BioWorld International Correspondent
LONDON - A novel transgenic mouse model is likely to speed the development of new vaccines to protect against meningococcal meningitis. The model, in which the animals express the human cell-surface receptor called CD46, also might help in the search for a vaccine for gonorrhea.
The model is exciting for researchers working on meningitis because until now there has been no satisfactory animal model for the disease.
Ann-Beth Jonsson, associate professor of microbiology at the Karolinska Institute in Stockholm, Sweden, told BioWorld International: "Neisseria meningitis causes disease only in humans, but now that we have a mouse model where the animals become infected and die, it will greatly speed up the evaluation of candidate vaccines. It will also help us to gain a better understanding of the pathogenesis of infection."
Jonsson, together with researchers from Sweden and the U.S., published a paper describing her experiments in the July 18, 2003, issue of Science. Its title is "CD46 in Meningococcal Disease."
In 1997, Jonsson and her colleagues published work demonstrating that CD46, a human protein that helps regulate the complement system, interacts with pili on the surface of the bacterium Neisseria meningitidis, which causes meningococcal meningitis.
They subsequently made transgenic mice containing the gene for CD46 and have shown that the pattern of expression of the protein in the animals is similar to that in humans.
The paper in Science describes what happened when they infected the transgenic mice with N. meningitidis. When they injected the bacteria intraperitoneally, bacteria could later be detected in the blood of both CD46 transgenic and nontransgenic mice. They also found high counts of bacteria in the cerebrospinal fluid of the transgenic mice, but not of the nontransgenic mice. Only mice in the CD46 transgenic group died; the mortality rate depended on the dose of bacteria given.
The normal route of transmission of N. meningitidis in humans is via the nasal epithelium. The group's next experiment aimed to replicate that type of transmission. First, they treated the animals with antibiotics to eliminate the normal bacterial flora in the nasopharynx, as this is known to protect mice from N. meningitidis infection. The researchers then delivered a dose of either N. meningitidis bearing pili, or N. meningitidis without pili, in order to check whether the pili - as they suspected - played a role in infection via CD46. They found that 15 percent of the CD46 transgenic mice that received piliated N. meningitidis died, whereas none of those given non-piliated N. meningitidis showed any sign of disease. "These results show that the bacteria only pass the blood-brain barrier in the CD46 transgenic mice, so it appears that CD46 plays a very important role in the pathogenesis of meningococcal meningitis," Jonsson said. "It seems to help the bacteria pass the nasal epithelial mucosa, and to allow them to enter the cerebrospinal fluid." In their paper, the authors speculated that the type of cytoplasmic tail carried by CD46 in the brain might help explain why N. meningitidis infection is lethal in CD46 transgenic mice. Differential splicing of the gene encoding CD46 results in several different forms of the protein being expressed. These include two variants with different cytoplasmic tails, Cyt-1 and Cyt-2. Jonsson said: "It was recently shown that CD46 can regulate inflammatory responses differentially, depending on which cytoplasmic tail is expressed. Engagement of CD46 that has Cyt-2 increases inflammation. Since Cyt-2 is expressed in the brain, one can speculate that meningococcal engagement of CD46 may increase inflammation, and lead to the lethal effects of the meningococcal meningitis." She predicted that the model also would help research aimed at understanding how other microorganisms, such as the measles virus, Group A streptococci and human herpes virus 6, also interact with human CD46. The group's plans for the future include back-crossing their CD46 transgenic mice with other transgenic mice containing the genes for other receptors for N. meningitidis, including a receptor called CEACAM, which binds to an outer membrane protein on the bacterium called Opa. "We want to find out if transgenic mice containing two human proteins that can interact with N. meningitidis have an even greater sensitivity to infection," Jonsson said. "We also want to study the immune responses of the CD46 transgenic mice when they are infected." Drug development also is a possibility, Jonsson added. She said: "We can try to target CD46 in many different ways to try to stop the infection. If we can find a drug to inhibit the interaction of the bacterium with CD46 without affecting its role in complement regulation, then the compound has the potential to be effective against many different diseases caused by microorganisms that use CD46 to help them enter the body."