July 19, 2004

UCSD Researchers’ Finding About Pathogen
In Newborns, May Aid Vaccine Development

By Sue Pondrom

A previously unrecognized molecular structure on the surface of the human bacterial pathogen Group B Streptococcus (GBS) – the most common cause of sepsis and meningitis in newborn infants – is described by researchers at the University of California, San Diego (UCSD) School of Medicine in Proceedings of the National Academy of Sciences published online the week of July 19, 2004.

The new discovery has important implications for understanding the mechanism of infection and the design of vaccines to boost human immunity against this potentially devastating pathogen. For example, potential GBS vaccines currently in clinical trials have been developed without this new knowledge, which could possibly impact their effectiveness.

The findings are a collaborative effort between the laboratories of senior author Ajit Varki, M.D., UCSD professor of medicine and cellular and molecular medicine, and co-director of the UCSD Glycobiology Research and Training Center (GRTC), and Victor Nizet, M.D., associate professor of pediatrics, UCSD Division of Infectious Diseases and an attending physician at Children’s Hospital, San Diego. The two groups have been studying the phenomenon in which certain bacterial pathogens coat their surfaces with a thick capsule made of carbohydrate sugars similar to those found on the surface of human cells. In the case of GBS, the bacterial surface capsule contains sialic acid, a sugar that is also displayed prominently on the surface of all cells in the human body. It is believed that GBS uses sialic acid as a form of “molecular mimicry”, where the bacteria disguises itself to look more like human cells and thereby avoids recognition by the immune system.

Using the sophisticated analytical techniques of the UCSD GRTC facility, graduate student Amanda Lewis discovered that the sialic acid of the GBS capsule contained a chemical modification known as O?acetylation, that had been previously overlooked in more than 30 years of published investigations. O-acetylation was detected in every one of 10 different GBS strains examined, with the overall level of modified sialic acid ranging from 5 percent to 55 percent.

“There are a number of reasons why previous researchers have missed this biochemical structure,” said Varki. “Older detection instruments may have been less sensitive, and some of the harsh chemical treatments employed to purify the capsule are known to destroy O-acetylation.”

He added that “since similar chemical treatments are commonly used to isolate GBS capsule for immunization studies, GBS vaccines in development are missing this component of the true or ‘native’ surface structure of the bacteria.”

In other bacterial pathogens where O-acetylation of surface sugars has been studied, it has been shown that the immune system is able to recognize and generate antibodies that specifically react with the O-acetyl modification. In the case of GBS, this possibility is particularly intriguing.

Varki noted that “an unmodified sialic acid-containing structure resembling the GBS capsule sugar, is present on the surface of all human cells; however, an O-acetylated form of this sugar has never, so far, been reported in humans”.

“This observation may have particular relevance for vaccine design,” Nizet added, “since the elimination of O?acetylation in a GBS vaccine potentially destroys a unique biochemical target for immune protection, inadvertently creating a vaccine antigen that more closely resembles normal human tissue structures”.

The discovery of the UCSD group has implications beyond vaccine design, and may also shed new light on the basic biology of the GBS infection. In previous studies, the presence or absence of O-acetylation on sialic acid has been shown to have important effects on the way the sugar can interact with molecules of the immune system such as antibodies and complement. The researchers are currently investigating whether GBS bacteria may use O?acetylation to vary their surface structure and create a “moving target” which is difficult for the human immune system to recognize.

It is estimated that 20 to 30 percent of women of childbearing age are asymptomatic carriers of GBS on their vaginal mucosal surface. Newborns can become infected with GBS that invade through the placenta to initiate infection in the womb, or alternatively, during delivery by exposure to contaminated vaginal fluids. Despite extensive screening of pregnant women and antibiotic prophylaxis during labor, it is estimated that approximately 3,600 newborns develop invasive GBS infections annually in the United States. In addition to neonatal disease, GBS is increasingly associated with serious infections in adult populations such as pregnant women, diabetics, and the elderly.

“The presence of sialic acid in the GBS surface capsule has long been recognized as a critical virulence factor in disease progression,” said Nizet. “A full appreciation of its biochemical complexity will be critical for development of GBS therapeutic or preventative strategies that target this molecule.”

The study was supported by grants to Varki from the National Institutes of Health (NIH) and to Nizet from the Edward J. Mallinckrodt, Jr. Foundation.

Media Contacts: Sue Pondrom (619) 543-6163