A fundamental question in immunology is how the innate immune system detects pathogenic microbes. Host health depends critically upon the ability of the innate immune system to respond rapidly and selectively to pathogens, while avoiding inappropriate responses to self or harmless commensal microbes. Our goal is to describe how this rapid, sensitive, and accurate detection of pathogens is achieved at a molecular level. We have been particularly interested in a family of cytosolic pathogen detectors called inflammasomes. Inflammasomes comprise a family of multiprotein complexes that assemble in the cytosol in response to noxious and infectious stimuli. Inflammasomes initiate innate immune responses by activating the Caspase-1 protease. In general, it is poorly understood how inflammasomes recognize pathogens and assemble to activate Caspase-1. To address these questions, our studies have focused on a sub-family of inflammasomes called the Naip/Nlrc4 inflammasomes. Naip proteins (of which there are four in C57BL/6 mice) and Nlrc4 are members of a broader superfamily of proteins called NLRs (nucleotide- binding domain, leucine rich repeat-containing proteins). In the past funding period, we found that Naip5 mediates specific cytosolic detection of bacterial flagellin, whereas Naip2 mediates specific cytosolic detection of the inner rod protein from diverse bacterial type III secretion systems. We have also developed novel biochemical assays to dissect ligand binding and inflammasome oligomerization, and have used these novel assays to show that a key biochemical function of the Naips is to recognize ligands and induce downstream oligomerization of Nlrc4. In this renewal application, we describe three aims that will dissect ligand binding, oligomerization, and the downstream in vivo effector functions of the Naip/Nlrc4 inflammasomes.
Aim 1 seeks to determine how specific bacterial ligands are recognized by Naip proteins. This will be significant because it will represent the first analysis of ligand binding by any mammalian NLR protein.
Aim 2 seeks to dissect the biochemical and cellular mechanisms of inflammasome assembly, a critical but poorly understood process. Lastly, Aim 3 will investigate how inflammasomes initiate effector responses in vivo. In particular, we seek to establish a novel link between inflammasome activation and eicosanoid lipid mediator production in vivo. Eicosanoids are known to be critical mediators of inflammation, but their production has not previously been linked to inflammasomes. We show in vivo that inflammasome activation results in eicosanoid production and a severe vascular leakage syndrome that can be rapidly fatal. Taken together, our studies of the Naip/Nlrc4 inflammasomes will provide novel insights into ligand recognition, assembly and in vivo function of this critical family of cytosolic immune detectors.

Public Health Relevance

Infectious diseases remain a major cause of global mortality and morbidity. The design of novel immunotherapeutics, adjuvants and vaccines is predicated on a better understanding of how the innate immune system detects pathogens and initiates protective responses. Our proposal aims to fulfill this goal by dissection of the molecular mechanisms by which intracellular bacterial pathogens are sensed by the immune system.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Palker, Thomas J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Berkeley
Schools of Arts and Sciences
United States
Zip Code
Price, Jordan V; Jiang, Kallie; Galantowicz, Abigail et al. (2018) Legionella pneumophila Is Directly Sensitive to 2-Deoxyglucose-Phosphate via Its UhpC Transporter but Is Indifferent to Shifts in Host Cell Glycolytic Metabolism. J Bacteriol 200:
Nichols, Randilea D; von Moltke, Jakob; Vance, Russell E (2017) NAIP/NLRC4 inflammasome activation in MRP8+ cells is sufficient to cause systemic inflammatory disease. Nat Commun 8:2209
Vance, Russell E; Eichberg, Michael J; Portnoy, Daniel A et al. (2017) Listening to each other: Infectious disease and cancer immunology. Sci Immunol 2:
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:
Tenthorey, Jeannette L; Haloupek, Nicole; López-Blanco, José Ramón et al. (2017) The structural basis of flagellin detection by NAIP5: A strategy to limit pathogen immune evasion. Science 358:888-893
De Leon, Justin A; Qiu, Jiazhang; Nicolai, Christopher J et al. (2017) Positive and Negative Regulation of the Master Metabolic Regulator mTORC1 by Two Families of Legionella pneumophila Effectors. Cell Rep 21:2031-2038
DiPeso, Lucian; Ji, Daisy X; Vance, Russell E et al. (2017) Cell death and cell lysis are separable events during pyroptosis. Cell Death Discov 3:17070
Rauch, Isabella; Deets, Katherine A; Ji, Daisy X et al. (2017) NAIP-NLRC4 Inflammasomes Coordinate Intestinal Epithelial Cell Expulsion with Eicosanoid and IL-18 Release via Activation of Caspase-1 and -8. Immunity 46:649-659
Rauch, Isabella; Tenthorey, Jeannette L; Nichols, Randilea D et al. (2016) NAIP proteins are required for cytosolic detection of specific bacterial ligands in vivo. J Exp Med 213:657-65
Chavarría-Smith, Joseph; Mitchell, Patrick S; Ho, Alvin M et al. (2016) Functional and Evolutionary Analyses Identify Proteolysis as a General Mechanism for NLRP1 Inflammasome Activation. PLoS Pathog 12:e1006052

Showing the most recent 10 out of 34 publications