Whooping cough persistence traced to key toxin

December 19, 2005

A key toxin associated with whooping cough helps the germs resist the human immune system and infect vaccinated populations. Discovery of this resistance mechanism could lead to potential new treatments for the disease, according to researchers at Penn State.

Whooping cough, or pertussis, is a highly contagious respiratory disease caused by the germ Bordetella pertussis. Whooping cough can occur at any age but is generally considered a childhood disease marked by severe spells of coughing and a characteristic whooping sound while inhaling. Though the widespread use of vaccines has helped reduce disease drastically, recent surveys reveal that the disease is increasingly being diagnosed in a large number of vaccinated adults, posing a serious health risk to unvaccinated children and infants.

"One of the great mysteries of pertussis is how it persists within populations despite high vaccination rates," says Eric Harvill, assistant professor of microbiology and infectious disease in the College of Agricultural Sciences.

Tests on infected mice show that serum antibodies are usually able to clear the germ from the lungs by recruiting large numbers of neutrophils, a type of white blood cells that kill germ cells, by surrounding and absorbing them. But while the technique is successful against B. bronchiseptica - a closely related germ that causes kennel cough in dogs - within a day, it takes longer to clear B. pertussis.

Antibodies produced by the vaccines are effective only seven days after they are administered, says Harvill, who is part of Penn State's Center for Infectious Disease Dynamics. "The bacterium appears to have a mechanism to resist the effects of antibodies during the first week of infection," he adds.

Harvill's group theorized that one or more genes specific to pertussis were somehow delaying the effectiveness of the vaccine. They looked specifically at the genes encoding Pertussis toxin, PTx, and hypothesized that this toxin somehow interfered with antibody-mediated bacterial clearance.

To test their theory that those pertussis germs without the toxin would be more susceptible to antibodies, Harvill and his colleagues inoculated one set of mice with genetically engineered B. pertussis that lacked the toxin, and another set with the naturally occurring strain. Both strains grew well in these mice, but when antibodies that recognize B. pertussis were given to each group they rapidly eliminated only the strain lacking the toxin.

Further tests suggest that the toxin acts directly on white blood cells to temporarily prevent their movement across tissues that line various organs.

"This is a particular strategy by B. pertussis," says Harvill, whose findings are published in the current (December) issue of Journal of Clinical Investigation.

The Penn State researcher says the mechanism for preventing the migration of white blood cells is a key adaptation by B. pertussis to prolong the infection period in immune and vaccinated hosts.

"B. pertussis effectively avoids the immune system during the first week of infection, giving it enough time to successfully grow, and potentially spread to more people," explains Harvill.

Acute infections are like forest fires, says Ottar Bjornstad, associate professor of entomology and biology at Penn State and a co-author of the study. He notes, "And while highly infectious pathogens will spread rapidly, they may burn through the susceptible population so quickly that they run the risk of extinction."

"Pertussis cleverly avoids this by using a toxin to allow re-infecting of those who have been vaccinated or infected earlier," adds Bjornstad, also co-director of the Center for Infectious Disease Dynamics.

According to Harvill, the new understanding could lead to potential new treatments for whooping cough.

"The most direct treatment could involve inactivating the toxin, or simply having vaccines that produce more antibodies specific to the toxin," notes the Penn State researcher.
-end-
Other authors of the paper include Mary Kennett, associate professor of veterinary science; Girish Kirimanjeswara, a former doctoral candidate of pathobiology who is currently at Albany Medical College; and Luis Agosto, a former undergraduate in biochemistry and molecular biology and now a graduate student at the University of Pennsylvania.

The National Institutes of Health funded this study.

Penn State

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