Outbreaks of whooping cough (pertussis) are unusual in elementary schools because young children in the U.S. are thought to have high rates of immunity from their vaccinations with the DTP (diphtheria, tetanus, pertussis) vaccine. So it came as a surprise to many when 17% of the elementary school population in Iowa City, Iowa, came down with pertussis. As might be expected, children who had not received their complete series of DTP shots were at much greater risk for getting pertussis, but even some children whose shots were up to date became ill (the vaccine is not 100% effective in all children).

There were other factors that led to this outbreak; for example, the elementary school children were exposed to pertussis from many others in the community and there were delays in identifying and treating (with antibiotics) those who developed pertussis. The authors point out that this epidemic could have been limited if officials had recognized that an outbreak of pertussis could indeed occur among children in elementary schools.

Whooping cough probably occurs more often than we think, and it should be suspected in a child who has an illness with a cough that lasts more than 10 days and particularly one that occurs in spasms and is accompanied by a "whoop" and/or vomiting at the end of the cough. While cases may continue to occur, making sure that children complete their full series of DTP shots is the best way to prevent individual children from getting the disease and spreading it to others.

The whooping cough bacterium, Bordetella pertussis, appears to be a master tactician. According to new findings, the pathogen, after invading the respiratory tract, induces some cells to kill certain of their neighbors with toxic gas. The result likely contributes to the intense gasping cough that not only gives the disease its name but also spreads the bacterium to other victims.

Physicians and researchers have known for decades that the pathogen destroys the ciliated cells in the epithelial lining of the respiratory tract. The hairlike cilia sweep away mucus, but when they die, coughing provides the only way to clear the airway. Exactly how B. pertussis kills these cells has been a mystery, however. Now, results described in the July issue of Cellular Microbiology by microbiologist William Goldman of Washington University School of Medicine in St. Louis and Tod Flak, Goldman's former graduate student, may have revealed the microbe's diabolical modus operandi.

Using a tissue culture system in which the microbe causes the same type of damage as in humans, the researchers found that two toxic substances produced by B. pertussis work together to kill the ciliated cells. One of those molecules, tracheal cytotoxin (TCT), has long been a suspect, but the other, endotoxin, is somewhat of a surprise. It is usually known for causing widespread immune system stimulation, which can lead to shock. "This is different," says Drusilla Burns, a microbiologist at the Food and Drug Administration's Center for Biologics Evaluation and Research in Bethesda, Maryland. "Endotoxin is not normally associated with specific pathology."

Even more surprising, the two toxins do not launch a direct attack on the ciliated cells. Instead, they work together to incite neighboring cells to produce a noxious molecule, nitric oxide (NO), which kills the ciliated cells by an as yet unknown mechanism. "This work might explain some of the pathology of pertussis," says Ferric Fang, a molecular biologist at the University of Colorado Health Sciences Center in Denver. And, he adds, it might also "provide strategies for intervention."

Such strategies are badly needed. In developed countries, vaccination largely holds whooping cough in check, but the incidence of the disease in adults appears to be increasing; in nondeveloped countries, B. pertussis still kills from 300,000 to 500,000 people every year. And although antibiotics eliminate the bacteria, by the time the characteristic cough develops, the microbes are often already gone, having set a cascade of destructive events in motion. Drugs that inhibit NO production might allow the tracheal epithelium to recover more quickly.

Earlier work by Goldman's group had shown that NO is involved in the attack on the ciliated cells and suggested that TCT acts as a trigger. But when the team tested whether TCT causes epithelial cells in cultured hamster tracheal tissue to activate production of an enzyme called inducible NO synthase (iNOS)--which makes NO--they got what Goldman describes as a "surprise result." TCT had no effect at all on iNOS production in epithelial cells. The researchers concluded that something in addition to TCT may be required to coerce the epithelium to produce NO.

Goldman and Flak suspected that this co-culprit might be endotoxin, because the team had previously uncovered another case of TCT-endotoxin cooperation, in preventing the growth of a single type of respiratory epithelial cell in culture. It prompted the researchers to add endotoxin along with TCT to their culture system. The combination worked.

Because not all the cells in the tracheal epithelium are ciliated, the team wondered whether the ciliated cells themselves or their neighbors produce the NO. As Goldman recalls asking, "Are the ciliated cells committing suicide, or are they being assisted by other cells in the epithelium?" Further studies provided an answer: TCT and endotoxin induce the nonciliated, mucus-secreting cells to produce the toxic gas.

Goldman notes that both TCT and endotoxin are made by many other bacteria in addition to B. pertussis, although most of the other microbes recycle TCT rather than release it. "You've got almost an ironic situation," he says, "where you have this extraordinary specificity of pathology and of nitric oxide production" spurred by two extremely common molecules. Endotoxin and TCT might collaborate to kill other ciliated cells in the body as well. Work by Raoul Rosenthal's group at Indiana University School of Medicine in Indianapolis and collaborators suggests that Neisseria gonorrhoeae destroys ciliated cells of the reproductive tract using these same two molecules.

The researchers do not yet understand how NO kills the ciliated cells without harming the secretory cells that produce it. But, as Goldman points out, the strategy might be "exactly what [B. pertussis] needs," because it allows mucus to accumulate while eliminating the normal way for expelling it. The result is a hacking cough--an ideal way to transfer the bacteria from one person to another.

Many questions remain about how both NO and the TCT-endotoxin partners produce their effects. Researchers also need to find out whether B. pertussis operates the same way in humans. This might be addressed, says Erik Hewlett, a B. pertussis expert at the University of Virginia, Charlottesville, by seeing whether the iNOS expression patterns in trachea specimens from children who died from whooping cough mimic those seen in Goldman's experiments. If so, it might indicate that B. pertussis is putting its subversive tactics to work in environments other than the culture dish.

Last updated Jan 4/07