Pyroptosis maintains the integrity of a granuloma

Granulomas are complex immunologic structures formed in tissues in response to infection. The general function of a granuloma has been elusive because many infections that stimulate granuloma responses do not resolve. Often, granulomas are described as immunologic responses that wall off an infectious agent that cannot be cleared by the immune system. Basic understandings of the fundamentals of a granuloma have been elusive because mouse models where granulomas form are rare or complicated. We have discovered a novel bacterial infection model where the murine immune system forms a granuloma. When mice are infected by Chromobacterium violaceum, the immunologic response fails to clear the bacterium from the liver within the first several days. Then a granuloma forms around the infected lesion, and this complex immunologic response successfully sterilizes the infection and returns the organ to homeostasis typically within 7-14 days post infection. Therefore, we have discovered a novel infectious model where basic granuloma biology can be elucidated. C. violaceum first infects hepatocytes and perhaps Kupffer cells in the liver. This rapidly stimulates a neutrophil swarm within the first day post infection. However, the neutrophil swarm fails to eradicate the infection, and the neutrophils themselves appear to become replicative intracellular niches for the bacterium. Three days post infection the neutrophil swarm dies and forms a central necrotic core of the lesion. Macrophages begin to appear at the periphery of the lesion at 3 days post infection and form a thick macrophage zone that surrounds the necrotic core by day 5-7. Thereafter, the bacteria are killed through the action of inducible nitric oxide synthase, the granuloma is sterilized, and shrinks over the next week. Granuloma burdens are sterilized between 7-21 days post infection. This all occurs in the absence of T cells or other adaptive immune cells. In this grant, we use this novel granuloma model to explore the importance of pyroptotic cell death in the granuloma.