The innate immune system comprises several classes of pattern recognition receptors, including Toll- like receptors (TLRs) and NOD-like receptors (NLRs). A set of NLR family members form a multi-protein complex termed 'the inflammasome', which contains the adaptor protein ASC and caspase-1, and promotes caspase-1 activation and maturation of IL-1? and IL-18, the secretion of which leads to a potent inflammatory response. Caspase-1 is the prototypical member of the inflammatory caspases and is a key target in several inflammatory, infectious and autoimmune diseases. Studies show that caspase-1-deficient mice are resistant to the toxic effects of lipopolysaccharide, Escherichia coli-induced shock, and apoptotic cell death. Interestingly, IL-1? and IL-18, the two major downstream target molecules of caspase-1 are not involved suggesting that some other downstream targets of caspase-1 are important. Additionally, our studies show that the commonly used lines of caspase-1-deficient mice are also deficient in caspase-11 suggesting that the inflammatory functions attributed to caspase-1 could be the combined actions of both caspase-1 and caspase-11. This proposal will address the central hypothesis that NLR/caspase-1 and caspase-11 signaling axis plays a crucial role in innate immunity to microbial pathogens. We identified several important caspase-1 substrates in a proteome-wide screen and our preliminary data suggest a key role for a set of these substrates in inflammation and sepsis induction. Overall, this study will elucidate the roles of caspase-1 and caspase-11 and their effector mechanisms in innate immunity and inflammation and will help identify the molecular and cellular mechanisms regulating innate immunity and inflammation, thus leading to novel therapeutic targets for inflammatory and infectious diseases.

Public Health Relevance

Recognition of microbial infection by the innate immune system results in acute inflammatory responses that help to eliminate the invading pathogens. This research focuses on understanding the role of key cellular proteins in the complex molecular and cellular inflammatory mechanisms. The outcomes of the proposed studies will reveal new elements of NLR/caspase-1 cascade function and the signaling pathways in inflammation and thus will help in the discovery of effective therapeutics to treat inflammation associated diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI101935-02
Application #
8463456
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Palker, Thomas J
Project Start
2012-05-01
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$411,250
Indirect Cost
$176,250
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Kesavardhana, Sannula; Kanneganti, Thirumala-Devi (2017) Mechanisms governing inflammasome activation, assembly and pyroptosis induction. Int Immunol 29:201-210
Qi, X; Gurung, P; Malireddi, R K S et al. (2017) Critical role of caspase-8-mediated IL-1 signaling in promoting Th2 responses during asthma pathogenesis. Mucosal Immunol 10:128-138
Man, Si Ming; Place, David E; Kuriakose, Teneema et al. (2017) Interferon-inducible guanylate-binding proteins at the interface of cell-autonomous immunity and inflammasome activation. J Leukoc Biol 101:143-150
Lupfer, Christopher R; Stokes, Kate L; Kuriakose, Teneema et al. (2017) Deficiency of the NOD-Like Receptor NLRC5 Results in Decreased CD8+ T Cell Function and Impaired Viral Clearance. J Virol 91:
Sharma, Deepika; Kanneganti, Thirumala-Devi (2017) Inflammatory cell death in intestinal pathologies. Immunol Rev 280:57-73
Zhu, Qifan; Kanneganti, Thirumala-Devi (2017) Cutting Edge: Distinct Regulatory Mechanisms Control Proinflammatory Cytokines IL-18 and IL-1?. J Immunol 198:4210-4215
Gurung, Prajwal; Fan, Gaofeng; Lukens, John R et al. (2017) Tyrosine Kinase SYK Licenses MyD88 Adaptor Protein to Instigate IL-1?-Mediated Inflammatory Disease. Immunity 46:635-648
Gresnigt, Mark S; Jaeger, Martin; Subbarao Malireddi, R K et al. (2017) The Absence of NOD1 Enhances Killing of Aspergillus fumigatus Through Modulation of Dectin-1 Expression. Front Immunol 8:1777
Sharma, Deepika; Sharma, Bhesh Raj; Vogel, Peter et al. (2017) IL-1? and Caspase-1 Drive Autoinflammatory Disease Independently of IL-1? or Caspase-8 in a Mouse Model of Familial Mediterranean Fever. Am J Pathol 187:236-244
Man, Si Ming; Karki, Rajendra; Kanneganti, Thirumala-Devi (2017) Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol Rev 277:61-75

Showing the most recent 10 out of 66 publications