John D. MacMicking
Vertebrates have evolved complex innate immune response repertoires beyond the primordial components found in lower multi-cellular organisms to combat intracellular infections. The interferon (IFN) family represents one such system, bridging both innate and acquired immunity as well as providing direct protection in a cell-autonomous manner. Our group is identifiying downstream IFN pathways that are crucial for controlling infection of macrophages and dendritic cells by Mycobacterium tuberculosis (Mtb), the causative agent of TB. Several IFN-inducible pathways have recently been discovered, among them a group of GTPases that remodel the phagosome of engulfed bacteria to restrict pathogen growth. We are currently using a combination of mammalian and mycobacterial genetics along with cell biology, immunology and protein crystallography to address the mechanisms involved in these processes. In addition, a search for Mtb components that combat IFN-induced host pathways is also underway. These studies should lead to a better understanding of the ancient dialogue between eukaryote and prokaryote while providing a basis for rational TB vaccine or drug design in the future.