Innate Immune Pathways Triggered by Listeria monocytogenes and Their Role in the Induction of Cell-Mediated Immunity.

Graduate Group in Microbiology, University of California, Berkeley, Berkeley, California, USA.

Acquired cell-mediated immunity to Listeria monocytogenes is induced by infection with live, replicating bacteria that grow in the host cell cytosol, whereas killed bacteria, or those trapped in a phagosome, fail to induce protective immunity. In this chapter, we focus on how L. monocytogenes is sensed by the innate immune system, with the presumption that innate immunity affects the development of acquired immunity. Infection by L. monocytogenes induces three innate immune pathways: an MyD88-dependent pathway emanating from a phagosome leading to expression of inflammatory cytokines; a STING/IRF3-dependent pathway emanating from the cytosol leading to the expression of IFN-ß and coregulated genes; and very low levels of a Caspase-1-dependent, AIM2-dependent inflammasome pathway resulting in proteolytic activation and secretion of IL-1ß and IL-18 and pyroptotic cell death. Using a combination of genetics and biochemistry, we identified the listerial ligand that activates the STING/IRF3 pathway as secreted cyclic diadenosine monophosphate, a newly discovered conserved bacterial signaling molecule. We also identified L. monocytogenes mutants that caused robust inflammasome activation due to bacteriolysis in the cytosol, release of DNA, and activation of the AIM2 inflammasome. A strain was constructed that ectopically expressed and secreted a fusion protein containing Legionella pneumophila flagellin that robustly activated the Nlrc4-dependent inflammasome and was highly attenuated in mice, also in an Nlrc4-dependent manner. Surprisingly, this strain was a poor inducer of adaptive immunity, suggesting that inflammasome activation is not necessary to induce cell-mediated immunity and may even be detrimental under some conditions. To the best of our knowledge, no single innate immune pathway is necessary to mount a robust acquired immune response to L. monocytogenes infection.

Copyright © 2012 Elsevier Inc. All rights reserved.

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Tumor Necrosis Factor-alpha (TNFα) Blockers: Label Change - Boxed Warning Updated for Risk of Infection from Legionella and Listeria

including Remicade (infliximab), Enbrel (etanercept), Humira (adalimumab), Cimzia (certolizumab pegol), and Simponi (golimumab)

AUDIENCE: Rheumatology, Gastroenterology, Oncology

ISSUE: FDA notified healthcare professionals that the Boxed Warning for the entire class of Tumor Necrosis Factor-alpha (TNFa) blockers has been updated to include the risk of infection from two bacterial pathogens, Legionella and Listeria. In addition, the Boxed Warning and Warnings and Precautions sections of the labels for all of the TNFa blockers have been revised so that they contain consistent information about the risk for serious infections and the associated disease-causing pathogens.

Patients treated with TNFa blockers are at increased risk for developing serious infections involving multiple organ systems and sites that may lead to hospitalization or death due to bacterial, mycobacterial, fungal, viral, parasitic, and other opportunistic pathogens.

BACKGROUND: The class of TNFa blockers are used to treat Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and/or juvenile idiopathic arthritis.

RECOMMENDATION: The risks and the benefits of TNFa blockers should be considered prior to initiating therapy in patients with chronic or recurrent infection and patients with underlying conditions that may predispose them to infection. See the Drug Safety Communication for a listing of recommendations for healthcare professionals and patients, as well as a data summary.

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

Complete and submit the report Online: www.fda.gov/MedWatch/report.htm
Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178
Read the MedWatch safety alert, including a link to the FDA Drug Safety Communication, at:

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm270977.htm

Posted: September 2011

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FDA issues label change for TNF-alpha blockers to include risk of infection from Legionella and Listeria

FDA has notified healthcare professionals that the Boxed Warning for the entire class of Tumor Necrosis Factor-alpha (TNFα) blockers has been updated to include the risk of infection from 2 bacterial pathogens, Legionella and Listeria. (Source: Modern Medicine)

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Tumor Necrosis Factor-alpha (TNFα) Blockers: Label Change - Boxed Warning Updated for Risk of Infection from Legionella and Listeria

including Remicade (infliximab), Enbrel (etanercept), Humira(adalimumab), Cimzia (certolizumab pegol), and Simponi(golimumab)AUDIENCE: Rheumatology, Gastroenterology, OncologyISSUE: FDA notified healthcare professionals that the... (Source: Drugs.com - Pharma News)

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Listeria monocytogenes engineered to activate the Nlrc4 inflammasome are severely attenuated and are poor inducers of protective immunity [Immunology]

Inflammasomes are intracellular multiprotein signaling complexes that activate Caspase-1, leading to the cleavage and secretion of IL-1ß and IL-18, and ultimately host cell death. Inflammasome activation is a common cellular response to infection; however, the consequences of inflammasome activation during acute infection and in the development of long-term protective immunity is not well understood. To investigate the role of the inflammasome in vivo, we engineered a strain of Listeria monocytogenes that ectopically expresses Legionella pneumophila flagellin, a potent activator of the Nlrc4 inflammasome. Compared with wild-type L. monocytogenes, strains that ectopically secreted flagellin induced robust host cell death and IL-1ß secretion. These strains were highly attenuated both in bo...

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