Grants and Contracts Details
Listeria monocytogenes (Lm) is important an important pathogen to study because: 1) it causes human food borne infections that are of significant public health concern, 2) it is a genetically tractable organism with a unique intracellular lifestyle that serves as a tool for understanding the cell biology of mammalian cells, and 3) systemic (i v) listeriosis is a highly reproducible infection frequently used by immunologists to study cell-mediated immune responses. However, due to the lack of a good animal model for oral transmission of Lm, we still know very little about the infectious dose required to establish intestinal infection, mechanisms of spread from the gut, or why the innate susceptibility to developing systemic listeriosis seems to vary among individuals, We recently developed a new model of oral infection using mice fed Lm-contaminated food that shows clear differences in the ability of Lm to colonize the gut and spread systemically in susceptible (BALB) vs resistant (B6) mice Thus, for the first time, we can now study how gut-adapted Lm that survive digestive processes in the stomach are able to colonize the intestinal mucosa and serve as a nidus for continual reseeding of peripheral tissues in susceptible mice that are unable to quickly clear the gut infection. Since the vast majority of patients hospitalized with listeriosis can be considered immune compromised in some way, it has long been thought that protective immune responses were critical for limiting the infection to a self-limiting gastroenteritis in resistant individuals.. Our central hypothesis predicts that one such innate immune mechanism is the rapid secretion of IFNy by a subset of memory phenotype CD8+ T cells, We postulate that this early IFNy response can limit the growth and spread of Lm in resistant individuals and that susceptible mice or humans who lack this ability will be more likely to develop life-threatening systemic listeriosis We have three specific aims: (1) to characterize the intestinal phase of infection after ingestion of Lm, (2) to identify routes of primary dissemination from the gut and pathways of secondary spread that occur later in infection, and (3) to identify IFNy-dependent innate immune mechanisms that operate to limit the growth and spread of Lm in resistant, but not susceptible mice. To study the role of CDS+ T cells in innate immunity, we will use a unique adoptive transfer system wherein T cells from a responsive mouse are injected into a MHC-matched non-responsive strain, This powerful strategy will allow us to specifically isolate the . function of IFNy rapidly produced by CDS"" T cells while leaving all other innate immune mechanisms intact. ,These studies will have a large impact on both microbiologists and immunologists as we anticipate that our natural feeding model will be widely used by both groups in the future to identify mechanisms that promote either bacterial virulence or host resistance during infection.
|Effective start/end date||9/30/11 → 9/29/13|
- National Institute of Allergy and Infectious Diseases: $366,565.00
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