Infectious diseases caused by bacteria, especially antibiotic resistant pathogens, have become an increasing burden on the US health care system, with direct medical costs for hospital associated infections estimated to range between 30-45 billion dollars annually. Moreover, the development of new antibiotics has been unable to keep pace with the rapid emergence of ever more resistant bacteria. Fortunately, a growing number of sophisticated innate "Sensor and Response Systems" that co-evolved with their hosts have been described. In vertebrates this includes several distinct families of innate sensors that recognize specialized bacterial molecules or "molecular patterns". These sensors initiate well-known pro-inflammatory signaling cascades that culminate in the expression of immune effectors, like TNF-1 and Interferons (IFNs). Characterization of theses Sensor and Responses Systems provides an important opportunity for the development of equally sophisticated new therapeutic strategies. In an effort to characterize the innate responses that direct an effective response towards Legionella pneumophila, we have determined that a novel bacterial regulatory molecule, 3',5'- cyclic diguanylate (c-diGMP) plays an important role in stimulating the expression of autocrine IFNs, which effectively suppress bacterial growth. An analogous response to Listeria monocytogenes derived 3',5'-cyclic diadenylate (c-diAMP), has also recently been reported. We propose biochemical and genetic approaches to characterize the components of the mammalian sensor system that specifically responds to c-diGMP. To this end we have developed a biotin modified c-diGMP and a c-diGMP reporter cell line. We anticipate that the sensor components we identify, or closely related homologs, will direct the response to c- diAMP. Specifically we propose to: 1. Exploit affinity chromatography to identify the mammalian receptor for c-diGMP. 2. Exploit a genetic screen to identify the components of the mammalian sensor system that direct inflammatory response to c-diGMP.

Public Health Relevance

Type I Interferons (IFN-Is), known for their antiviral activity, also direct an effective innate response towards facultative intracellular bacteria, like Francisella tularensis and Legionella pneumophila. The proposed studies explore the mechanism by which c-diGMP, an important L. pneumophila regulatory molecule, stimulates NF-:B activation and IFN-I expression. These studies focus on identifying a new innate immune response pathway, which has important implications on antibacterial therapy and vaccine development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI096088-02
Application #
8274633
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Palker, Thomas J
Project Start
2011-06-07
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$200,000
Indirect Cost
$75,000
Name
Columbia University (N.Y.)
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Abdul-Sater, Ali A; Tattoli, Ivan; Jin, Lei et al. (2013) Cyclic-di-GMP and cyclic-di-AMP activate the NLRP3 inflammasome. EMBO Rep 14:900-6
Abdul-Sater, Ali A; Grajkowski, Andrzej; Erdjument-Bromage, Hediye et al. (2012) The overlapping host responses to bacterial cyclic dinucleotides. Microbes Infect 14:188-97