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. A new, more effective vaccine is clearly 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 (Danish;50 x 10E6), and a control group (saline) 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. Immune function genes such as FoxP3, MIP, IL-6 and IL-24, which were expressed in both vaccinated and control groups, as well as IFN-g, IL-8, IL-21b, IL-17, IL-27 and RANTES, which were specifically expressed, only in BCG vaccinated animal lungs. 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. These preliminary data helped us obtain cooperative seed funding ($75,000 per year total costs for a period of two years), from the Louisiana Board of Regents, through the Louisiana Vaccine Center (LVC)/South Louisiana Institute for Infectious Disease Research mechanism. Using samples from the TNPRC pilot, we looked at gene expression changes 8 months post Mtb infection. The LVC funds will allow us to look at short term (1-3 month post infection) changes in gene-expression as a function of Mtb infection and BCG vaccination, as the dynamics of the granuloma evolve.
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