DETERMINANTS OF PROTECTIVE IMMUNITY TO TUBERCULOSIS

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Abstract: A new, more effective vaccine is essential for the long-term control of TB. It is crucial to identify the correlates of protection for TB, in the context of BCG vaccination, and to utilize this information during the search for future anti-TB vaccines. Nonhuman Primates (NHPs) are excellent models of TB due to their genetic, genomic and physiological similarity with humans. NHPs develop human-like disease with various outcomes, ranging from active to chronic to latent disease and display an entire spectrum of pathological features characteristic of human TB. Six macaques, intradermally vaccinated with BCG and a control group were challenged with 1000 CFU of Mtb Erdman, via bronchoscopic instillation after vaccination. We used lung tissue from all the above animals, to compare: i) transcriptome of NHP lung response to Mtb infection;and ii) transcriptomic evaluation of the effect of BCG vaccination on the NHP lung response to Mtb infection. We identified a small, discrete group of genes whose expression was perturbed in a statistically significant manner, as a result of BCG vaccination. Our results clearly indicate that vaccination with BCG clearly and effectively modulates the immune system at the site of Mtb infection. Some of these changes may play a role in inducing localized protection from Mtb infection. It is important to characterize the changes observed following BCG vaccination, in our preliminary studies, in order to identify key molecular correlates of protection from TB. Validation of these microarray data was performed using a real-time RT-PCR approach on randomly selected outlier genes. Another level of validation is currently in progress using the laser-confocal immunofluorescence approach in collaboration with Dr. Alvarez's group.