Legionella pneumophila is a protypical example of an emerging infectious disease threat. Recent exciting data from several labs have indicated that type I interferons (IFNs) are an important signature of infection with many, if not all, intracellular pathogens. Our hypothesis is that a cytosolic surveillance pathway detects Legionella-derived ligands in the cytosol leading to the transcriptional induction of type I IFNs and coregulated genes. Preliminary data indicate that type I interferons are induced by Legionella in a manner dependent on L. pneumophila's type IV (Dot/Icm) secretion system. We also find that type I interferons are required to restrict intracellular replication of Legionella. The putative Legionella-derived ligand that stimulates host production of interferon is unknown, but our preliminary studies have identified Mda5 as a key host sensor of L. pneumophila. Since Mda5 is a cytosolic sensor of RNA, our finding suggests the exciting possibility that L. pneumophila may translocate bacterial RNA into the host cell cytosol. Even if a non-RNA ligand from L. pneumophila is sensed by Mda5, our results challenge existing paradigms since Mda5 is widely believed to be solely a sensor of viruses, rather than of bacteria. Thus, our specific aims are: 1. Identify and characterize molecular determinants of L. pneumophila that positively or negatively regulate host production of type I interferon. 2. Characterize the host pathways that sense L. pneumophila in the cytosol, leading to transcriptional induction of type I interferon and other genes. 3. Determine the role of cytosolic sensing and type I interferons in innate immunity against L. pneumophila using in vitro and in vivo models.

Public Health Relevance

Legionella pneumophila is a bacterium that replicates in host cells called macrophages, thereby causing a severe, and often lethal, pneumonia called Legionnaires'Disease. In this proposal we seek to use Legionella as a model for understanding how macrophages sense and defend against infection, with the ultimate goal of using this information to develop more effective therapeutics and vaccines.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Immunity and Host Defense Study Section (IHD)
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Palker, Thomas J
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University of California Berkeley
Schools of Arts and Sciences
United States
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Barry, Kevin C; Ingolia, Nicholas T; Vance, Russell E (2017) Global analysis of gene expression reveals mRNA superinduction is required for the inducible immune response to a bacterial pathogen. Elife 6:
Kranzusch, Philip J; Lee, Amy S Y; Wilson, Stephen C et al. (2014) Structure-guided reprogramming of human cGAS dinucleotide linkage specificity. Cell 158:1011-1021
Tenthorey, Jeannette L; Kofoed, Eric M; Daugherty, Matthew D et al. (2014) Molecular basis for specific recognition of bacterial ligands by NAIP/NLRC4 inflammasomes. Mol Cell 54:17-29
von Moltke, Jakob; Ayres, Janelle S; Kofoed, Eric M et al. (2013) Recognition of bacteria by inflammasomes. Annu Rev Immunol 31:73-106
Aachoui, Youssef; Leaf, Irina A; Hagar, Jon A et al. (2013) Caspase-11 protects against bacteria that escape the vacuole. Science 339:975-8
Chavarría-Smith, Joseph; Vance, Russell E (2013) Direct proteolytic cleavage of NLRP1B is necessary and sufficient for inflammasome activation by anthrax lethal factor. PLoS Pathog 9:e1003452
Barry, Kevin C; Fontana, Mary F; Portman, Jonathan L et al. (2013) IL-1? signaling initiates the inflammatory response to virulent Legionella pneumophila in vivo. J Immunol 190:6329-39
Barker, Jeffrey R; Koestler, Benjamin J; Carpenter, Victoria K et al. (2013) STING-dependent recognition of cyclic di-AMP mediates type I interferon responses during Chlamydia trachomatis infection. MBio 4:e00018-13
Conlon, Joseph; Burdette, Dara L; Sharma, Shruti et al. (2013) Mouse, but not human STING, binds and signals in response to the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid. J Immunol 190:5216-25
Diner, Elie J; Burdette, Dara L; Wilson, Stephen C et al. (2013) The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING. Cell Rep 3:1355-61

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