Toxin discovery could lead to therapy for asthma, other conditions


The mycoplasmas are the smallest of all bacteria, almost inscrutable in their ways of operating. Microbe hunters seek the answers to many questions about them. What are mycoplasmas doing to our bodies? How do they persist in our tissues? Can we develop vaccines against them? For more than three decades, Joel B. Baseman, Ph.D., professor and chair of the department of microbiology and immunology at the Health Science Center, has looked at countless microscope slides and bacterial cultures to answer the questions.

This spring, Dr. Baseman, senior author, and his protégé, T.R. Kannan, Ph.D., lead author, reported what Dr. Baseman says is the most exciting discovery ever to come out of his laboratory: identification of the first toxin produced by a disease-causing mycoplasma. “This discovery is arguably the most important in the field since the discovery of the classical toxins of diphtheria and pertussis decades ago,” Dr. Baseman said.

The toxin is produced by the respiratory pathogen Mycoplasma pneumoniae. “This mycoplasma species is incredibly common, and is spread by sneezing, coughing, talking and touching hands to nose,” said Dr. Kannan, instructor of microbiology and immunology.

Half of all people are infected with it. By persisting in the lungs and flaring up from time to time, it is thought to be responsible for millions of cases of child and adult asthma. “Even cases of the sniffles that we call colds may actually be manifestations of infection with this bacterium,”
Dr. Kannan said. “Studies of its mechanisms of operation could improve diagnosis and treatment of a wide range of human diseases, including acute and chronic airway diseases, but also diseases affecting other parts of the body, such as the heart, central nervous system, skin, joints, kidney and liver, that appear to be targets of M. pneumoniae and its toxin, as well.”

The historic paper was published in Proceedings of the National Academy of Sciences, and was so well received by the world’s scientists that it was included in the Research Highlights section of Nature. Harvard Medical School’s R. John Collier, Ph.D., one of the leading toxin experts in the world, highlighted the paper as a must read for the Faculty of 1000 Biology, composed of elite scientists around the world.

M. pneumoniae accomplishes its ill effects by escaping drug therapy, by having the unique ability to persist in its host for long periods, and by producing the newly discovered toxin, the researchers said. “It can go deep inside cells to escape therapy, becoming quiet and dormant to escape detection,” Dr. Kannan said. “This bacterium is so small that it cannot live outside the host, so it persists in order to maintain its relationship with the host.”

It is the first microbial toxin found to date that carries out dual cell-disrupting functions, called ribosylation and vacuolation, rather than one, Dr. Baseman said.

Ribosylation involves enzymatically cutting an essential cell molecule called NAD into two pieces. One of the pieces is attached to specific proteins by the toxin, resulting in protein dysfunction or inactivation and ultimately to cell death. Vacuolation is disruption of cell membrane structure and integrity, also leading to cell death.

Infections caused by the diphtheria and pertussis bacteria initiate ribosylation through the action of their respective toxins. Helicobacter toxin, which causes stomach and intestinal ulcers, initiates vacuolation. ButM. pneumoniae is more versatile than that.

M. pneumoniae is involved in disease paths throughout the body,” Dr. Baseman said. “We have looked for a toxin that can explain it all. Now we’ve got it. We have uncovered a 50-year-old mystery in bacterial pathogenesis.”

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