To produce an illness, tuberculosis bacteria must sneak through the lungs' well-patrolled upper airways and head for deeper regions where fewer microbiocidal cells are policing. (Credit: iStockphoto)

How hitchhiking TB sneaks deep into lungs

To intrude into the deeper regions of the lungs, the bacteria that cause tuberculosis appear to mask their identity and hitch a ride on white blood cells.

The findings suggest an explanation for the longstanding observation that tuberculosis infections begin in the comparatively sterile lower lungs. In the upper respiratory tract, resident microbes and inhaled microbes of a variety of species signal their presence.

These tip-offs alert and attract many infection-fighting cells to the upper airways. The presence of other microbes in the upper airway may thereby help to keep TB infections at bay by creating a hostile environment.

Their presence may explain why TB is less contagious than diseases caused by several other respiratory pathogens. To produce an illness, TB bacteria must sneak through this well-patrolled area and head for parts of the lungs where fewer microbiocidal cells are policing.

Like most other bacteria, TB pathogens have telltale molecular patterns that should activate an immune response.

However, TB pathogens have evolved mechanisms to circumvent tripping the alarm. Almost like home intruders wearing a stocking over their faces, the TB pathogens produce particular types of fatty substances, or lipids, on their cell surfaces.

Recruitment cells

These lipids, abbreviated as PDIM, are already known to be associated with bacterial virulence. For the new study, published in the journal Nature, researchers showed that PDIM lipids function by masking the underlying molecular patterns that would reveal their dangerous nature to infection-fighting cells.

At the same time, a related lipid—called PGL—on the bacterium’s cell surface promotes the recruitment of clean-up cells that engulf but don’t kill the TB pathogens. Instead, they take them across the lung lining, deep into the lung tissue where the bacteria can establish an infection.

The TB pathogens then use the other lipid molecule, PGL, to co-opt a host chemical pathway that triggers the recruitment of the permissive macrophages.

Lalita Ramakrishan, professor of microbiology, medicine and immunology at the University of Washington is the lead author on the new study that expands on her earlier work which helped describe the strategies by which TB pathogens manipulate host pathways for their own purposes after they enter certain host cells.

Manipulating pathogens

These include the secretion of proteins that expand the niche for TB by recruiting macrophages to the early lung tubercles characteristic of the disease. The present study describes earlier stages in infection, when the pathogens first come in contact with their potential host at the surface of the lung lining.

“The current study suggests the manner in which the TB pathogens manipulate recruitment of the first responding macrophages to gain access to their preferred niche,” the researchers note.

“The choreographed entry involves two related TB cell lipids acting in concert to avoid one host pathway while inducing another,” they write.

The findings link the previously known, absolutely essential virulence factor on the surface of TB cells, PDIM, to the evasion of immune cell detection. On the other hand, PGL is not required on the surface of TB cells for them to infect the body.

Globally, a lot of samples of TB taken from infected patients do not have PGL, Ramakrishnan says.

“However, the importance of PGL in mediating TB virulence or transmission is underscored by its presence in many of the W-Beijing strains” of TB which are starting to appear in more patient samples, and which have predominated in outbreaks in North America.

The findings suggest how PGL may be important in increasing TB’s infectivity, the researchers say.

“The presence of PGL in ancestral strains of TB suggest it played an integral role in the evolution of TB infectivity. TB is an ancient disease and the enhanced infectivity conferred by PGL may have been essential for most of its history before human crowding, with its increased opportunity for transmission, made it dispensable.”

The study findings, and previous work on TB, might also explain why smaller droplets of TB are more infectious than larger ones. Only the smaller droplets can make their way down into the lower airways. All it takes is 3 or fewer TB mycobacteria with PGL-producing ability to enter the lower lungs and start an infection.

The research was supported by training and research grants from the National Science Foundation, American Lung Association, National Institutes of Health, and American Cancer Society.

Source: University of Washington

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