Immunology

TB-causing bacteria appear to mask their identity to avoid recognition by infection-killing cells in the upper airways. The bacteria call up more permissive white blood cells in the deeper regions of the lungs and hitch a ride inside them to get into the host's body.

Details on this finding are reported Dec. 16 in the advanced online edition of the journal Nature. The research was a collaboration between the University of Washington and the Seattle Biomedical Research Institute.

Dr. Lalita Ramakrishan, who studies how TB evades the body's immune system and manipulates the body's defenses for its own ends, is the senior author. She is a UW professor of microbiology, medicine and immunology. The lead author is C.J. Cambier of the UW Department of Immunology.

Ramakrishnan noted that the recent study also suggests 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 a less contagious disease than those caused by several other respiratory pathogens.

To cause disease, TB bacteria must sneak through this well-patrolled area and head for parts of the lungs where fewer microbiocidal cells are policing.

Almost like intruders wearing a stocking over their faces to keep surveillance cameras from clearly recording their features, the TB pathogens produce particular types of fatty substances, or lipids, on their cell surfaces.

These lipids, abbreviated as PDIM, are already known to be associated with bacterial virulence. The researchers showed that PDIM lipids function by masking the underlying molecular patterns that would reveal their dangerous nature to macrophages, a first-line defense of infection-fighting cells.

At the same time, a related lipid - called PGL - on the bacterium's cell surface promotes the recruitment of cells described as permissive macrophages. These clean-up cells 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.

According to the researchers on this study, these mechanisms appear to allow certain TB pathogens to avoid detection by the pattern recognition receptors that enable some infection-fighting cells to spot a variety of different disease microbes through the pathogen-associated molecular patterns on or near their cell surface.

Like most other bacteria, TB pathogens have many of these telltale molecular patterns that should activate an immune response. However, TB pathogens have evolved mechanisms to circumvent tripping the alarm, in this case by physically masking the otherwise detectable pattern. This cover-up allows them to infect the airway initially by avoiding the infection-fighting cell populations that are detrimental to their survival, the researchers noted.

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.

The present study expands on earlier work in the Ramakrishan and collaborative labs, which helped describe the strategies by which TB pathogens manipulate host pathways for their own purposes after they enter certain host cells.

These include the secretion of proteins that help 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 lining of the lung.