Francisella tularensis (FT), the causative agent for tularemia, can infect humans by a number of routes, including vector-borne transmission. However, inhalation of the bacterium, and the resulting pneumonic tularemia, is the most dangerous form of disease. This is due to the short incubation time (3-5 days), non-specific symptoms, and a high mortality rate (greater than 80%) in untreated individuals. Furthermore, FT has been weaponized by both the United States and the former Soviet Union making it a viable candidate for use as a biological weapon. Despite over 80 years of research on FT around the world, very little is understood about the dynamic interaction of this bacterium with the host, especially following aerosol infection.
Specific Aim 1 : There are no vaccines currently licensed for tularemia. Development of novel vaccines has been impaired by the lack of comprehensive understanding both the elements of the bacterium and the host response that are required to drive adaptive immunity against FT. This is, in part, due to a lack of tools that can aid in delineation of protective versus non-protective (as determined by survival) immune responses. Over the past year we made our major advance in understanding the requirements for strong adaptive immune responses directed against FT were uncovered as a role for effector T cells in the lung. We discovered that a prime- boost strategy is essential for provoking long term immunity against FT infection. We have determined the relative contribution of resident pulmonary T cells and T cells that circulate through the pulmonary compartment for protection against FT. Specifically, it appears that, while both population of cells is critical for clearance of the virulent bacterium, there is a strong temporal requirement for each population. Thus, vaccination strategies that greatly expand both population are required for optimal development of new vaccines directed against tularemia. We have also found that resident and circulating T cells in the lung have differences in their metabolic potential that influences their ability to participate in antimicrobial responses. Importantly this was not restricted to vaccination against Francisella but was applicable to vaccination with other unrelated bacterium. This suggests that we have uncovered an important feature of pulmonary T cell immunity that was not previously appreciated and will impact development of new vaccines against an array of pulmonary pathogens.
Specific Aim 2 and 3: We have established that FT lipids and its capsule direct an anti-inflammatory program in host cells and tissues Over the past year we have further dissected the mechanism by which FT lipid and capsule suppress host cell responses by redirecting host metabolism. We have discovered that these molecules independently manipulate mitochondrial function to establish and anti-inflammatory state in the cell. We have also found that both components contribute to inhibiting specific cell death pathways throughout infection. We have also found that strains of Francisella with targeted mutations in lipid synthesis pathways are attenuated following in vivo infection, thus underscoring the importance of specific lipid classes.
Showing the most recent 10 out of 31 publications
