Tuberculosis bacteria rely on a family of genes that help them survive the challenging journey from one person’s lungs to another person’s during coughing, sneezing or talking, according to researchers from Weill Cornell Medicine and the Massachusetts Institute of Technology. The findings provide new targets for tuberculosis therapies that could simultaneously treat infection and prevent the spread of bacteria.
Until now, very little was known about this transmission process—when bacteria-laden droplets are expelled into the air, where they must withstand changes in temperature, oxygen levels, humidity and chemical composition. The study, published March 7 in PNAS, revealed for the first time that tuberculosis bacteria don’t passively endure these transitions but actively engage hundreds of genes to adapt and survive.
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Many identified genes were previously considered unimportant since they appear not to play a role in disease progression when a person is infected. Instead, the new study suggests that these genes are essential for successful transmission from person to person.
Curbing the spread
“If a drug were to target these same genes, it could effectively treat an individual, and even before that person is cured, keep the infection from spreading to others,” said co-senior author Dr. Carl Nathan, chair of the Department of Microbiology and Immunology and R.A. Rees Pritchett Professor of Microbiology at Weill Cornell Medicine.
So far, much of the research on tuberculosis centers on its pathophysiology—the mechanisms the bacteria use to infect a host — as well as ways to diagnose and treat the disease. “There is a blind spot that we have toward airborne transmission, in terms of how a pathogen can survive these sudden changes as it circulates in the air,” said co-senior author Dr. Lydia Bourouiba, head of the Fluid Dynamics of Disease Transmission Laboratory, part of the Fluids and Health Network, and professor in Civil and Environmental and Mechanical Engineering departments and the Institute for Medical Engineering and Science at MIT. “Now we have a sense, through these genes, of the tools tuberculosis uses to protect itself.”
Bacterial transmission
To understand bacterial transmission more accurately, Dr. Nathan, a leader in the field of tuberculosis and genes the bacteria rely on throughout their life cycle, teamed up with Dr. Bourouiba, an expert in the biophysics of how droplets can spread particles and pathogens.
Myobacterium tuberculosis causes a respiratory disease that leads to over a million deaths worldwide each year. The bacteria are extremely contagious and spread through microdroplets released into the air from a person with the infection. The droplets can be inhaled by nearby individuals.
Most previous experimental work on the tuberculosis has been based on bacteria grown in a laboratory solution. But the team found that this fluid is very different in chemical composition from the actual microdoplets expelled from patients with tuberculosis. They also eliminated sputum, a viscous fluid that a patient spits out, often for a diagnostic test, because it is too thick and sticky to break into inhalable droplets.
More realistic fluid
The researchers developed a more realistic fluid based on analyses of infected lung tissues from patients. It is similar in composition, viscosity, surface tension and droplet size to what a patient would exhale into the air.
Next, they used this fluid to deposit different mixtures onto plates in tiny individual droplets and measured in detail how they evaporate. To mimic what would happen to droplets in flight, the plates were put in an extremely dry chamber to accelerate evaporation. Each droplet contained a different strain of bacteria with a specific gene knocked down to see which genes impacted the bacteria’s survival as the droplets evaporated.
Out of 4,000 genes tested, they discovered a family of several hundred that seem to become important only when the tuberculosis bacteria face airborne conditions. The genes help them adapt to the realistic fluid, the atmospheric changes of moving from deep in the lung into air and the stress of evaporating.
Clues to damage control
The researchers found that many of the genes the bacteria depend on for survival are involved in repairing damage to oxidized proteins, such as proteins exposed to air, or destroying damaged proteins beyond repair. Another subset of genes help the bacteria resist desiccation, drying out in the microdroplets.
“What we turned up was a candidate list that’s very long,” Dr. Nathan said. “There are hundreds of genes, some more prominently implicated than others, that may be critically involved in helping tuberculosis survive its transmission phase.”
Completing the model
The researchers noted that the experiments are not a complete model of the bacteria’s airborne transmission. Going forward, the researchers have designed and started experiments that allow them to study evaporation while the droplets are in flight. This more accurate platform will help confirm whether the newly discovered genes shield M. tuberculosis during transmission, potentially leading the way to a treatment that blocks these defenses.
“The idea of waiting to identify someone with tuberculosis, then treating and curing them, is a totally inefficient way to stop the pandemic,” Dr. Nathan said. “Most people who exhale tuberculosis bacteria do not yet have a diagnosis. So, we have to interrupt its transmission. And how do you do that, if you don’t know anything about the process itself? We have some ideas now.”
This article is adapted from an original story that appears on the MIT news site.
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