NOD-like receptors (NLRs) are a family of intracellular sensor molecules involved in the regulation of inflammatory signaling in response to infection and cellular stress. Recent studies have revealed pivotal roles for NLR-mediated inflammation in a spectrum of diverse human autoimmune and inflammatory disorders. The vast majority of NLRs to date have been defined as activators of inflammatory signaling in innate immune cells. For instance, the prototypical NLR members, NOD1 and NOD2, initiate proinflammatory NF-?B and MAPK signaling in response to their direct recognition of bacterial peptidoglycan fragments. Multiple NLRs have also been described to promote the activation and secretion of the proinflammatory cytokines IL-1? and IL-18 by coordinating the assembly of the inflammasome complex. In contrast, some NLRs, such as NLRP6, NLRP12, NLRC3 and NLRX1, negatively regulate inflammatory signaling. However, the cellular and molecular mechanisms that direct the suppression of inflammation by this new class of inhibitory NLRs are not known. Missense mutations in NLRP12 are associated with inflammatory diseases in humans, but the biochemical mechanisms and pathways underlying these pathologies remain unclear. Recent work from our lab demonstrates that NLRP12 functions as a key negative regulator of NF-?B signaling. Importantly, inflammation and immunopathology are not exclusively restricted to inflammatory and autoimmune diseases. The dysregulation of innate and adaptive immunity can also result in striking differences with regard to morbidity and mortality during infectious disease. In this regard, NLRP12's role in viral infection and generation of adaptive immune responses has not been investigated. Therefore, this project is highly significant, as it will lead to the identification of key immune mechanisms involved in host defense and inflammatory control mechanisms dependent on NLRP12 that regulate inflammation. We will examine these mechanisms through the use of influenza A virus.

Public Health Relevance

Missense mutations in Nlrp12 lead to inflammatory diseases in humans. The studies proposed in this application on the signaling pathways involved in innate and acquired host immune responses, regulated by NLRP12 will increase our understanding of key regulators of immunity and host defense that operate in major human diseases. These studies uncover novel signaling pathways that will help in the design of therapeutics to treat infectious and inflammatory diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI124346-01
Application #
9110633
Study Section
Special Emphasis Panel (ZRG1-IMM-J (90))
Program Officer
Palker, Thomas J
Project Start
2016-03-15
Project End
2021-02-28
Budget Start
2016-03-15
Budget End
2017-02-28
Support Year
1
Fiscal Year
2016
Total Cost
$447,500
Indirect Cost
$197,500
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
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
Kesavardhana, Sannula; Kuriakose, Teneema; Guy, Clifford S et al. (2017) ZBP1/DAI ubiquitination and sensing of influenza vRNPs activate programmed cell death. J Exp Med 214:2217-2229

Showing the most recent 10 out of 27 publications