More Americans came down with whooping cough in 1993 thanin any year since 1967. According to the Centers for DiseaseControl in Atlanta, 5,457 cases of pertussis were reported inthe first 11 months of the year. But that statistic "represented10 to 20 percent at most of the total number that actuallyoccurred," internist Eric Hewlett, who specializes in Bordatellapertussis toxins at the University of Virginia, told BioWorld.
Hewlett was discussing a paper in this week's Proceedings ofthe National Academy of Sciences (PNAS) titled "Epithelialautotoxicity of nitric oxide: Role in the respiratorycytopathology of pertussis." Its principal author is molecularmicrobiologist William Goldman of Washington University in St.Louis.
Whooping cough is a localized infection of the trachea, denudedof its hair-like cilia, which normally beat in rhythm like theoars of a racing shell crew. The cilia sweep mucus, bacteria andinflammatory debris out of the airway. When the B. pertussisbacterium interrupts this cleansing action, staccato coughing,which attempts in vain to take over the ciliary function, isfollowed by screeching spasmodic whoops as the body tries toregain breath.
"There is no treatment for pertussis," Goldman told BioWorld."That's something that's lost on a lot of people right now. Oncesomeone is diagnosed with whooping cough, there is simply noway to alter the clinical course of the disease." Antibiotics, heexplained, can kill off the germs and thereby limit the spreadof the infection, but the violent coughing episodes maycontinue for weeks.
"There's kind of a myth that only kids catch whooping cough,"he said. "In fact, adults do get it in large numbers, in not nearlyas violent a form.
"A lot of the focus in pertussis research has always been onvaccines," Goldman continued. "There's really almost noattention to therapeutic intervention." His research aims PP or atleast hopes PP to correct this incurability of whooping cough.
"Adults don't whoop," Hewlett told BioWorld, "so most of thetime, when adults have pertussis they don't know it and theirphysicians don't know it. They're not trained to think ofpertussis as an adult illness.
"In consequence, adults are probably the major mechanism bywhich whooping cough is spread in our relatively well-immunized population," Goldman added.
That vaccinated population consists entirely of infants andyoungsters in the pre-teen years. Teen-agers and adults can'tget booster shots -- as they do for tetanus and diphtheria --because of possible side effects.
Goldman and his co-workers have scouted out a pathwaylinking B. pertussis to its wounded tracheal target and testedinhibitors that can block that pathogenic path.
When the bacterium enters the airway, it releases a specifictracheal cytotoxin (TCT) that wreaks the ciliary damage andprovokes the cough. Goldman found in vitro that TCT inhibitedDNA synthesis in hamster epithelial cells. It also triggersproduction in the cells of interleukin-1, which he suspects ofacting as a relay signaler along the pathway to TCT toxicity. Theultimate culprit, as he reported in PNAS, is nitric oxide (NO),itself generated by IL-1.
NO's deleterious effects in climaxing the cilia-slaying work ofTCT, Goldman's group discovered, could be attenuated byinhibitors of the enzyme, NO synthase, which produces thegaseous free radical.
Now the Washington University team is about to move from invitro to in vivo, using rats as their animal model "becauseprimates are so incredibly expensive," Goldman lamented.Eventually, he hopes to try his NO inhibitors in humans,beginning with safety studies. His current inhibitor of choice isamino-guanidine, an analog of arginine, the amino acid thatgenerates NO directly in the presence of oxygen.
Goldman said he regards such potential therapy as still prettyspeculative. He imagines that the inhibitor might be deliveredto the injured trachea by inhalation. Meanwhile, he has justreceived notification from the U.S. Patent Office of an allowancefor his pending patent, "Method for Treatment of Pertussis."
There is evidence that the TCT-IL-1-NO pathway leads to otherdisease states besides pertussis, such as diabetes andgonorrhea.
Microbiologist Stanley Falkow of Stanford University (and aconsultant for Protein Design Labs Inc.) is a dean of infectiousdisease research in general and pertussis in particular."Goldman's research on pertussis pathogenesis is very nice," hetold BioWorld. "He had a truly intractable toxin to study andmade an unexpected finding, which says a whole lot about howpertussis really works," Falkow added.
"Everybody thought it was going to be 'the big-gun toxins,' andit turned out not to be," he continued. "The effect that Goldmansees is really the host doing as much damage as themicroorganism."
Knowing the mechanism, Falkow suggested, "if in principle youcan intervene with at least the initial coughing and localtracheal damage, you probably will alleviate a lot ofsymptoms." Hewlett hailed Goldman's work as "identifying awhole new area in the pathophysiology of whooping cough, andproviding a new perspective on the disease and what we cando with it and about it."
But he added a note of caution: "I think we haven't reallygotten to the point yet with NO to know about interruptingpathways and whether agents that might alter the generationof that mediator could alter the sequence of events in thedisease process. But it certainly gives us some targets to thinkabout (in terms of) therapeutic intervention."
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.