin changes at the vaccination site.

Many people who receive the BCG vaccine develop a pustule or blister at the vaccination site. This typically appears 10 to 14 days after vaccination. It can be present for 4 to 6 weeks before it goes away.

Other potential side effects of the BCG vaccine include:

There are also some more serious, although rare, side effects of the BCG vaccine, including:

Is there anyone who shouldn't receive BCG?

Some people should not receive BCG, such as:

People with a weakened immune system: BCG is a live vaccine and can cause potentially serious problems for people with a weakened immune system. You may have a weakened immune system if you:

Pregnant people: According to the BCG package insert, although no harmful effects to a developing fetus have been seen, reproduction studies haven't been done. As such, BCG isn't currently recommended for pregnant people.

Allergies: If you have a known allergy to any component of the BCG vaccine, it's not recommended that you get it.

The rate of TB in the United States is low. According to the CDC, a total of 7,174 cases of TB were reported in 2020.

While TB isn't a large public health threat in the United States, that's not the case for many other parts of the world.

According to the WHO, a total of 10 million people across the globe fell ill with TB in 2020. There were also 1.5 million deaths from TB worldwide in 2020.

The WHO also notes that 30 countries with high TB levels account for most new TB cases. Countries that are especially impacted include:

India

China

Indonesia

the Philippines

Pakistan

Nigeria

Bangladesh

South Africa

Researchers are working to develop a newer, more effective TB vaccine. However, the lack of understanding about why exactly BCG is so variable in effectiveness makes designing a new vaccine quite challenging.

A 2022 review notes that at least 14 new vaccines for TB are in clinical development. These use different types of vaccine technology, including:

live, which uses a weakened form of a germ

subunit, which uses only a piece of a germ

viral vector, which uses a modified virus to deliver the vaccine contents

The success of the mRNA vaccines for COVID-19 has also sparked interest in using the same technology to develop a TB vaccine. In fact, a 2022 paper has already proposed a potential mRNA construct to begin testing in laboratory studies.

BCG is currently the only vaccine for TB. Because TB isn't common in the United States, it's not typically recommended for use in the country. However, it's still a widely used vaccine in many other parts of the world.

BCG is mainly given to infants and young children to help protect them from very severe forms of TB. When used in this context, it's very effective. However, BCG isn't very protective in older children, adolescents, and adults.

This variation in effectiveness is driving a search for a newer, more effective TB vaccine. Researchers are exploring many technologies to achieve this, including mRNA vaccine technology.

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