For most infections, the immune system confers long-term and sometimes life-long protection against many microbial pathogens. One encounter with a microbial pathogen is sufficient to allow the immune system to remember this pathogen for decades to come. This fundamental property forms the basis for vaccination with the main purpose of eliciting long-term protective immunity. Several good vaccines exist, but they were derived quite empirically and we still do not understand the molecular mechanisms that make them so successful. Vaccine preparations based on live attenuated pathogens are notoriously more effective than killed preparations. Our increasing knowledge of the critical elements involved in the initiation of immune responses points us towards two central players, antigen presenting cells (APCs) and pattern recognition receptors (PRRs). APCs capture microbial pathogens and mobilize a sequence of events that forms the basis for mounting an effective immune response against the pathogen. Adjuvants, used in most vaccine preparations, are a mixture of microbial components that trigger PRR activation and signal the transcriptional initiation of immune response genes. Our studies so far provide strong support for differential innate immune recognition of live and dead bacteria. While live bacteria trigger production of inflammatory alert cytokines, dead bacteria fail to do so. Thus, a component differentially present in live and dead bacteria, and which correlates with microbial viability, appears to be uniquely recognized by APCs. Recognition of this component requires the TLR signaling adaptor MyD88. We hypothesize that the innate immune system is capable of discriminating between live and dead pathogens, and accordingly mobilizes distinct signaling pathways and cellular immune responses. The unique responses triggered by live bacteria may hold the key to long-term immunity.
Our specific aims are designed to: 1) Determine the ability of live bacteria to activate cytosolic sensors of infection. 2) Characterize the nature of intracellular compartments carrying live versus dead bacteria.

Public Health Relevance

This proposal is aimed to understand the basis for a new mode of immune recognition, the innate sensing of microbial viability.
We aim to identify those pathways specifically triggered by live and not dead pathogens. Our work will help set the stage for novel generations of vaccines that hold the promise of conferring protection against many new and existing microbial threats.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI080959-02
Application #
7860326
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Palker, Thomas J
Project Start
2009-06-05
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
2
Fiscal Year
2010
Total Cost
$254,250
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Moretti, Julien; Roy, Soumit; Bozec, Dominique et al. (2017) STING Senses Microbial Viability to Orchestrate Stress-Mediated Autophagy of the Endoplasmic Reticulum. Cell 171:809-823.e13
Moretti, Julien; Blander, J Magarian (2017) Cell-autonomous stress responses in innate immunity. J Leukoc Biol 101:77-86
Campisi, Laura; Barbet, Gaetan; Ding, Yi et al. (2016) Apoptosis in response to microbial infection induces autoreactive TH17 cells. Nat Immunol 17:1084-92
Moretti, Julien; Blander, J Magarian (2014) Insights into phagocytosis-coupled activation of pattern recognition receptors and inflammasomes. Curr Opin Immunol 26:100-10
Rimmelé, Pauline; Bigarella, Carolina L; Liang, Raymond et al. (2014) Aging-like phenotype and defective lineage specification in SIRT1-deleted hematopoietic stem and progenitor cells. Stem Cell Reports 3:44-59
Blander, J Magarian (2014) A long-awaited merger of the pathways mediating host defence and programmed cell death. Nat Rev Immunol 14:601-18
Agudo, Judith; Ruzo, Albert; Kitur, Kipyegon et al. (2012) A TLR and non-TLR mediated innate response to lentiviruses restricts hepatocyte entry and can be ameliorated by pharmacological blockade. Mol Ther 20:2257-67
Blander, J Magarian; Sander, Leif E (2012) Beyond pattern recognition: five immune checkpoints for scaling the microbial threat. Nat Rev Immunol 12:215-25
Sander, Leif E; Davis, Michael J; Boekschoten, Mark V et al. (2011) Detection of prokaryotic mRNA signifies microbial viability and promotes immunity. Nature 474:385-9
Torchinsky, Miriam Beer; Garaude, Johan; Blander, J Magarian (2010) Infection and apoptosis as a combined inflammatory trigger. Curr Opin Immunol 22:55-62

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