Boston -- Using a novel mouse model that allows scientists to study how the immune system's fighter cells respond to invaders in the genital tract during the initial stage of infection, Harvard Medical School (HMS) researchers have found a way to track immunity against Chlamydia trachomatis. The new findings could help hasten the development of vaccines for Chlamydia – the most common cause of bacterial sexually transmitted disease (STD) in the United States – and other STDs. The study appears in the July 24 early edition online of the Proceedings of the National Academy of Sciences.
"Right now Chlamydia is sensitive to treatment with antibiotics, but the problem is that many people have 'silent' infections that remain untreated," said researcher Michael Starnbach, PhD, HMS associate professor of microbiology and molecular genetics. "These undiagnosed infections over time lead to complications like tubal pregnancy and infertility. The goal would be to vaccinate young people to keep them from suffering from undiagnosed infection and the bad outcomes associated with it."
Most pathogens (disease-causing bacteria or viruses) enter a host by penetrating mucosal surfaces such as the lung, intestine, or genito-urinary tract. The prevalence of sexually transmitted diseases has prompted studies to understand how infection is established in the genital tract and how pathogens are cleared from this site. Before Starnbach's study, however, it had not been possible to monitor invader-specific T cell (fighter cell) responses to initial infection in reproductive tissue, despite the recognized importance of T cells in controlling a number of genital pathogens
"Humans and mice have an enormous variety of T cells that are prepared to respond to pathogens – even pathogens to which they have never been exposed," Starnbach said. "Yet prior to infection, the number of T cells specific for any single pathogen is extremely low. The number is so low that it is impossible to track and monitor the activity of these T cells during their first encounter with the microbe."
To circumvent the problem, Starnbach and colleagues in the HMS Department of Microbiology and Molecular Genetics identified one of the Chlamydia proteins recognized by T cells during infection and engineered mice where all the T cells in the mice exclusively respond to this Chlamydia protein. These mice are known as T cell receptor transgenic (TCRtg) mice and have none of the T cell diversity found in a normal mouse. Starnbach and his team harvested T cells from the Chlamydia-specific TCRtg mice, labeled them with a dye, and injected them into normal mice. By boosting the number of Chlamydia-specific T cells in the recipient mice, they were able to identify and monitor them as they responded to infection.
"We found that when the recipient mice were infected with Chlamydia, the labeled T cells became activated specifically in the lymph nodes near the reproductive tract, expanded in number in those lymph nodes, and migrated into the mucosa lining the genital tract," Starnbach said. "We also found that the T cells recruited to the genital mucosa secrete gamma interferon as they respond to Chlamydia infection. Gamma interferon secretion has been described as the key molecule T cells use to rid the body of Chlamydia."
The findings show how T cell responses can be studied in reproductive tissues, which is likely to reveal avenues to the development of vaccines against Chlamydia, and possibly other STDs.
"In this report, we identify one candidate protein, Cta1, and show that T cells specific for Cta1 can reduce Chlamydia infection," Starnbach said. "In designing a vaccine, we would want to make sure the vaccine stimulates T cells with characteristics that cause them to home to the genital tract - the site of infection. We also would want them to respond with the same arsenal of protective factors – such as the secretion of gamma interferon that we show occurs using our TCRtg tools."
The goal of vaccines is to stimulate a response that mimics exposure to a pathogen, without the risks of actual infection. When a vaccine successfully accomplishes this, protection against future infection results.
This study was funded by the National Institutes of Health.
HARVARD MEDICAL SCHOOL
Harvard Medical School has more than 7,000 full-time faculty working in 10 academic departments housed on the School's Boston quadrangle or in one of 48 academic departments at 18 Harvard teaching hospitals and research institutes. Those Harvard hospitals and research institutions include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Health Alliance, The CBR Institute for Biomedical Research, Children's Hospital Boston, Dana-Farber Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Joslin Diabetes Center, Judge Baker Children's Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, Massachusetts Mental Health Center, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, and the VA Boston Healthcare System.
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